Biomarkers in Neural Disorders

ClinicalTrials.gov

2017-09-07

Parkinson's Disease; Alzheimer's Disease; Progressive Supranuclear Palsy; Essential Tremor; Multiple System Atrophy; Drug Induced Parkinson's Disease; Diffuse Lewy Body Disease; Myasthenia Gravis; Spinal Cord Injuries

Brain Network Activation in Patients With Movement Disorders

ClinicalTrials.gov

2017-08-29

Parkinson Disease; Essential Tremor; Dystonia; Normal Pressure Hydrocephalus; Cerebellar Ataxia; Multiple System Atrophy; Progressive Supranuclear Palsy; Corticobasal Degeneration; Dementia With Lewy Bodies

Natural History Study of Synucleinopathies

ClinicalTrials.gov

2018-01-23

Patients With Synucleinopathies; Neurogenic Orthostatic Hypotension; Pure Autonomic Failure; REM Sleep Behavior Disorder; Parkinson Disease; Dementia With Lewy Bodies; Multiple System Atrophy; Shy-Drager Disease

Intellectual enrichment lessens the effect of brain atrophy on learning and memory in multiple sclerosis

PubMed Central

Sumowski, James F.; Wylie, Glenn R.; Chiaravalloti, Nancy; DeLuca, John

2010-01-01

Objective: Learning and memory impairments are prevalent among persons with multiple sclerosis (MS); however, such deficits are only weakly associated with MS disease severity (brain atrophy). The cognitive reserve hypothesis states that greater lifetime intellectual enrichment lessens the negative impact of brain disease on cognition, thereby helping to explain the incomplete relationship between brain disease and cognitive status in neurologic populations. The literature on cognitive reserve has focused mainly on Alzheimer disease. The current research examines whether greater intellectual enrichment lessens the negative effect of brain atrophy on learning and memory in patients with MS. Methods: Forty-four persons with MS completed neuropsychological measures of verbal learning and memory, and a vocabulary-based estimate of lifetime intellectual enrichment. Brain atrophy was estimated with third ventricle width measured from 3-T magnetization-prepared rapid gradient echo MRIs. Hierarchical regression was used to predict learning and memory with brain atrophy, intellectual enrichment, and the interaction between brain atrophy and intellectual enrichment. Results: Brain atrophy predicted worse learning and memory, and intellectual enrichment predicted better learning; however, these effects were moderated by interactions between brain atrophy and intellectual enrichment. Specifically, higher intellectual enrichment lessened the negative impact of brain atrophy on both learning and memory. Conclusion: These findings help to explain the incomplete relationship between multiple sclerosis disease severity and cognition, as the effect of disease on cognition is attenuated among patients with higher intellectual enrichment. As such, intellectual enrichment is supported as a protective factor against disease-related cognitive impairment in persons with multiple sclerosis. GLOSSARY AD = Alzheimer disease; ANOVA = analysis of variance; MPRAGE = magnetization-prepared rapid gradient echo; MS = multiple sclerosis; SRT = Selective Reminding Test; TVW = third ventricle width; WASI = Wechsler Abbreviated Scale of Intelligence. PMID:20548040

Intellectual enrichment lessens the effect of brain atrophy on learning and memory in multiple sclerosis.

PubMed

Sumowski, James F; Wylie, Glenn R; Chiaravalloti, Nancy; DeLuca, John

2010-06-15

Learning and memory impairments are prevalent among persons with multiple sclerosis (MS); however, such deficits are only weakly associated with MS disease severity (brain atrophy). The cognitive reserve hypothesis states that greater lifetime intellectual enrichment lessens the negative impact of brain disease on cognition, thereby helping to explain the incomplete relationship between brain disease and cognitive status in neurologic populations. The literature on cognitive reserve has focused mainly on Alzheimer disease. The current research examines whether greater intellectual enrichment lessens the negative effect of brain atrophy on learning and memory in patients with MS. Forty-four persons with MS completed neuropsychological measures of verbal learning and memory, and a vocabulary-based estimate of lifetime intellectual enrichment. Brain atrophy was estimated with third ventricle width measured from 3-T magnetization-prepared rapid gradient echo MRIs. Hierarchical regression was used to predict learning and memory with brain atrophy, intellectual enrichment, and the interaction between brain atrophy and intellectual enrichment. Brain atrophy predicted worse learning and memory, and intellectual enrichment predicted better learning; however, these effects were moderated by interactions between brain atrophy and intellectual enrichment. Specifically, higher intellectual enrichment lessened the negative impact of brain atrophy on both learning and memory. These findings help to explain the incomplete relationship between multiple sclerosis disease severity and cognition, as the effect of disease on cognition is attenuated among patients with higher intellectual enrichment. As such, intellectual enrichment is supported as a protective factor against disease-related cognitive impairment in persons with multiple sclerosis.

Progression of regional grey matter atrophy in multiple sclerosis

PubMed Central

Marinescu, Razvan V; Young, Alexandra L; Firth, Nicholas C; Jorge Cardoso, M; Tur, Carmen; De Angelis, Floriana; Cawley, Niamh; Brownlee, Wallace J; De Stefano, Nicola; Laura Stromillo, M; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A; Rovira, Alex; Sastre-Garriga, Jaume; Geurts, Jeroen J G; Vrenken, Hugo; Wottschel, Viktor; Leurs, Cyra E; Uitdehaag, Bernard; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Gandini Wheeler-Kingshott, Claudia A; Chard, Declan; Thompson, Alan J; Barkhof, Frederik; Alexander, Daniel C; Ciccarelli, Olga

2018-01-01

Abstract See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article. Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis. Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry. All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls. T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed. The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001). The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes. The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis. PMID:29741648

Progression of regional grey matter atrophy in multiple sclerosis.

PubMed

Eshaghi, Arman; Marinescu, Razvan V; Young, Alexandra L; Firth, Nicholas C; Prados, Ferran; Jorge Cardoso, M; Tur, Carmen; De Angelis, Floriana; Cawley, Niamh; Brownlee, Wallace J; De Stefano, Nicola; Laura Stromillo, M; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A; Rovira, Alex; Sastre-Garriga, Jaume; Geurts, Jeroen J G; Vrenken, Hugo; Wottschel, Viktor; Leurs, Cyra E; Uitdehaag, Bernard; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Gandini Wheeler-Kingshott, Claudia A; Chard, Declan; Thompson, Alan J; Barkhof, Frederik; Alexander, Daniel C; Ciccarelli, Olga

2018-06-01

See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis. Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry. All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls. T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed. The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001). The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes. The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis.

The Swedish BioFINDER 2 Study

ClinicalTrials.gov

2018-04-16

Dementia; Alzheimer Disease; Parkinson Disease; Lewy Body Disease; Parkinson-Dementia Syndrome; Frontotemporal Degeneration; Semantic Dementia; Progressive Nonfluent Aphasia; Progressive Supranuclear Palsy; Corticobasal Degeneration; Multiple System Atrophy; Mild Cognitive Impairment

The putaminal abnormalities on 3.0T magnetic resonance imaging: can they separate parkinsonism-predominant multiple system atrophy from Parkinson's disease?

PubMed

Feng, Jie-Ying; Huang, Biao; Yang, Wan-Qun; Zhang, Yu-Hu; Wang, Li-Min; Wang, Li-Juan; Zhong, Xiao-Ling

2015-03-01

The putaminal abnormalities detected on 1.5 T magnetic resonance imaging (MRI), such as putaminal atrophy, slit-like hyperintense rim, and hypointensity in the putamen on T2-weighted (T2W) imaging are important signs on differentiating multiple system atrophy with parkinsonism (MSA-P) from Parkinson's disease (PD). However, the putaminal abnormalities may have different manifestations on 3.0 T from those on 1.5 T. To investigate the diagnostic value of putaminal abnormalities on 3.0 T MRI for differentiating MSA-P from PD. The study included a MSA-P group (9 men, 9 women), a PD group (12 men, 14 women), and a control group (11 men, 13 women). All subjects were examined with 3.0 T MRI using the conventional protocol. Putaminal atrophy, T2-hypointensity in the dorsolateral putamenat, and a slit-like hyperintense rim on the lateral putamen were evaluated in each subject. There were no significant differences in the slit-like hyperintense rim (P = 0.782) or T2-hypointensity in the dorsolateral putamen (P = 0.338) among the three groups. Bilateral putaminal atrophy was found in 44.4% (8 of 18) of the MSA-P patients, in only 7.7% (2 of 26) of the PD patients, and in none of the controls. The proportion of subjects with putaminal atrophy was significantly higher in the MAS-P group (P = 0.008) and control group (P < 0.001). The specificity and sensitivity of putaminal atrophy for distinguishing MSA-P from PD was 92.3% and 44.4%, respectively. The signal changes in the putamen on T2W imaging on 3.0 T MRI, including slit-like hyperintense rim and putaminal hypointensity, are not specific signs for MSA-P. Putaminal atrophy is highly specific for differentiating MSA-P from PD and healthy controls, but its insufficient sensitivity limits its diagnostic value. © The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Multiple system atrophy

MedlinePlus

... syndrome; Neurologic orthostatic hypotension; Shy-McGee-Drager syndrome; Parkinson plus syndrome; MSA-P; MSA-C ... ncbi.nlm.nih.gov/pubmed/25587949 . Jankovic J. Parkinson disease and other movement disorders. In: Daroff RB, ...

Multiple System Atrophy

MedlinePlus

... which can be expected to aid in the design of future trials. Additionally, MSA is one of ... Outcomes Data Training & Career Development High School, Undergraduate, & Post-Baccalaureate Predoctoral Fellows Postdoctoral Fellows Clinician-Scientists Faculty ...

Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis.

PubMed

Gobbi, C; Rocca, M A; Riccitelli, G; Pagani, E; Messina, R; Preziosa, P; Colombo, B; Rodegher, M; Falini, A; Comi, G; Filippi, M

2014-02-01

Involvement of selected central nervous system (CNS) regions has been associated with depression and fatigue in MS. We assessed whether specific regional patterns of lesion distribution and atrophy of the gray (GM) and white matter (WM) are associated with these symptoms in MS. Brain dual-echo and 3D T1-weighted images were acquired from 123 MS patients (69 depressed (D), 54 non-depressed (nD), 64 fatigued, 59 non-fatigued) and 90 controls. Lesion distribution, GM and WM atrophy were estimated using VBM and SPM8. Gender, age, disease duration and conventional MRI characteristics did not differ between D-MS and nD-MS patients. Fatigued patients experienced higher EDSS and depression than non-fatigued ones. Lesion distribution and WM atrophy were not related to depression and fatigue. Atrophy of regions in the frontal, parietal and occipital lobes had a combined effect on depression and fatigue. Atrophy of the left middle frontal gyrus and right inferior frontal gyrus were selectively related to depression. No specific pattern of GM atrophy was found to be related to fatigue. Depression in MS is linked to atrophy of cortical regions located in the bilateral frontal lobes. A distributed pattern of GM atrophy contributes to the concomitant presence of depression and fatigue in these patients.

A regional consensus recommendation on brain atrophy as an outcome measure in multiple sclerosis.

PubMed

Alroughani, Raed; Deleu, Dirk; El Salem, Khalid; Al-Hashel, Jasem; Alexander, K John; Abdelrazek, Mohamed Assem; Aljishi, Adel; Alkhaboori, Jaber; Al Azri, Faisal; Al Zadjali, Nahida; Hbahbih, Majed; Sokrab, Tag Eldin; Said, Mohamed; Rovira, Àlex

2016-11-24

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory and neurodegenerative processes leading to irreversible neurological impairment. Brain atrophy occurs early in the course of the disease at a rate greater than the general population. Brain volume loss (BVL) is associated with disability progression and cognitive impairment in patients with MS; hence its value as a potential target in monitoring and treating MS is discussed. A group of MS neurologists and neuro-radiologists reviewed the current literature on brain atrophy and discussed the challenges in assessing and implementing brain atrophy measurements in clinical practice. The panel used a voting system to reach a consensus and the votes were counted for the proposed set of questions for cognitive and brain atrophy assessments. The panel of experts was able to identify recent studies, which demonstrated the correlation between BVL and future worsening of disability and cognition. The current evidence revealed that reduction of BVL could be achieved with different disease-modifying therapies (DMTs). BVL provided a better treatment and monitoring strategy when it is combined to the composite measures of "no evidence of disease activity" (NEDA). The panel recommended a set of cognitive assessment tools and MRI methods and software applications that may help in capturing and measuring the underlying MS pathology with high degree of specificity. BVL was considered to be a useful measurement to longitudinally assess disease progression and cognitive function in patients with MS. Brain atrophy measurement was recommended to be incorporated into the concept of NEDA. Consequently, a consensus recommendation was reached in anticipation for implementation of the use of cognitive assessment and brain atrophy measurements on a regional level.

The nature of the autonomic dysfunction in multiple system atrophy

NASA Technical Reports Server (NTRS)

Parikh, Samir M.; Diedrich, Andre; Biaggioni, Italo; Robertson, David

2002-01-01

The concept that multiple system atrophy (MSA, Shy-Drager syndrome) is a disorder of the autonomic nervous system is several decades old. While there has been renewed interest in the movement disorder associated with MSA, two recent consensus statements confirm the centrality of the autonomic disorder to the diagnosis. Here, we reexamine the autonomic pathophysiology in MSA. Whereas MSA is often thought of as "autonomic failure", new evidence indicates substantial persistence of functioning sympathetic and parasympathetic nerves even in clinically advanced disease. These findings help explain some of the previously poorly understood features of MSA. Recognition that MSA entails persistent, constitutive autonomic tone requires a significant revision of our concepts of its diagnosis and therapy. We will review recent evidence bearing on autonomic tone in MSA and discuss their therapeutic implications, particularly in terms of the possible development of a bionic baroreflex for better control of blood pressure.

The use of lisuride in the treatment of multiple system atrophy with autonomic failure (Shy-Drager syndrome).

PubMed Central

Lees, A J; Bannister, R

1981-01-01

In a controlled trial lisuride, an ergolene derivative with dopamine receptor agonist properties was given maximum tolerated doses (2.4 mg/day) to seven patients with multiple system atrophy with autonomic failure (Shy-Drager syndrome). Improvement in Parkinsonian features occurred in only one patient and another patient who had been deriving marked benefit from levodopa treatment before the study began failed to respond to large doses of lisuride. Psychiatric side effects (including nightmares, isolated visual hallucinations and toxic confusional states) were the dose-limiting factor in six patients. A modest reduction in orthostatic hypotension occurred in two patients, one of whom had experienced an aggravation of this disturbance on levodopa and bromocriptine. Destruction of post-synaptic dopamine receptors and damage to central noradrenergic systems may offer an explanation for the lack of therapeutic effect of lisuride. PMID:7241162

Dementia with Lewy Bodies

MedlinePlus

... NINDS Focus on Disorders Alzheimer's & Related Dementias Epilepsy Parkinson's Disease Spinal Cord Injury Traumatic Brain Injury Focus On ... that alpha-synuclein accumulation is also linked to Parkinson's disease, multiple system atrophy, and several other disorders, which ...

Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting.

PubMed

Walsh, Ryan R; Krismer, Florian; Galpern, Wendy R; Wenning, Gregor K; Low, Phillip A; Halliday, Glenda; Koroshetz, Walter J; Holton, Janice; Quinn, Niall P; Rascol, Olivier; Shaw, Leslie M; Eidelberg, David; Bower, Pam; Cummings, Jeffrey L; Abler, Victor; Biedenharn, Judy; Bitan, Gal; Brooks, David J; Brundin, Patrik; Fernandez, Hubert; Fortier, Philip; Freeman, Roy; Gasser, Thomas; Hewitt, Art; Höglinger, Günter U; Huentelman, Matt J; Jensen, Poul H; Jeromin, Andreas; Kang, Un Jung; Kaufmann, Horacio; Kellerman, Lawrence; Khurana, Vikram; Klockgether, Thomas; Kim, Woojin Scott; Langer, Carol; LeWitt, Peter; Masliah, Eliezer; Meissner, Wassilios; Melki, Ronald; Ostrowitzki, Susanne; Piantadosi, Steven; Poewe, Werner; Robertson, David; Roemer, Cyndi; Schenk, Dale; Schlossmacher, Michael; Schmahmann, Jeremy D; Seppi, Klaus; Shih, Lily; Siderowf, Andrew; Stebbins, Glenn T; Stefanova, Nadia; Tsuji, Shoji; Sutton, Sharon; Zhang, Jing

2018-01-09

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided. Copyright © 2017 American Academy of Neurology.

Voxel-wise mapping of cervical cord damage in multiple sclerosis patients with different clinical phenotypes.

PubMed

Rocca, Maria A; Valsasina, Paola; Damjanovic, Dusan; Horsfield, Mark A; Mesaros, Sarlota; Stosic-Opincal, Tatjana; Drulovic, Jelena; Filippi, Massimo

2013-01-01

To apply voxel-based methods to map the regional distribution of atrophy and T2 hyperintense lesions in the cervical cord of multiple sclerosis (MS) patients with different clinical phenotypes. Brain and cervical cord 3D T1-weighted and T2-weighted scans were acquired from 31 healthy controls (HC) and 77 MS patients (15 clinically isolated syndromes (CIS), 15 relapsing-remitting (RR), 19 benign (B), 15 primary progressive (PP) and 13 secondary progressive (SP) MS). Hyperintense cord lesions were outlined on T2-weighted scans. The T2- and 3D T1-weighted cord images were then analysed using an active surface method which created output images reformatted in planes perpendicular to the estimated cord centre line. These unfolded cervical cord images were co-registered into a common space; then smoothed binary cord masks and lesion masks underwent spatial statistic analysis (SPM8). No cord atrophy was found in CIS patients versus HC, while PPMS had significant cord atrophy. Clusters of cord atrophy were found in BMS versus RRMS, and in SPMS versus RRMS, BMS and PPMS patients, mainly involving the posterior and lateral cord segments. Cord lesion probability maps showed a significantly greater likelihood of abnormalities in RRMS, PPMS and SPMS than in CIS and BMS patients. The spatial distributions of cord atrophy and cord lesions were not correlated. In progressive MS, regional cord atrophy was correlated with clinical disability and impairment in the pyramidal system. Voxel-based assessment of cervical cord damage is feasible and may contribute to a better characterisation of the clinical heterogeneity of MS patients.

Quantitative analysis of structural variations in corpus callosum in adults with multiple system atrophy (MSA)

NASA Astrophysics Data System (ADS)

Bhattacharya, Debanjali; Sinha, Neelam; Saini, Jitender

2017-03-01

Multiple system atrophy (MSA) is a rare, non-curable, progressive neurodegenerative disorder that affects nervous system and movement, poses a considerable diagnostic challenge to medical researchers. Corpus callosum (CC) being the largest white matter structure in brain, enabling inter-hemispheric communication, quantification of callosal atrophy may provide vital information at the earliest possible stages. The main objective is to identify the differences in CC structure for this disease, based on quantitative analysis on the pattern of callosal atrophy. We report results of quantification of structural changes in regional anatomical thickness, area and length of CC between patient-groups with MSA with respect to healthy controls. The method utilizes isolating and parcellating the mid-sagittal CC into 100 segments along the length - measuring the width of each segment. It also measures areas within geometrically defined five callosal compartments of the well-known Witelson, and Hofer-Frahma schemes. For quantification, statistical tests are performed on these different callosal measurements. From the statistical analysis, it is concluded that compared to healthy controls, width is reduced drastically throughout CC for MSA group and as well as changes in area and length are also significant for MSA. The study is further extended to check if any significant difference in thickness is found between the two variations of MSA, Parkinsonian MSA and Cerebellar MSA group, using the same methodology. However area and length of this two sub-MSA group, no substantial difference is obtained. The study is performed on twenty subjects for each control and MSA group, who had T1-weighted MRI.

Multiple System Atrophy with Orthostatic Hypotension (Shy-Drager Syndrome)

MedlinePlus

... Strategy Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ... Diversity Resources Jobs at NINDS Director, Division of Neuroscience Director, NIH BRAIN Initiative® Health Scientist Administrator Channels ...

The α‐synuclein gene in multiple system atrophy

PubMed Central

Ozawa, T; Healy, D G; Abou‐Sleiman, P M; Ahmadi, K R; Quinn, N; Lees, A J; Shaw, K; Wullner, U; Berciano, J; Moller, J C; Kamm, C; Burk, K; Josephs, K A; Barone, P; Tolosa, E; Goldstein, D B; Wenning, G; Geser, F; Holton, J L; Gasser, T; Revesz, T; Wood, N W

2006-01-01

Background The formation of α‐synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. Method The linkage disequilibrium (LD) structure of the α‐synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. Results and conclusion In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag‐defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases. PMID:16543523

Management of sleep disorders in Parkinson's disease and multiple system atrophy.

PubMed

Videnovic, Aleksandar

2017-05-01

Parkinson's disease (PD) and multiple system atrophy (MSA) are disorders associated with α synuclein-related neurodegeneration. Nonmotor symptoms are common hallmarks of these disorders, and disturbances of the sleep-wake cycle are among the most common nonmotor symptoms. It is only recently that sleep disturbances have received the attention of the medical and research community. Significant progress has been made in understanding the pathophysiology of sleep and wake disruption in alphasynucleinopathies during the past few decades. Despite these advancements, treatment options are limited and frequently associated with problematic side effects. Further studies that center on the development of novel treatment approaches are very much needed. In this article, the author discusses the current state of the management of disturbed sleep and alertness in PD and MSA. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Visual event-related potential changes in multiple system atrophy: delayed N2 latency in selective attention to a color task.

PubMed

Kamitani, Toshiaki; Kuroiwa, Yoshiyuki

2009-01-01

Recent studies demonstrated an altered P3 component and prolonged reaction time during the visual discrimination tasks in multiple system atrophy (MSA). In MSA, however, little is known about the N2 component which is known to be closely related to the visual discrimination process. We therefore compared the N2 component as well as the N1 and P3 components in 17 MSA patients with these components in 10 normal controls, by using a visual selective attention task to color or to shape. While the P3 in MSA was significantly delayed in selective attention to shape, the N2 in MSA was significantly delayed in selective attention to color. N1 was normally preserved both in attention to color and in attention to shape. Our electrophysiological results indicate that the color discrimination process during selective attention is impaired in MSA.

Multiple System Atrophy (MSA)

MedlinePlus

... coordination, such as unsteady gait and loss of balance Slurred, slow or low-volume speech (dysarthria) Visual disturbances, such as blurred or double vision and difficulty focusing your eyes Difficulty swallowing (dysphagia) or chewing General signs and symptoms In addition, the primary sign ...

Transcriptional profile of a myotube starvation model of atrophy

NASA Technical Reports Server (NTRS)

Stevenson, Eric J.; Koncarevic, Alan; Giresi, Paul G.; Jackman, Robert W.; Kandarian, Susan C.

2005-01-01

Skeletal muscle wasting is a pervasive phenomenon that can result from a wide range of pathological conditions as well as from habitual muscular inactivity. The present work describes a cell-culture condition that induces significant atrophy in skeletal muscle C2C12 myotubes. The failure to replenish differentiation media in mature myotubes leads to rapid atrophy (53% in diameter), which is referred to here as starvation. Affymetrix microarrays were used to develop a transcriptional profile of control (fed) vs. atrophied (nonfed) myotubes. Myotube starvation was characterized by an upregulation of genes involved in translational inhibition, amino acid biosynthesis and transport, and cell cycle arrest/apoptosis, among others. Downregulated genes included several structural and regulatory elements of the extracellular matrix as well as several elements of Wnt/frizzled and TGF-beta signaling pathways. Interestingly, the characteristic transcriptional upregulation of the ubiquitin-proteasome system, calpains, and cathepsins known to occur in multiple in vivo models of atrophy were not seen during myotube starvation. With the exception of the downregulation of extracellular matrix genes, serine protease inhibitor genes, and the upregulation of the translation initiation factor PHAS-I, this model of atrophy in cell culture has a transcriptional profile quite distinct from any study published to date with atrophy in whole muscle. These data show that, although the gross morphology of atrophied muscle fibers may be similar in whole muscle vs. myotube culture, the processes by which this phenotype is achieved differ markedly.

Spectrum of PORCN mutations in Focal Dermal Hypoplasia

USDA-ARS?s Scientific Manuscript database

Focal Dermal Hypoplasia (FDH), also known as Goltz syndrome (OMIM 305600), is a genetic disorder that affects multiple organ systems early in development. Features of FDH include skin abnormalities, (hypoplasia, atrophy, linear pigmentation, and herniation of fat through dermal defects); papillomas...

Abnormal resting-state connectivity of motor and cognitive networks in early manifest Huntington's disease.

PubMed

Wolf, R C; Sambataro, F; Vasic, N; Depping, M S; Thomann, P A; Landwehrmeyer, G B; Süssmuth, S D; Orth, M

2014-11-01

Functional magnetic resonance imaging (fMRI) of multiple neural networks during the brain's 'resting state' could facilitate biomarker development in patients with Huntington's disease (HD) and may provide new insights into the relationship between neural dysfunction and clinical symptoms. To date, however, very few studies have examined the functional integrity of multiple resting state networks (RSNs) in manifest HD, and even less is known about whether concomitant brain atrophy affects neural activity in patients. Using MRI, we investigated brain structure and RSN function in patients with early HD (n = 20) and healthy controls (n = 20). For resting-state fMRI data a group-independent component analysis identified spatiotemporally distinct patterns of motor and prefrontal RSNs of interest. We used voxel-based morphometry to assess regional brain atrophy, and 'biological parametric mapping' analyses to investigate the impact of atrophy on neural activity. Compared with controls, patients showed connectivity changes within distinct neural systems including lateral prefrontal, supplementary motor, thalamic, cingulate, temporal and parietal regions. In patients, supplementary motor area and cingulate cortex connectivity indices were associated with measures of motor function, whereas lateral prefrontal connectivity was associated with cognition. This study provides evidence for aberrant connectivity of RSNs associated with motor function and cognition in early manifest HD when controlling for brain atrophy. This suggests clinically relevant changes of RSN activity in the presence of HD-associated cortical and subcortical structural abnormalities.

Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis.

PubMed

Kroth, Julia; Ciolac, Dumitru; Fleischer, Vinzenz; Koirala, Nabin; Krämer, Julia; Muthuraman, Muthuraman; Luessi, Felix; Bittner, Stefan; Gonzalez-Escamilla, Gabriel; Zipp, Frauke; Meuth, Sven G; Groppa, Sergiu

2017-12-01

Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSF IgA and CSF IgM showed higher functional disability at follow-up. CSF markers of blood-brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.

Brain MRI volumetry in a single patient with mild traumatic brain injury.

PubMed

Ross, David E; Castelvecchi, Cody; Ochs, Alfred L

2013-01-01

This letter to the editor describes the case of a 42 year old man with mild traumatic brain injury and multiple neuropsychiatric symptoms which persisted for a few years after the injury. Initial CT scans and MRI scans of the brain showed no signs of atrophy. Brain volume was measured using NeuroQuant®, an FDA-approved, commercially available software method. Volumetric cross-sectional (one point in time) analysis also showed no atrophy. However, volumetric longitudinal (two points in time) analysis showed progressive atrophy in several brain regions. This case illustrated in a single patient the principle discovered in multiple previous group studies, namely that the longitudinal design is more powerful than the cross-sectional design for finding atrophy in patients with traumatic brain injury.

Wolfram Syndrome presenting with optic atrophy and diabetes mellitus: two case reports

PubMed Central

2009-01-01

Wolfram syndrome is the constellation of juvenile onset diabetes mellitus and optic atrophy, known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). Patients demonstrate diabetes mellitus followed by optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts early in the third decade, and multiple neurological abnormalities early in the fourth decade. This study reports two siblings with late diagnosed wolfram syndrome with diabetes insipidus, diabetes mellitus, optic atrophy, deafness and severe urological abnormalities. In conclusion, cases having early onset insulin-dependent diabetes mellitus and optic atrophy together need to be evaluated with respect to Wolfram. PMID:20062605

Memory Impairment in Multiple Sclerosis is Due to a Core Deficit in Initial Learning

PubMed Central

DeLuca, John; Leavitt, Victoria M.; Chiaravalloti, Nancy; Wylie, Glenn

2013-01-01

Persons with multiple sclerosis (MS) suffer memory impairment, but research on the nature of MS-related memory problems is mixed. Some have argued for a core deficit in retrieval, while others have identified deficient initial learning as the core deficit. We used a selective reminding paradigm to determine whether deficient initial learning or delayed retrieval represents the primary memory deficit in 44 persons with MS. Brain atrophy was measured from high-resolution MRIs. Regression analyses examined the impact of brain atrophy on (a) initial learning and delayed retrieval separately, and then (b) delayed retrieval controlling for initial learning. Brain atrophy was negatively associated with both initial learning and delayed retrieval (ps < .01), but brain atrophy was unrelated to retrieval when controlling for initial learning (p > .05). In addition, brain atrophy was associated with inefficient learning across initial acquisition trials, and brain atrophy was unrelated to delayed recall among MS subjects who successfully acquired the word list (although such learning frequently required many exposures). Taken together, memory deficits in MS are a result of deficits in initial learning; moreover, initial learning mediates the relationship between brain atrophy and subsequent retrieval, thereby supporting the core learning-deficit hypothesis of memory impairment in MS. PMID:23832311

Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: Case report and literature review

PubMed Central

Ogaki, Kotaro; Koga, Shunsuke; Aoki, Naoya; Lin, Wenlang; Suzuki, Kinuko; Ross, Owen A.; Dickson, Dennis W.

2015-01-01

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy confirmed cases exceedingly rare. We report a 69-year-old white man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison’s disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities, and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss, and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of multiple system atrophy. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be considered in the differential diagnosis of MSA. PMID:26227820

Hyperconnective and hypoconnective cortical and subcortical functional networks in multiple system atrophy.

PubMed

Rosskopf, Johannes; Gorges, Martin; Müller, Hans-Peter; Pinkhardt, Elmar H; Ludolph, Albert C; Kassubek, Jan

2018-04-01

In multiple system atrophy (MSA), the organization of the functional brain connectivity within cortical and subcortical networks and its clinical correlates remains to be investigated. Whole-brain based 'resting-state' fMRI data were obtained from 22 MSA patients (11 MSA-C, 11 MSA-P) and 22 matched healthy controls, together with standardized clinical assessment and video-oculographic recordings (EyeLink ® ). MSA patients vs. controls showed significantly higher ponto-cerebellar functional connectivity and lower default mode network connectivity (p < .05, corrected). No differences were observed in the motor network and in the control network. The higher the ponto-cerebellar network functional connectivity was, the more pronounced was smooth pursuit impairment. This functional connectivity analysis supports a network-dependent combination of hyper- and hypoconnectivity states in MSA, in agreement with adaptive compensatory responses (hyperconnectivity) and a function disconnection syndrome (hypoconnectivity) that may occur in a consecutive sequence. Copyright © 2018 Elsevier Ltd. All rights reserved.

Differences in early speech patterns between Parkinson variant of multiple system atrophy and Parkinson's disease.

PubMed

Huh, Young Eun; Park, Jongkyu; Suh, Mee Kyung; Lee, Sang Eun; Kim, Jumin; Jeong, Yuri; Kim, Hee-Tae; Cho, Jin Whan

2015-08-01

In Parkinson variant of multiple system atrophy (MSA-P), patterns of early speech impairment and their distinguishing features from Parkinson's disease (PD) require further exploration. Here, we compared speech data among patients with early-stage MSA-P, PD, and healthy subjects using quantitative acoustic and perceptual analyses. Variables were analyzed for men and women in view of gender-specific features of speech. Acoustic analysis revealed that male patients with MSA-P exhibited more profound speech abnormalities than those with PD, regarding increased voice pitch, prolonged pause time, and reduced speech rate. This might be due to widespread pathology of MSA-P in nigrostriatal or extra-striatal structures related to speech production. Although several perceptual measures were mildly impaired in MSA-P and PD patients, none of these parameters showed a significant difference between patient groups. Detailed speech analysis using acoustic measures may help distinguish between MSA-P and PD early in the disease process. Copyright © 2015 Elsevier Inc. All rights reserved.

[A sixty-year-old man suffering from multiple system atrophy with pneumatosis intestinalis].

PubMed

Shimizu, Fumitaka; Kawai, Motoharu; Ogasawara, Jun-Ichi; Negoro, Kiyoshi; Kanda, Takashi

2007-01-01

We herein report a 60-year-old man demonstrating multiple system atrophy of the cerebellar type (MSA-C) with a five-year of clinical history, who developed severe constipation followed by watery diarrhea. An abdominal CT scan showed free air in the abdominal cavity and extensive pericolic gas accumulation in the ascending and transverse colon. He was diagnosed to have pneumatosis intestinalis (PI). The air in the abdominal cavity as well as in the wall of the colon thereafter disappeared after nine days' of conservative therapy. The presense of chronic idiopathic intestinal pseudo-obstruction due to severe dysautonomia and a longstanding bed-ridden state may have been the cause of PI in this patient. This is the first case report of PI associated with MSA; however, the association of PI may have been overlooked in this disorder because of severe constipation and diarrhea, the two cardinal symptoms of PI, which happen to also be two of the typical symptoms of MSA itself.

Atrophied Brain Lesion Volume: A New Imaging Biomarker in Multiple Sclerosis.

PubMed

Dwyer, Michael G; Bergsland, Niels; Ramasamy, Deepa P; Jakimovski, Dejan; Weinstock-Guttman, Bianca; Zivadinov, Robert

2018-06-01

Lesion accrual in multiple sclerosis (MS) is an important and clinically relevant measure, used extensively as an imaging trial endpoint. However, lesions may also shrink or disappear entirely due to atrophy. Although generally ignored or treated as a nuisance, this phenomenon may actually be an important stand-alone imaging biomarker. Therefore, we investigated the rate of brain lesion loss due to atrophy (atrophied lesion volume) in MS subtypes compared to baseline lesion volume and to new and enlarging lesion volumes, and evaluated the independent predictive value of this phenomenon for clinical disability. A total of 192 patients (18 clinically isolated syndrome, 126 relapsing-remitting MS, and 48 progressive) received 3T magnetic resonance imaging at baseline and 5 years. Lesions were quantified at baseline, and new/enlarging lesion volumes were calculated over the study interval. Atrophied lesion volume was calculated by combining baseline lesion masks with follow-up SIENAX-derived cerebrospinal fluid partial volume maps. Measures were compared between disease subgroups, and correlations with disability change (Expanded Disability Status Scale [EDSS]) were evaluated. Hierarchical regression was employed to determine the unique additive value of atrophied lesion volume. Atrophied lesion volume was different between MS subtypes (P = .02), and exceeded new lesion volume accumulation in progressive MS (298.1 vs. 75.5 mm 3 ). Atrophied lesion volume was the only significant correlate of EDSS change (r = .192 relapsing, r = .317 progressive, P < .05), and explained significant additional variance when controlling for brain atrophy and new/enlarging lesion volume (R 2 .092 vs. .045, P = .003). Atrophied lesion volume is a unique and clinically relevant imaging marker in MS, with particular promise in progressive MS. Copyright © 2018 by the American Society of Neuroimaging.

No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).

PubMed

Lanzillo, Roberta; Quarantelli, Mario; Pozzilli, Carlo; Trojano, Maria; Amato, Maria Pia; Marrosu, Maria G; Francia, Ada; Florio, Ciro; Orefice, Giuseppe; Tedeschi, Gioacchino; Bellantonio, Paolo; Annunziata, Pasquale; Grimaldi, Luigi M; Comerci, Marco; Brunetti, Arturo; Bonavita, Vincenzo; Alfano, Bruno; Marini, Stefano; Brescia Morra, Vincenzo

2016-08-01

A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis. © The Author(s), 2015.

Central hemodynamics and arterial stiffness in idiopathic and multiple system atrophy.

PubMed

Franzen, Klaas; Fliegen, Sabine; Koester, Jelena; Martin, Rafael Campos; Deuschl, Günther; Reppel, Michael; Mortensen, Kai; Schneider, Susanne A

2017-02-01

Blood pressure is commonly abnormal in parkinsonian disorders, but central hemodynamics and arterial stiffness, well-established predictors of total cardiovascular risk, have rarely been studied in these disorders. 32 patients [27 with idiopathic Parkinson's disease (iPD); 5 with multiple system atrophy (MSA)] and 15 controls matched for cardiac risk factors underwent 24 h-ambulatory blood pressure recordings using an I.E.M. device (Mobil-O-Graph™), measuring peripheral pressure and calculating central pressures and arterial stiffness. Mean augmentation indices corrected for heart rate (AIx@75) were significantly lower and pulse wave velocities were significantly elevated in patients compared to controls. Central systolic blood pressure, cardiac output and daytime total vascular resistance were significantly elevated in patients. Mean nocturnal systolic peripheral blood pressure and nocturnal heart rates were also significantly higher; 56.3% of patients had nocturnal hypertension (80% of the MSA group); 85.2% showed non-dipping. This supports previous findings of reduced vulnerability to systemic atherosclerosis and end-organ damage in treated PD. Yet, hemodynamic abnormalities were common and often remained asymptomatic.

Greater regional brain atrophy rate in healthy elders with a history of cigarette smoking

PubMed Central

Durazzo, Timothy C.; Insel, Philip S.; Weiner, Michael W.; Initiative, the Alzheimer Disease Neuroimaging

2011-01-01

Background Little is known about the effects of cigarette smoking on brain morphological changes in the elderly. This study investigated the effects of a history of cigarette smoking on changes in regional brain volumes over 2-years in healthy, cognitively-intact elderly individuals. We predicted individuals with a history of cigarette smoking, compared to never smokers, demonstrate greater rate of atrophy over 2-years in regions that manifest morphological abnormalities in the early stages of Alzheimer Disease (AD), as well as the extended brain reward system (BRS), which is implicated in the development and maintenance of substance use disorders. Methods Participants were healthy, cognitively normal elderly controls (75.9±4.8 years of age) with any lifetime history of cigarette smoking (n = 68) and no history of smoking (n = 118). Data was obtained via the Alzheimer Disease Neuroimaging Initiative from 2005–2010. Participants completed four magnetic resonance scans over 2-years. A standardized protocol employing high resolution 3D T1-weighted sequences at 1.5 Tesla was used for structural imaging and regional brain volumetric analyses. Results Smokers demonstrated significantly greater rate atrophy over 2-years than non-smokers in multiple brain regions associated with the early stages of AD as well as in the BRS. Groups were not different on rate of global cortical atrophy. Conclusions A history of cigarette smoking in this healthy elderly cohort was associated with decreased structural integrity of multiple brain regions, which was manifest as a greater rate of atrophy over 2-years in regions specifically affected by incipient AD as well as chronic substance abuse. PMID:23102121

Left-Ventricular Energetics in Pulmonary Arterial Hypertension-Induced Right-Ventricular Hypertrophic Failure

PubMed Central

Han, June-Chiew; Guild, Sarah-Jane; Pham, Toan; Nisbet, Linley; Tran, Kenneth; Taberner, Andrew J.; Loiselle, Denis S.

2018-01-01

Pulmonary arterial hypertension (PAH) alters the geometries of both ventricles of the heart. While the right ventricle (RV) hypertrophies, the left ventricle (LV) atrophies. Multiple lines of clinical and experimental evidence lead us to hypothesize that the impaired stroke volume and systolic pressure of the LV are a direct consequence of the effect of pressure overload in the RV, and that atrophy in the LV plays only a minor role. In this study, we tested this hypothesis by examining the mechanoenergetic response of the atrophied LV to RV hypertrophy in rats treated with monocrotaline. Experiments were performed across multiple-scales: the whole-heart in vivo and ex vivo, and its trabeculae in vitro. Under the in vivo state where the RV was pressure-overloaded, we measured reduced systemic blood pressure and LV ventricular pressure. In contrast, under both ex vivo and in vitro conditions, where the effect of RV pressure overload was circumvented, we found that LV was capable of developing normal systolic pressure and stress. Nevertheless, LV atrophy played a minor role in that LV stroke volume remained lower, thereby contributing to lower LV mechanical work output. Concomitantly lower oxygen consumption and change of enthalpy were observed, and hence LV energy efficiency was unchanged. Our internally consistent findings between working-heart and trabecula experiments explain the rapid improvement of LV systolic function observed in patients with chronic pulmonary hypertension following surgical relief of RV pressure overload. PMID:29375394

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

PubMed Central

Jellinger, Kurt A.

2017-01-01

Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a “prion-like” manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed. PMID:28984582

Orphan disease: Cherubism, optic atrophy, and short stature.

PubMed

Jeevanandham, Balaji; Ramachandran, Rajoo; Dhanapal, Vignesh; Subramanian, Ilanchezhian; Sai, Venkata

2018-01-01

A 12-year-old female presented with complaints of progressive visual impairment in both her eyes. On clinical examination, she was short for her age and her ophthalmoscopic examination revealed bilateral optic atrophy. Computed tomography of the patient revealed multiple expansile lytic lesions of mandible suggesting cherubism. The optic atrophy was confirmed on magnetic resonance imaging, which additionally revealed bilateral retrocerebellar arachnoid cysts. This association of cherubism with optic atrophy and short stature was grouped as orphan disease by National Institutes of Health and only one case was reported in the literature so far.

76 FR 82310 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-30

... (Parkinson's Disease, Multiple System Atrophy, and Pure Autonomic Failure), Dopamine Beta-Hydroxylase... recommendations to the Agency on FDA's regulatory issues. Date and Time: The meeting will be held on February 23... Colesville Rd., Silver Spring, MD 20910. The hotel's telephone number is (301) 589-5200. Contact Person...

[Evaluation of Gastric Atrophy. Comparison between Sidney and OLGA Systems].

PubMed

Ramírez-Mendoza, Pablo; González-Angulo, Jorge; Angeles-Garay, Ulises; Segovia-Cueva, Gustavo Adolfo

2008-01-01

histopathologic identification of atrophy and metaplasia is decisive to stop the way of gastritis?carcinoma in patients with chronic gastritis. to compare diagnostic concordance between Sidney system and the operative Link on Gastritis Assessment (OLGA) system. 120 consecutive biopsies were analyzed by general pathologists according to the Sidney system. All of them were evaluated by a second pathologist who used OLGA System. We employed kappa index to evaluate diagnostic concordance between the classifications. the clinical picture includes dyspepsia (94 %), abdominal pain (50 %), gastroesophageal reflux (30 %), bleed of the upper digestive system (24 %), and presence of Helicobacter pylori (47.5 %). Four were diagnosed as atrophy by Sidney system and 26 cases with atrophy by OLGA system. The concordance between two classifications systems was too low (p = 0.05). the atrophy diagnosis, between systems, had low concordance. The description of metaplastic atrophy in the OLGA system represents the only one difference. The non-metaplastic atrophy is the same for both classifications. Therefore, the general pathologist should include this evaluation more consistently using OLGA system.

Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition.

PubMed

Goos, Jeroen D C; Kester, M I; Barkhof, Frederik; Klein, Martin; Blankenstein, Marinus A; Scheltens, Philip; van der Flier, Wiesje M

2009-11-01

Microbleeds (MBs) are commonly observed in Alzheimer disease. A minority of patients has multiple MBs. We aimed to investigate associations of multiple MBs in Alzheimer disease with clinical and MRI characteristics and cerebrospinal fluid biomarkers. Patients with Alzheimer disease with multiple (>or=8) MBs on T2*-weighted MRI were matched for age, sex, and field strength with patients with Alzheimer disease without MBs on a 1:2 basis. We included 21 patients with multiple MBs (73+/-7 years, 33% female) and 42 patients without MBs (72+/-7 years, 38% female). Mini-Mental State Examination was used to assess dementia severity. Cognitive functions were assessed using neuropsychological tests. Medial temporal lobe atrophy (0 to 4), global cortical atrophy (0 to 3), and white matter hyperintensities (0 to 30) were assessed using visual rating scales. In a subset, apolipoprotein E genotype and cerebrospinal fluid amyloid beta 1-42, total tau and tau phosphorylated at threonine 181 were determined. Patients with multiple MBs performed worse on Mini-Mental State Examination (multiple MB: 17+/-7; no MB: 22+/-4, P<0.05) despite similar disease duration. Atrophy was not related to presence of MBs, but patients with multiple MBs had more white matter hyperintensities (multiple MB: 8.8+/-4.8; no MB: 3.2+/-3.6, P<0.05). Adjusted for age, sex, white matter hyperintensities, and medial temporal lobe atrophy, the multiple MB group additionally performed worse on Visual Association Test object naming and animal fluency. Patients with multiple MBs had lower cerebrospinal fluid amyloid beta 1-42 levels (307+/-61) than patients without MBs (505+/-201, P<0.05). Adjusted for the same covariates, total tau, and tau phosphorylated at threonine 181 were higher in the multiple MB group. Microbleeds are associated with the clinical manifestation and biochemical hallmarks of Alzheimer disease, suggesting possible involvement of MBs in the pathogenesis of Alzheimer disease.

ɑ-Synuclein strains and seeding in Parkinson's disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences.

PubMed

Peelaerts, W; Bousset, L; Baekelandt, V; Melki, R

2018-04-27

Several age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded endogenous proteins. These proteins have prion-like propagation and amplification properties but so far appear nontransmissible between individuals. Because of the features they share with the prion protein, PrP, the characteristics of pathogenic protein aggregates in several progressive brain disorders, including different types of Lewy body diseases (LBDs), such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), have been actively investigated. Even though the pleomorphic nature of these syndromes might suggest different underlying causes, ɑ-synuclein (ɑSyn) appears to play an important role in this heterogeneous group of diseases (the synucleinopathies). An attractive hypothesis is that different types of ɑSyn protein assemblies have a unique and causative role in distinct synucleinopathies. We will discuss the recent research progress on ɑSyn assemblies involved in PD, MSA and DLB; their behavior as strains; current spreading hypotheses; their ability to seed centrally and peripherally; and their implication for disease pathogenesis.

Frontal parenchymal atrophy measures in multiple sclerosis.

PubMed

Locatelli, Laura; Zivadinov, Robert; Grop, Attilio; Zorzon, Marino

2004-10-01

The aim of this study was to establish whether, in a cross-sectional study, the normalized measures of whole and regional brain atrophy correlate better with tests assessing the cognitive function than the absolute brain atrophy measures. The neuropsychological performances and disability have been assessed in 39 patients with relapsing-remitting multiple sclerosis (MS). T1- and T2-lesion load (LL) of total brain and frontal lobes (FLs) were measured using a reproducible semiautomated technique. The whole brain volume and the regional brain parenchymal volume (RBPV) of FLs were obtained using a computerized interactive program, which incorporates semiautomated and automated segmentation processes. Normalized measures of brain atrophy, i.e., brain parenchymal fraction (BPF) and regional brain parenchymal fraction (RBPF) of FLs, were calculated. The scan-rescan, inter- and intrarater coefficient of variation (COV) and intraclass correlation coefficient (ICC) have been estimated. The RBPF of FLs showed an acceptable level of reproducibility which ranged from 1.7% for intrarater variability to 3.2% for scan-rescan variability. The mean ICC was 0.88 (CI 0.82-0.93). The RBPF of FLs demonstrated stronger magnitudes of correlation with neuropsychological functioning, disability and quantitative MRI lesion measures than RBPV. These differences were statistically significant: P<0.001 for Stroop Color Word Interference test, P<0.001 for Paced Auditory Serial Addition Test, P=0.04 for Standard Raven Progressive Matrices, P=0.049 for Expanded Disability Status Scale, P=0.01 for T2-LL of FLs and P<0.001 for T1-LL of FLs. BPF demonstrated significant correlations with tests assessing cognitive functions, whereas BPAV did not. The correlation analysis results were supported by the results of multiple regression analysis which showed that only the normalized brain atrophy measures were associated with tests exploring the cognitive functions. These data suggest that RBPF is a reproducible and sensitive method for measuring frontal parenchymal atrophy. The normalized measures of whole and regional brain parenchymal atrophy should be preferred to absolute measures in future studies that correlate neuropsychological performances and brain atrophy measures in patients with MS.

Inter-hemispheric Functional Connectivity Changes with Corpus Callosum Morphology in Multiple Sclerosis

PubMed Central

Zito, Giancarlo; Luders, Eileen; Tomasevic, Leo; Lupoi, Domenico; Toga, Arthur W.; Thompson, Paul M.; Rossini, Paolo M.; Filippi, Maria M.; Tecchio, Franca

2014-01-01

Multiple sclerosis (MS) affects myelin sheaths within the central nervous system, concurring to cause brain atrophy and neurodegeneration as well as gradual functional disconnections. To explore early signs of altered connectivity in MS from a structural and functional perspective, the morphology of corpus callosum (CC) was correlated with a dynamic inter-hemispheric connectivity index. Twenty mildly disabled patients affected by a relapsing-remitting (RR) form of MS (EDSS ≤ 3.5) and 15 healthy subjects underwent structural MRI to measure CC thickness over 100 sections and electroencephalography to assess a spectral coherence index between primary regions devoted to hand control, at rest and during an isometric handgrip. In patients, an overall CC atrophy was associated with increased lesion load. A less efficacious inter-hemispheric coherence during movement was associated with CC atrophy in sections interconnecting homologous primary motor areas (anterior mid-body). In healthy controls, less efficacious inter-hemispheric coherence at rest was associated with a thinner CC splenium. Our data suggest that in mildly disabled RR-MS patients a covert impairment may be detected in the correlation between the structural (CC thickness) and functional (inter-hemispheric coherence) measures of homologous networks, whereas these two counterparts do not yet differ individually from controls. PMID:24486438

Abnormal pulmonary function and respiratory muscle strength findings in Chinese patients with Parkinson's disease and multiple system atrophy--comparison with normal elderly.

PubMed

Wang, Yao; Shao, Wei-bo; Gao, Li; Lu, Jie; Gu, Hao; Sun, Li-hua; Tan, Yan; Zhang, Ying-dong

2014-01-01

There have been limited comparative data regarding the investigations on pulmonary and respiratory muscle function in the patients with different parkinsonism disorders such as Parkinson's disease (PD) and multiple system atrophy (MSA) versus normal elderly. The present study is aiming to characterize the performance of pulmonary function and respiratory muscle strength in PD and MSA, and to investigate the association with severity of motor symptoms and disease duration. Pulmonary function and respiratory muscle strength tests were performed in 30 patients with PD, 27 with MSA as well as in 20 age-, sex-, height-, weight-matched normal elderly controls. All the patients underwent United Parkinson's disease rating scale (UPDRS) or united multiple system atrophy rating scale (UMSARS) separately as diagnosed. Vital capacity, forced expiratory volume in 1 second and forced vital capacity decreased, residual volume and ratio of residual volume to total lung capacity increased in both PD and MSA groups compared to controls (p<0.05). Diffusing capacity was decreased in the MSA group, compared with PD and normal elderly control groups (p<0.05). Respiratory muscle strength was lower in both PD and MSA groups than in controls (p<0.05). The values representing spirometry function and respiratory muscle strength were found to have a negative linear correlation with mean score of UPDRS-III in PD and mean score of UMSARS-I in MSA. Respiratory muscle strength showed a negative linear correlation with the mean score of UMSARS-II and disease duration in MSA patients. These findings suggest that respiratory dysfunction is involved in PD and MSA. Respiratory muscle strength is remarkably reduced, and some of the parameters correlate with disease duration and illness severity. The compromised respiratory function in neurodegenerative disorders should be the focus of further researches.

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease.

PubMed

Kanoto, Masafumi; Hosoya, Takaaki; Toyoguchi, Yuuki; Oda, Atsuko

2013-01-01

Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. The subjects consist of a CPNBD group (n=4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n=19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n=23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p<0.05), and between the CPNBD group and the normal control group (p<0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p<0.001, p<0.01 respectively), and between the CPNBD group and the normal control group (p<0.001). Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Ubiquitin-protein ligases in muscle wasting: multiple parallel pathways?

NASA Technical Reports Server (NTRS)

Lecker, Stewart H.; Goldberg, A. L. (Principal Investigator)

2003-01-01

PURPOSE OF REVIEW: Studies in a wide variety of animal models of muscle wasting have led to the concept that increased protein breakdown via the ubiquitin-proteasome pathway is responsible for the loss of muscle mass seen as muscle atrophy. The complexity of the ubiquitination apparatus has hampered our understanding of how this pathway is activated in atrophying muscles and which ubiquitin-conjugating enzymes in muscle are responsible. RECENT FINDINGS: Recent experiments have shown that two newly identified ubiquitin-protein ligases (E3s), atrogin-1/MAFbx and MURF-1, are critical in the development of muscle atrophy. Other in-vitro studies also implicated E2(14k) and E3alpha, of the N-end rule pathway, as playing an important role in the process. SUMMARY: It seems likely that multiple pathways of ubiquitin conjugation are activated in parallel in atrophying muscle, perhaps to target for degradation specific classes of muscle proteins. The emerging challenge will be to define the protein targets for, as well as inhibitors of, these E3s.

Bilateral hippocampal atrophy in temporal lobe epilepsy: Effect of depressive symptoms and febrile seizures

PubMed Central

Finegersh, Andrey; Avedissian, Christina; Shamim, Sadat; Dustin, Irene; Thompson, Paul M.; Theodore, William H.

2011-01-01

Summary Purpose Neuroimaging studies suggest a history of febrile seizures, and depression, are associated with hippocampal volume reductions in patients with temporal lobe epilepsy (TLE). Methods We used radial atrophy mapping (RAM), a three-dimensional (3D) surface modeling tool, to measure hippocampal atrophy in 40 patients with unilateral TLE, with or without a history of febrile seizures and symptoms of depression. Multiple linear regression was used to single out the effects of covariates on local atrophy. Key Findings Subjects with a history of febrile seizures (n = 15) had atrophy in regions corresponding to the CA1 and CA3 subfields of the hippocampus contralateral to seizure focus (CHC) compared to those without a history of febrile seizures (n = 25). Subjects with Beck Depression Inventory II (BDI-II) score ≥14 (n = 11) had atrophy in the superoanterior portion of the CHC compared to subjects with BDI-II <14 (n = 29). Significance Contralateral hippocampal atrophy in TLE may be related to febrile seizures or depression. PMID:21269286

Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases.

PubMed

Dodge, James C

2017-01-01

Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot-Marie-Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research.

Mechanisms of Botulinum Neurotoxin Induced Skeletal Muscle Atrophy

NASA Astrophysics Data System (ADS)

Hain, Brian A.

Our previous research suggests that the mechanism of botulinum neurotoxintype A (BoNT/A)-induced atrophy does not occur via a NF-kappaB/Foxo-dependent process. We thus hypothesized that the primary mechanism would be activation of either the proteosomal or calpain pathways. BoNT/A injection induced elevations in proteolytic activity markers of the ubiquitin-proteasome-system (UPS) and calpain systems after 3 days of a single dose. Inhibition of the proteasome significantly attenuated BoNT/Ainduced atrophy 3-days post BoNT/A injection. Calpastatin overexpression prevented BoNT/A-induced calpain activity at 3 days, and but did not result in a significant attenuation of atrophy. Concurrent attenuation of the UPS and calpain systems was sufficient to attenuate all of the atrophy associated with BoNT/A induced atrophy. In conclusion, it appears that the UPS and calpain system work in an additive fashion with neurotoxin-induced muscle atrophy. Inhibiting both of these pathways while administering BoNT/A attenuates all of the observed muscle atrophy.

Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

USDA-ARS?s Scientific Manuscript database

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghreli...

Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.

PubMed

Bullard, Steven A; Seo, Seongjin; Schilling, Birgit; Dyle, Michael C; Dierdorff, Jason M; Ebert, Scott M; DeLau, Austin D; Gibson, Bradford W; Adams, Christopher M

2016-08-19

Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Orthostatic hypotension: epidemiology, pathophysiology and management

NASA Technical Reports Server (NTRS)

Jacob, G.; Robertson, D.

1995-01-01

Orthostatic hypotension is characterized by low upright blood pressure levels and symptoms of cerebral hypoperfusion. Whereas orthostatic hypotension is heterogeneous, correct pathophysiologic diagnosis is important because of therapeutic and prognostic considerations. Although therapy is not usually curative, it can be extraordinarily beneficial if it is individually tailored. Management of the Shy-Drager syndrome (multiple-system atrophy) remains a formidable challenge.

Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid have less global and regional brain atrophy.

PubMed

Ferreira, Daniel; Voevodskaya, Olga; Imrell, Kerstin; Stawiarz, Leszek; Spulber, Gabriela; Wahlund, Lars-Olof; Hillert, Jan; Westman, Eric; Karrenbauer, Virginija Danylaité

2014-09-15

To investigate whether multiple sclerosis (MS) patients with and without cerebrospinal fluid (CSF) oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. Twenty-eight OCB-negative and thirty-five OCB-positive patients were included. Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. OCB-negative patients, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS patients may represent a clinically relevant MS subgroup. Copyright © 2014 Elsevier B.V. All rights reserved.

Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.

PubMed

Lundell, H; Svolgaard, O; Dogonowski, A-M; Romme Christensen, J; Selleberg, F; Soelberg Sørensen, P; Blinkenberg, M; Siebner, H R; Garde, E

2017-10-01

To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior-posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Difference in the effects of tandospirone on ataxia in various types of spinocerebellar degeneration: an open-label study.

PubMed

Takei, Asako; Hamada, Shinsuke; Homma, Sanae; Hamada, Keiko; Tashiro, Kunio; Hamada, Takeshi

2010-12-01

The aim of this study was to investigate the effects of tandospirone on ataxia in various types of spinocerebellar degeneration (SCD). Fifteen milligram per day of tandospirone was administered to 39 patients with SCD (spinocerebellar atrophy (SCA) 1, five patients; SCA2, six patients; Machado-Joseph disease (MJD), 14 patient; SCA6, five patients; multiple system atrophy-cerebellar type (MSA-C), seven patients; and multiple system atrophy-Parkinson type (MSA-P), two patients). All patients were assessed before and 4 weeks after administration of the drug using the international cooperative ataxia rating scale total score (ARS), total length traveled (TLT) of body stabilometry, and a self-rating depression scale. Statistically, ARS showed a significant difference in MJD (p = 0.005) and SCA6 (p = 0.043). TLT also showed a significant difference in MJD (p = 0.002) and SCA6 (p = 0.043). Eight of 39 patients (SCA1, 1/5; SCA2, 0/6; MJD, 4/14; SCA6, 3/5; MSA-C, 0/7; and MSA-P, 0/2) showed more than a five point reduction in ARS, and 13 of 39 patients (SCA1, 0/5; SCA2, 1/6; MJD, 8/14; SCA6, 4/5; MSA-C, 0/7; and MSA-P, 0/2) showed a reduction of TLT. Our data indicate that the effects of tandospirone on ataxia are different between types of SCD. Therefore, tandospirone is useful for cerebellar ataxia in patients with MJD and SCA6.

Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy

PubMed Central

Bongers, Kale S.; Fox, Daniel K.; Kunkel, Steven D.; Stebounova, Larissa V.; Murry, Daryl J.; Pufall, Miles A.; Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.

2014-01-01

Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy. PMID:25406264

Studies on the lymphoid system of mice with lethal acute toxoplasmosis.

PubMed

Szeri, I; Csóka, R

1976-01-01

Acute toxoplasmosis was induced in CFLP mice by infecting them intraperitoneally with the 25 x 10(3) multiplicity of the virulent RH strain of Toxoplasma gondii. The lymphoid system of mice succumbing to acute toxoplasmosis showed characteristic changes. Significant spleen hypertrophy (spleen index: 1.76), severe thymus atrophy (thymus index: 0.27) and a striking decrease of the lymphocyte count in blood (86%) was found as compared with the uninfected controls.

Task deactivation reductions and atrophy within parietal default mode regions are overlapping but only weakly correlated in mild cognitive impairment

PubMed Central

Threlkeld, Zachary D.; Jicha, Greg A.; Smith, Charles D.; Gold, Brian T.

2012-01-01

Reduced task deactivation within regions of the default mode network (DMN) has been frequently reported in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). As task deactivations reductions become increasingly used in the study of early AD states, it is important to understand their relationship to atrophy. To address this issue, the present study compared task deactivation reductions during a lexical decision task and atrophy in aMCI, using a series of parallel voxel-wise and region-wise analyses of fMRI and structural data. Our results identified multiple regions within parietal cortex as convergence areas of task deactivation and atrophy in aMCI. Relationships between parietal regions showing overlapping task deactivation reductions and atrophy in aMCI were then explored. Regression analyses demonstrated minimal correlation between task deactivation reductions and either local or global atrophy in aMCI. In addition, a logistic regression model which combined task deactivation reductions and atrophy in parietal DMN regions showed higher classificatory accuracy of aMCI than separate task deactivation or atrophy models. Results suggest that task deactivation reductions and atrophy in parietal regions provide complementary rather than redundant information in aMCI. Future longitudinal studies will be required to assess the utility of combining task deactivation reductions and atrophy in the detection of early AD. PMID:21860094

Regional gray matter atrophy in relapsing remitting multiple sclerosis: baseline analysis of multi-center data.

PubMed

Datta, Sushmita; Staewen, Terrell D; Cofield, Stacy S; Cutter, Gary R; Lublin, Fred D; Wolinsky, Jerry S; Narayana, Ponnada A

2015-03-01

Regional gray matter (GM) atrophy in multiple sclerosis (MS) at disease onset and its temporal variation can provide objective information regarding disease evolution. An automated pipeline for estimating atrophy of various GM structures was developed using tensor based morphometry (TBM) and implemented on a multi-center sub-cohort of 1008 relapsing remitting MS (RRMS) patients enrolled in a Phase 3 clinical trial. Four hundred age and gender matched healthy controls were used for comparison. Using the analysis of covariance, atrophy differences between MS patients and healthy controls were assessed on a voxel-by-voxel analysis. Regional GM atrophy was observed in a number of deep GM structures that included thalamus, caudate nucleus, putamen, and cortical GM regions. General linear regression analysis was performed to analyze the effects of age, gender, and scanner field strength, and imaging sequence on the regional atrophy. Correlations between regional GM volumes and expanded disability status scale (EDSS) scores, disease duration (DD), T2 lesion load (T2 LL), T1 lesion load (T1 LL), and normalized cerebrospinal fluid (nCSF) were analyzed using Pearson׳s correlation coefficient. Thalamic atrophy observed in MS patients compared to healthy controls remained consistent within subgroups based on gender and scanner field strength. Weak correlations between thalamic volume and EDSS (r=-0.133; p<0.001) and DD (r=-0.098; p=0.003) were observed. Of all the structures, thalamic volume moderately correlated with T2 LL (r=-0.492; P-value<0.001), T1 LL (r=-0.473; P-value<0.001) and nCSF (r=-0.367; P-value<0.001). Copyright © 2015 Elsevier B.V. All rights reserved.

Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy

PubMed Central

Kaski, Diego; Yong, Keir X. X.; Paterson, Ross W.; Slattery, Catherine F.; Ryan, Natalie S.; Schott, Jonathan M.; Crutch, Sebastian J.

2015-01-01

The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal ‘visual dementia’ and most common atypical Alzheimer’s disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients’ (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer’s disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer’s disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer’s disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with ‘sticky fixation’. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer’s disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer’s disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer’s disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment. PMID:25895507

Depression and anxiety in multiple system atrophy.

PubMed

Zhang, L-Y; Cao, B; Zou, Y-T; Wei, Q-Q; Ou, R-W; Zhao, B; Wu, Y; Shang, H-F

2018-01-01

It has been noticed that the patients with multiple system atrophy (MSA) can accompany with depression and anxiety. This study aimed to establish the incidence and determinants of depression and anxiety symptoms in Chinese MSA patients. A total of 237 MSA patients were enrolled in the study. Neuropsychological assessment was performed using Hamilton Depression Rating Scale-24 items and Hamilton Anxiety Rating Scale. We found that 62.0% and 71.7% patients had at least mild depression and anxiety symptoms, respectively. The severity of depression of MSA patients was associated with lower educational years (P=.024), longer disease duration (P<.001), and disease severity (P<.001). The severity of anxiety was associated with increased disease duration (P<.001), disease severity (P=.013), and orthostatic hypotension (P=.005). Binary logistic regression showed the determinants of depression and anxiety were female gender, longer disease duration, and disease severity. Depression and anxiety symptoms are common in patients with MSA. Neurologists should pay attention to depression and anxiety in patients with MSA, especially in female patients and those with longer disease duration and severe disease condition. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Use of diffusion tensor imaging to identify similarities and differences between cerebellar and Parkinsonism forms of multiple system atrophy.

PubMed

Wang, Po-Shan; Wu, Hsiu-Mei; Lin, Ching-Po; Soong, Bing-Wen

2011-07-01

We performed diffusion tensor imaging to determine if multiple system atrophy (MSA)-cerebellar (C) and MSA-Parkinsonism (P) show similar changes, as shown in pathological studies. Nineteen patients with MSA-C, 12 patients with MSA-P, 20 patients with Parkinson disease, and 20 healthy controls were evaluated with the use of voxel-based morphometry analysis of diffusion tensor imaging. There was an increase in apparent diffusion coefficient values in the middle cerebellar peduncles and cerebellum and a decrease in fractional anisotropy in the pyramidal tract, middle cerebellar peduncles, and white matter of the cerebellum in patients with MSA-C and MSA-P compared to the controls (P < 0.001). In addition, isotropic diffusion-weighted image values were reduced in the cerebellar cortex and deep cerebellar nuclei in patients with MSA-C and increased in the basal ganglia in patients with MSA-P. These results indicate that despite their disparate clinical manifestations, patients with MSA-C and MSA-P share similar diffusion tensor imaging features in the infratentorial region. Further, the combination of FA, ADC and iDWI images can be used to distinguish between MSA (either form) and Parkinson disease, which has potential therapeutic implications.

Brain atrophy and lesion load measures over 1 year relate to clinical status after 6 years in patients with clinically isolated syndromes.

PubMed

Di Filippo, M; Anderson, V M; Altmann, D R; Swanton, J K; Plant, G T; Thompson, A J; Miller, D H

2010-02-01

Conventional MRI lesion measures modestly predict long term disability in some clinically isolated syndrome (CIS) studies. Brain atrophy suggests neuroaxonal loss in multiple sclerosis (MS) with the potential to reflect disease progression to a greater extent than lesion measures. To investigate whether brain atrophy and lesion load, during the first year in patients presenting with CIS, independently predict clinical outcome (development of MS and disability at 6 years). 99 patients presenting with CIS were included in the study. T1 gadolinium enhanced and T2 weighted brain MRI was acquired at baseline and approximately 1 year later. Percentage brain atrophy rate between baseline and follow-up scans was analysed using SIENA. Mean annual brain atrophy rates were -0.38% for all patients, -0.50% in patients who had developed MS at 6 years and -0.26% in those who had not. Brain atrophy rate (p = 0.005) and baseline T2 lesion load (p<0.001) were independent predictors of clinically definite MS. While brain atrophy rate was a predictor of Expanded Disability Status Scale (EDSS) score in a univariate analysis, only 1 year T2 lesion load change (p = 0.007) and baseline gadolinium enhancing lesion number (p = 0.03) were independent predictors of EDSS score at the 6 year follow-up. T1 lesion load was the only MRI parameter which predicted Multiple Sclerosis Functional Composite score at the 6 year follow-up. The findings confirm that brain atrophy occurs during the earliest phases of MS and suggest that 1 year longitudinal measures of MRI change, if considered together with baseline MRI variables, might help to predict clinical status 6 years after the first demyelinating event in CIS patients, better than measurements such as lesion or brain volumes on baseline MRI alone.

Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy

PubMed Central

Bialek, Peter; Morris, Carl; Parkington, Jascha; St. Andre, Michael; Owens, Jane; Yaworsky, Paul; Seeherman, Howard

2011-01-01

Skeletal muscle atrophy can be a consequence of many diseases, environmental insults, inactivity, age, and injury. Atrophy is characterized by active degradation, removal of contractile proteins, and a reduction in muscle fiber size. Animal models have been extensively used to identify pathways that lead to atrophic conditions. We used genome-wide expression profiling analyses and quantitative PCR to identify the molecular changes that occur in two clinically relevant mouse models of muscle atrophy: hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7, and 14 days after casting or injury. The total amount of muscle loss, as measured by wet weight and muscle fiber size, was equivalent between models on day 14, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tenotomy resulted in the regulation of significantly more mRNA transcripts then did casting. Analysis of the regulated genes and pathways suggest that the mechanisms of atrophy are distinct between these models. The degradation following casting was ubiquitin-proteasome mediated, while degradation following tenotomy was lysosomal and matrix-metalloproteinase mediated, suggesting a possible role for autophagy. These data suggest that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat atrophy resulting from different conditions. PMID:21791639

Brain MRI atrophy quantification in MS

PubMed Central

Rocca, Maria A.; Battaglini, Marco; Benedict, Ralph H.B.; De Stefano, Nicola; Geurts, Jeroen J.G.; Henry, Roland G.; Horsfield, Mark A.; Jenkinson, Mark; Pagani, Elisabetta

2017-01-01

Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain atrophy in MS is summarized, including whole brain and various compartments thereof (i.e., white matter, gray matter, selected CNS structures). Current methods provide sufficient precision for cohort studies, but are not adequate for confidently assessing changes in individual patients over the scale of months or a few years. PMID:27986875

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: a voxel-based analysis study.

PubMed

Mallik, Shahrukh; Muhlert, Nils; Samson, Rebecca S; Sethi, Varun; Wheeler-Kingshott, Claudia A M; Miller, David H; Chard, Declan T

2015-04-01

In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently. © The Author(s), 2014.

Quantifying brain volumes for Multiple Sclerosis patients follow-up in clinical practice - comparison of 1.5 and 3 Tesla magnetic resonance imaging.

PubMed

Lysandropoulos, Andreas P; Absil, Julie; Metens, Thierry; Mavroudakis, Nicolas; Guisset, François; Van Vlierberghe, Eline; Smeets, Dirk; David, Philippe; Maertens, Anke; Van Hecke, Wim

2016-02-01

There is emerging evidence that brain atrophy is a part of the pathophysiology of Multiple Sclerosis (MS) and correlates with several clinical outcomes of the disease, both physical and cognitive. Consequently, brain atrophy is becoming an important parameter in patients' follow-up. Since in clinical practice both 1.5Tesla (T) and 3T magnetic resonance imaging (MRI) systems are used for MS patients follow-up, questions arise regarding compatibility and a possible need for standardization. Therefore, in this study 18 MS patients were scanned on the same day on a 1.5T and a 3T scanner. For each scanner, a 3D T1 and a 3D FLAIR were acquired. As no atrophy is expected within 1 day, these datasets can be used to evaluate the median percentage error of the brain volume measurement for gray matter (GM) volume and parenchymal volume (PV) between 1.5T and 3T scanners. The results are obtained with MSmetrix, which is developed especially for use in the MS clinical care path, and compared to Siena (FSL), a widely used software for research purposes. The MSmetrix median percentage error of the brain volume measurement between a 1.5T and a 3T scanner is 0.52% for GM and 0.35% for PV. For Siena this error equals 2.99%. When data of the same scanner are compared, the error is in the order of 0.06-0.08% for both MSmetrix and Siena. MSmetrix appears robust on both the 1.5T and 3T systems and the measurement error becomes an order of magnitude higher between scanners with different field strength.

Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy.

PubMed

Shakespeare, Timothy J; Kaski, Diego; Yong, Keir X X; Paterson, Ross W; Slattery, Catherine F; Ryan, Natalie S; Schott, Jonathan M; Crutch, Sebastian J

2015-07-01

The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal 'visual dementia' and most common atypical Alzheimer's disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients' (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer's disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer's disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer's disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with 'sticky fixation'. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer's disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer's disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer's disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Corpus callosum atrophy as a marker of clinically meaningful cognitive decline in secondary progressive multiple sclerosis. Impact on employment status.

PubMed

Papathanasiou, Athanasios; Messinis, Lambros; Zampakis, Petros; Papathanasopoulos, Panagiotis

2017-09-01

Cognitive impairment in Multiple Sclerosis (MS) is more frequent and pronounced in secondary progressive MS (SPMS). Cognitive decline is an important predictor of employment status in patients with MS. Magnetic Resonance Imaging (MRI) markers have been used to associate tissue damage with cognitive dysfunction. The aim of the study was to designate the MRI marker that predicts cognitive decline in SPMS and explore its effect on employment status. 30 SPMS patients and 30 healthy participants underwent neuropsychological assessment using the Trail Making Test (TMT) parts A and B, semantic and phonological verbal fluency task and a computerized cognitive screening battery (Central Nervous System Vital Signs). Employment status was obtained as a quality of life measure. Brain MRI was performed in all participants. We measured total lesion volume, third ventricle width, thalamic and corpus callosum atrophy. The frequency of cognitive decline for our SPMS patients was 80%. SPMS patients differed significantly from controls in all neuropsychological measures. Corpus callosum area was correlated with cognitive flexibility, processing speed, composite memory, executive functions, psychomotor speed, reaction time and phonological verbal fluency task. Processing speed and composite memory were the most sensitive markers for predicting employment status. Corpus callosum area was the most sensitive MRI marker for memory and processing speed. Corpus callosum atrophy predicts a clinically meaningful cognitive decline, affecting employment status in our SPMS patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer's disease.

PubMed

Zhang, Xiuming; Mormino, Elizabeth C; Sun, Nanbo; Sperling, Reisa A; Sabuncu, Mert R; Yeo, B T Thomas

2016-10-18

We used a data-driven Bayesian model to automatically identify distinct latent factors of overlapping atrophy patterns from voxelwise structural MRIs of late-onset Alzheimer's disease (AD) dementia patients. Our approach estimated the extent to which multiple distinct atrophy patterns were expressed within each participant rather than assuming that each participant expressed a single atrophy factor. The model revealed a temporal atrophy factor (medial temporal cortex, hippocampus, and amygdala), a subcortical atrophy factor (striatum, thalamus, and cerebellum), and a cortical atrophy factor (frontal, parietal, lateral temporal, and lateral occipital cortices). To explore the influence of each factor in early AD, atrophy factor compositions were inferred in beta-amyloid-positive (Aβ+) mild cognitively impaired (MCI) and cognitively normal (CN) participants. All three factors were associated with memory decline across the entire clinical spectrum, whereas the cortical factor was associated with executive function decline in Aβ+ MCI participants and AD dementia patients. Direct comparison between factors revealed that the temporal factor showed the strongest association with memory, whereas the cortical factor showed the strongest association with executive function. The subcortical factor was associated with the slowest decline for both memory and executive function compared with temporal and cortical factors. These results suggest that distinct patterns of atrophy influence decline across different cognitive domains. Quantification of this heterogeneity may enable the computation of individual-level predictions relevant for disease monitoring and customized therapies. Factor compositions of participants and code used in this article are publicly available for future research.

[Staging gastritis with the OLGA system: prevalence of advanced stages of gastric atrophy in Mexican patients].

PubMed

Ramírez-Mendoza, P; Ruiz-Castillo, S A; Maroun-Marun, C; Trujillo-Benavides, O; Baltazar-Montúfar, P; Méndez del Monte, R; Angeles-Garay, U

2011-01-01

Gastric adenocarcinoma of intestinal type is preceded by inflammation, which produces mucosal atrophy and intestinal metaplasia, progressing eventually to dysplasia and invasive cancer. Recently an international group, the Operative Link on Gastritis Assessment (OLGA) proponed a staging system for gastric biopsies. To recognize the distribution of advanced stages of gastric mucosal atrophy in Mexican patients with dyspepsia according to the OLGA system. We apply the OLGA system for cancer risk (Stages 0 to IV) to 322 gastric biopsies from consecutive patients with dyspepsia. Using the Sydney protocol, we recorded the presence of atrophy, dysplasia and the relationship with ulcer disease. We report the stage of atrophy for each region and the Helicobacter pylori infection status. We documented 72 (22.4%) cases with atrophy, 50 of them (69.4%) were metaplastic-type. Overall, nine biopsies (2.78%) were stage III (all of them with metaplastic-type atrophy) and there was not stage IV cases. We did not find high-grade dysplasia or intramucosal carcinoma. In 8 of subjects with stage III, we observed low-grade dysplasia. We documented gastric ulcer in 5 patients with stage II, 60% of them with associated low-grade dysplasia. Five patients with duodenal ulcer were found in stages 0 and I. We found low prevalence of advanced stages of mucosal gastric atrophy among patients with dyspepsia. However we recognized 9 patients with stage III according to OLGA system worthy of follow-up because the high risk for developing gastric cancer.

Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

PubMed Central

Yakabe, Mitsutaka; Ota, Hidetaka; Iijima, Katsuya; Eto, Masato; Ouchi, Yasuyoshi; Akishita, Masahiro

2018-01-01

Background Interleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear. Methods Tail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy. Results Serum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice. Conclusion Systemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy. PMID:29351340

Non-Gaussianity of Low Frequency Heart Rate Variability and Sympathetic Activation: Lack of Increases in Multiple System Atrophy and Parkinson Disease

PubMed Central

Kiyono, Ken; Hayano, Junichiro; Kwak, Shin; Watanabe, Eiichi; Yamamoto, Yoshiharu

2012-01-01

The correlates of indices of long-term ambulatory heart rate variability (HRV) of the autonomic nervous system have not been completely understood. In this study, we evaluated conventional HRV indices, obtained from the daytime (12:00–18:00) Holter recording, and a recently proposed non-Gaussianity index (λ; Kiyono et al., 2008) in 12 patients with multiple system atrophy (MSA) and 10 patients with Parkinson disease (PD), known to have varying degrees of cardiac vagal and sympathetic dysfunction. Compared with the age-matched healthy control group, the MSA patients showed significantly decreased HRV, most probably reflecting impaired vagal heart rate control, but the PD patients did not show such reduced variability. In both MSA and PD patients, the low-to-high frequency (LF/HF) ratio and the short-term fractal exponent α1, suggested to reflect the sympathovagal balance, were significantly decreased, as observed in congestive heart failure (CHF) patients with sympathetic overdrive. In contrast, the analysis of the non-Gaussianity index λ showed that a marked increase in intermittent and non-Gaussian HRV observed in the CHF patients was not observed in the MSA and PD patients with sympathetic dysfunction. These findings provide additional evidence for the relation between the non-Gaussian intermittency of HRV and increased sympathetic activity. PMID:22371705

Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis.

PubMed

MacKenzie-Graham, Allan; Kurth, Florian; Itoh, Yuichiro; Wang, He-Jing; Montag, Michael J; Elashoff, Robert; Voskuhl, Rhonda R

2016-08-01

Multiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown. To understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS. In this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014. Voxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores). Among the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P < .001) and a cluster in the precentral gyrus bilaterally (P = .004). In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortices (P < .001), whereas worse performance on the 9-Hole Peg Test correlated with GM volume loss in Brodmann area 44 (Broca area; P = .02). Finally, voxelwise GM loss in the right paracentral lobulus correlated with bowel and bladder disability (P = .03). Thus, deficits in specific clinical test results were directly associated with localized GM loss in clinically eloquent locations. These biology-driven data indicate that specific disabilities in MS are associated with voxelwise GM loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.

Transcranial sonography in movement disorders: an interesting tool for diagnostic perspectives.

PubMed

Sanzaro, E; Iemolo, F

2016-03-01

Transcranial sonography has become an important tool for the diagnosis of various movement disorders. In most patients with idiopathic Parkinson disease, a markedly hyperechogenic substantia nigra (SN) was detected on at least one side. We have highlighted the sonographic features that might help the differential diagnosis of PD and other movement disorders. Our investigation involved 30 patients (age 45-85 years) with idiopathic Parkinson disease, 2 multiple system atrophy, 3 progressive supranuclear palsy and 2 patients with restless legs syndrome. In accordance with several previous studies, we detected hyperechogenicity of the SN by TCS in 90% of patients with idiopathic Parkinson disease. Subjects with a marked severity disease had a larger extent of the hyperechogenic SN signal. All progressive supranuclear palsy patients had an enlarged third ventricle and, in two cases, we observed the presence of hyperechoic areas in the lentiform nucleus. This last ultrasonographic feature was also seen in our patients with multiple system atrophy. TCS abnormalities of the SN, midbrain raphe and basal ganglia are characteristics of several movement and affective disorders. These features are less easily detected by other techniques, such as CT and MRI, which enable the exclusion of structural lesions, such as tumours and multi-infarct disease, because the physical principle differs from other imaging methods.

Use of a new generation of adaptive servo ventilation for sleep-disordered breathing in patients with multiple system atrophy.

PubMed

Hamada, Satoshi; Takahashi, Ryosuke; Mishima, Michiaki; Chin, Kazuo

2015-11-06

A 70-year-old man (case 1) and a 64-year-old woman (case 2) with multiple system atrophy (MSA) and snoring were admitted for polysomnography. Their awake PaCO2 indicated normocapnia. Apnoea-hypopnoea index (AHI), max transcutaneous carbon dioxide partial pressure (PtcCO2) and ΔPtcCO2 (max PtcCO2 (during sleep)-baseline PtcCO2 (while awake)) were 11.4/h, 63 mm Hg and 18 mm Hg, respectively, in case 1 and 53.1/h, 59 mm Hg and 13 mm Hg, respectively, in case 2. Their sleep-disordered breathing (SDB) was diagnosed as obstructive sleep apnoea with hypoventilation. We thought that variable expiratory positive airway pressure and pressure support ventilation (advanced-adaptive servo ventilation (ASV)) might be favourable for their SDB. Polysomnography after introducing advanced-ASV revealed that AHI, max PtcCO2 and ΔPtcCO2 were 0.2/h, 53 mm Hg and 5 mm Hg, respectively, in case 1 and 1.5/h, 56 mm Hg and 9 mm Hg, respectively, in case 2. Advanced-ASV for treating Cheyne-Stokes breathing may be helpful in SDB in patients with MSA. 2015 BMJ Publishing Group Ltd.

The Economic Costs of Progressive Supranuclear Palsy and Multiple System Atrophy in France, Germany and the United Kingdom

PubMed Central

McCrone, Paul; Payan, Christine Anne Mary; Knapp, Martin; Ludolph, Albert; Agid, Yves; Leigh, P. Nigel; Bensimon, Gilbert

2011-01-01

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are progressive disabling neurological conditions usually fatal within 10 years of onset. Little is known about the economic costs of these conditions. This paper reports service use and costs from France, Germany and the UK and identifies patient characteristics that are associated with cost. 767 patients were recruited, and 760 included in the study, from 44 centres as part of the NNIPPS trial. Service use during the previous six months was measured at entry to the study and costs calculated. Mean six-month costs were calculated for 742 patients. Data on patient sociodemographic and clinical characteristics were recorded and used in regression models to identify predictors of service costs and unpaid care costs (i.e., care from family and friends). The mean six-month service costs of PSP were €24,491 in France, €30,643 in Germany and €25,655 in the UK. The costs for MSA were €28,924, €25,645 and €19,103 respectively. Unpaid care accounted for 68–76%. Formal and unpaid costs were significantly higher the more severe the illness, as indicated by the Parkinson's Plus Symptom scale. There was a significant inverse relationship between service and unpaid care costs. PMID:21931694

Differences in skin sympathetic involvements between two chronic autonomic disorders: multiple system atrophy and pure autonomic failure.

PubMed

Asahina, Masato; Akaogi, Yuichi; Yamanaka, Yoshitaka; Koyama, Yu; Hattori, Takamichi

2009-06-01

Certain stimuli evoke increased sweat secretion (sympathetic sweat response; SSwR) and reduced skin blood flow (skin vasomotor reflex; SkVR) in the palm/sole. We evaluated SSwR and SkVR in patients with multiple system atrophy (MSA) and pure autonomic failure (PAF). SSwR and SkVR on the palm in response to deep inspiration and mental arithmetic were recorded in 11 MSA patients, 11 PAF patients, and 11 healthy controls. In addition, the head-up tilt test was performed, and the coefficient of variation of R-R intervals (CV(R-R)) was obtained. SSwR amplitudes were significantly lower in the MSA and PAF patients than the controls. SkVR amplitudes in the PAF patients were significantly lower than the controls, but preserved in the MSA patients. In head-up tilt tests, all MSA and PAF patients showed orthostatic hypotension, with similar severity. CV(R-R) was low in the MSA and PAF patients, but a significant difference was found only between the PAF and control groups. In the MSA patients, SkVR was preserved, but SSwR was diminished. In the PAF patients, both SkVR and SSwR were attenuated. The combination of SkVR and SSwR tests may differentiate MSA and PAF.

Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease

PubMed Central

2012-01-01

Background Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA) and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci. Case Presentation Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C) missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome. Conclusion This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients. PMID:22226368

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: A voxel-based analysis study

PubMed Central

Muhlert, Nils; Samson, Rebecca S; Sethi, Varun; Wheeler-Kingshott, Claudia AM; Miller, David H; Chard, Declan T

2015-01-01

Background: In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing–remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). Methods: A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. Results: MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. Conclusions: These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently. PMID:25145689

Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect.

PubMed

Durand, Paul D; Couto, Rafael A; Isakov, Raymond; Yoo, Donald B; Azizzadeh, Babak; Guyuron, Bahman; Zins, James E

2016-04-01

While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Skeletal Muscle Pathophysiology: The Emerging Role of Spermine Oxidase and Spermidine.

PubMed

Cervelli, Manuela; Leonetti, Alessia; Duranti, Guglielmo; Sabatini, Stefania; Ceci, Roberta; Mariottini, Paolo

2018-02-14

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, causes muscle atrophy, a pathological state with adverse outcomes such as poor quality of life, physical disability, and high mortality. In murine skeletal muscle C2C12 cells, increased expression of the spermine oxidase (SMOX) enzyme has been found during cell differentiation. Notably, SMOX overexpression increases muscle fiber size, while SMOX reduction was enough to induce muscle atrophy in multiple murine models. Of note, the SMOX reaction product spermidine appears to be involved in skeletal muscle atrophy/hypertrophy. It is effective in reactivating autophagy, ameliorating the myopathic defects of collagen VI-null mice. Moreover, spermidine treatment, if combined with exercise, can affect D-gal-induced aging-related skeletal muscle atrophy. This review hypothesizes a role for SMOX during skeletal muscle differentiation and outlines its role and that of spermidine in muscle atrophy. The identification of new molecular pathways involved in the maintenance of skeletal muscle health could be beneficial in developing novel therapeutic lead compounds to treat muscle atrophy.

miR-182 attenuates atrophy-related gene expression by targeting FoxO3 in skeletal muscle

PubMed Central

Rahnert, Jill A.; Zheng, Bin; Woodworth-Hobbs, Myra E.; Franch, Harold A.; Russ Price, S.

2014-01-01

Skeletal muscle atrophy occurs in response to a variety of conditions including chronic kidney disease, diabetes, cancer, and elevated glucocorticoids. MicroRNAs (miR) may play a role in the wasting process. Activation of the forkhead box O3 (FoxO3) transcription factor causes skeletal muscle atrophy in patients, animals, and cultured cells by increasing the expression of components of the ubiquitin-proteasome and autophagy-lysosome proteolytic systems. To identify microRNAs that potentially modulate the atrophy process, an in silico target analysis was performed and miR-182 was predicted to target FoxO3 mRNA. Using a combination of immunoblot analysis, quantitative real-time RT-PCR, and FoxO3 3′-UTR luciferase reporter genes, miR-182 was confirmed to regulate FoxO3 expression in C2C12 myotubes. Transfection of miR-182 into muscle cells decreased FoxO3 mRNA 30% and FoxO3 protein 67% (P < 0.05) and also prevented a glucocorticoid-induced upregulation of multiple FoxO3 gene targets including MAFbx/atrogin-1, autophagy-related protein 12 (ATG12), cathepsin L, and microtubule-associated protein light chain 3 (LC3). Treatment of C2C12 myotubes with dexamethasone (Dex) (1 μM, 6 h) to induce muscle atrophy decreased miR-182 expression by 63% (P < 0.05). Similarly, miR-182 was decreased 44% (P < 0.05) in the gastrocnemius muscle of rats injected with streptozotocin to induce diabetes compared with controls. Finally, miR-182 was present in exosomes isolated from the media of C2C12 myotubes and Dex increased its abundance. These data identify miR-182 as an important regulator of FoxO3 expression that participates in the control of atrophy-inducing genes during catabolic diseases. PMID:24871856

Brain tissues atrophy is not always the best structural biomarker of physiological aging: A multimodal cross-sectional study.

PubMed

Cherubini, Andrea; Caligiuri, Maria Eugenia; Péran, Patrice; Sabatini, Umberto; Cosentino, Carlo; Amato, Francesco

2015-01-01

This study presents a voxel-based multiple regression analysis of different magnetic resonance image modalities, including anatomical T1-weighted, T2* relaxometry, and diffusion tensor imaging. Quantitative parameters sensitive to complementary brain tissue alterations, including morphometric atrophy, mineralization, microstructural damage, and anisotropy loss, were compared in a linear physiological aging model in 140 healthy subjects (range 20-74 years). The performance of different predictors and the identification of the best biomarker of age-induced structural variation were compared without a priori anatomical knowledge. The best quantitative predictors in several brain regions were iron deposition and microstructural damage, rather than macroscopic tissue atrophy. Age variations were best resolved with a combination of markers, suggesting that multiple predictors better capture age-induced tissue alterations. These findings highlight the importance of a combined evaluation of multimodal biomarkers for the study of aging and point to a number of novel applications for the method described.

Corticobasal degeneration with olivopontocerebellar atrophy and TDP-43 pathology: an unusual clinicopathologic variant of CBD

PubMed Central

Kouri, Naomi; Oshima, Kenichi; Takahashi, Makio; Murray, Melissa E.; Ahmed, Zeshan; Parisi, Joseph E.; Yen, Shu-Hui C.; Dickson, Dennis W.

2013-01-01

CBD is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus was comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. Additionally, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology. PMID:23371366

Corticobasal degeneration with olivopontocerebellar atrophy and TDP-43 pathology: an unusual clinicopathologic variant of CBD.

PubMed

Kouri, Naomi; Oshima, Kenichi; Takahashi, Makio; Murray, Melissa E; Ahmed, Zeshan; Parisi, Joseph E; Yen, Shu-Hui C; Dickson, Dennis W

2013-05-01

Corticobasal degeneration (CBD) is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon, and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus were comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. In addition, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology.

Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy.

PubMed

Calabrese, Massimiliano; Gajofatto, Alberto; Gobbin, Francesca; Turri, Giulia; Richelli, Silvia; Matinella, Angela; Oliboni, Eugenio Simone; Benedetti, Maria Donata; Monaco, Salvatore

2015-04-01

Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40-58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as "The Hummingbird sign," was observed in eight CI-MS and in three PSP patients. Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs. © The Author(s), 2014.

Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis.

PubMed

Batista, Sonia; Zivadinov, Robert; Hoogs, Marietta; Bergsland, Niels; Heininen-Brown, Mari; Dwyer, Michael G; Weinstock-Guttman, Bianca; Benedict, Ralph H B

2012-01-01

Information-processing speed (IPS) slowing is a primary cognitive deficit in multiple sclerosis (MS). Basal ganglia, thalamus and neocortex are thought to have a key role for efficient information-processing, yet the specific relative contribution of these structures for MS-related IPS impairment is poorly understood. To determine if basal ganglia and thalamus atrophy independently contribute to visual and auditory IPS impairment in MS, after controlling for the influence of neocortical volume, we enrolled 86 consecutive MS patients and 25 normal controls undergoing 3T brain MRI and neuropsychological testing. Using Sienax and FIRST software, neocortical and deep gray matter (DGM) volumes were calculated. Neuropsychological testing contributed measures of auditory and visual IPS using the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), respectively. MS patients exhibited significantly slower IPS relative to controls and showed reduction in neocortex, caudate, putamen, globus pallidus, thalamus and nucleus accumbens volume. SDMT and PASAT were significantly correlated with all DGM regions. These effects were mitigated by controlling for the effects of neocortical volume, but all DGM volumes remained significantly correlated with SDMT, putamen (r = 0.409, p < 0.001) and thalamus (r = 0.362, p < 0.001) having the strongest effects, whereas for PASAT, the correlation was significant for putamen (r = 0.313, p < 0.01) but not for thalamus. We confirm the significant role of thalamus atrophy in MS-related IPS slowing and find that putamen atrophy is also a significant contributor to this disorder. These DGM structures have independent, significant roles, after controlling for the influence of neocortex atrophy.

Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control.

PubMed

Glytsou, Christina; Calvo, Enrique; Cogliati, Sara; Mehrotra, Arpit; Anastasia, Irene; Rigoni, Giovanni; Raimondi, Andrea; Shintani, Norihito; Loureiro, Marta; Vazquez, Jesùs; Pellegrini, Luca; Enriquez, Jose Antonio; Scorrano, Luca; Soriano, Maria Eugenia

2016-12-13

The mitochondrial contact site and cristae organizing system (MICOS) and Optic atrophy 1 (OPA1) control cristae shape, thus affecting mitochondrial function and apoptosis. Whether and how they physically and functionally interact is unclear. Here, we provide evidence that OPA1 is epistatic to MICOS in the regulation of cristae shape. Proteomic analysis identifies multiple MICOS components in native OPA1-containing high molecular weight complexes disrupted during cristae remodeling. MIC60, a core MICOS protein, physically interacts with OPA1, and together, they control cristae junction number and stability, OPA1 being epistatic to MIC60. OPA1 defines cristae width and junction diameter independently of MIC60. Our combination of proteomics, biochemistry, genetics, and electron tomography provides a unifying model for mammalian cristae biogenesis by OPA1 and MICOS. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Obestatin controls the ubiquitin–proteasome and autophagy–lysosome systems in glucocorticoid‐induced muscle cell atrophy

PubMed Central

Cid‐Díaz, Tania; Santos‐Zas, Icía; González‐Sánchez, Jessica; Gurriarán‐Rodríguez, Uxía; Mosteiro, Carlos S.; Casabiell, Xesús; García‐Caballero, Tomás; Mouly, Vincent; Pazos, Yolanda

2017-01-01

Abstract Background Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid‐induced and wasting disorder‐related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid‐induced muscle cell atrophy. Methods In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes. Results The activation of the obestatin/GPR39 system protects from glucocorticoid‐induced atrophy by regulation of Akt, PKD/PKCμ, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin–proteasome system and autophagy–lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post‐translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes. Conclusions Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions. PMID:28675664

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems.

PubMed

Komatsu, Riyo; Okazaki, Tatsuma; Ebihara, Satoru; Kobayashi, Makoto; Tsukita, Yoko; Nihei, Mayumi; Sugiura, Hisatoshi; Niu, Kaijun; Ebihara, Takae; Ichinose, Masakazu

2018-05-22

Repetition of the onset of aspiration pneumonia in aged patients is common and causes chronic inflammation. The inflammation induces proinflammatory cytokine production and atrophy in the muscles. The proinflammatory cytokines induce muscle proteolysis by activating calpains and caspase-3, followed by further degradation by the ubiquitin-proteasome system. Autophagy is another pathway of muscle atrophy. However, little is known about the relationship between aspiration pneumonia and muscle. For swallowing muscles, it is not clear whether they produce cytokines. The main objective of this study was to determine whether aspiration pneumonia induces muscle atrophy in the respiratory (the diaphragm), skeletal (the tibialis anterior, TA), and swallowing (the tongue) systems, and their possible mechanisms. We employed a mouse aspiration pneumonia model and computed tomography (CT) scans of aged pneumonia patients. To induce aspiration pneumonia, mice were inoculated with low dose pepsin and lipopolysaccharide solution intra-nasally 5 days a week. The diaphragm, TA, and tongue were isolated, and total RNA, proteins, and frozen sections were stored. Quantitative real-time polymerase chain reaction determined the expression levels of proinflammatory cytokines, muscle E3 ubiquitin ligases, and autophagy related genes. Western blot analysis determined the activation of the muscle proteolysis pathway. Frozen sections determined the presence of muscle atrophy. CT scans were used to evaluate the muscle atrophy in aged aspiration pneumonia patients. The aspiration challenge enhanced the expression levels of proinflammatory cytokines in the diaphragm, TA, and tongue. Among muscle proteolysis pathways, the aspiration challenge activated caspase-3 in all the three muscles examined, whereas calpains were activated in the diaphragm and the TA but not in the tongue. Activation of the ubiquitin-proteasome system was detected in all the three muscles examined. The aspiration challenge activated autophagy in the TA and the tongue, whereas weak or little activation was detected in the diaphragm. The aspiration challenge resulted in a greater proportion of smaller myofibers than in controls in the diaphragm, TA, and tongue, suggesting muscle atrophy. CT scans clearly showed that aspiration pneumonia was followed by muscle atrophy in aged patients. Aspiration pneumonia induced muscle atrophy in the respiratory, skeletal, and swallowing systems in a preclinical animal model and in human patients. Diaphragmatic atrophy may weaken the force of cough to expectorate sputum or mis-swallowed contents. Skeletal muscle atrophy may cause secondary sarcopenia. The atrophy of swallowing muscles may weaken the swallowing function. Thus, muscle atrophy could become a new therapeutic target of aspiration pneumonia. © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

An electrophysiological approach to the diagnosis of neurogenic dysphagia: implications for botulinum toxin treatment.

PubMed

Alfonsi, E; Merlo, I M; Ponzio, M; Montomoli, C; Tassorelli, C; Biancardi, C; Lozza, A; Martignoni, E

2010-01-01

Botulinum toxin (BTX) injection into the cricopharyngeal (CP) muscle has been proposed for the treatment of neurogenic dysphagia due to CP hyperactivity. The aim was to determine whether an electrophysiological method exploring oropharyngeal swallowing could guide treatment and discriminate responders from non-responders, based on the association of CP dysfunction with other electrophysiological abnormalities of swallowing. Patients with different neurological disorders were examined: Parkinson disease, progressive supranuclear palsy, multiple system atrophy-Parkinson variant, multiple system atrophy cerebellar variant, stroke, multiple sclerosis and ataxia telangiectasia. All patients presented with clinical dysphagia, and with complete absence of CP muscle inhibition during the hypopharyngeal phase of swallowing. Each patient underwent clinical and electrophysiological investigations before and after treatment with BTX into the CP muscle of one side (15 units of Botox). Clinical and electrophysiological procedures were performed in a blind manner by two different investigators. The following electrophysiological measures were analysed: (1) duration of EMG activity of suprahyoid/submental muscles (SHEMG-D); (2) duration of laryngopharyngeal mechanogram (LPM-D); (3) duration of the inhibition of the CP muscle EMG activity (CPEMG-ID); and (4) interval between onset of EMG activity of suprahyoid/submental muscles and onset of laryngopharyngeal mechanogram (I-SHEMG-LPM). Two months after treatment, 50% of patients showed a significant improvement. Patients with prolonged or reduced SHEMG-D values and prolonged I-SHEMG-LPM values did not respond to BTX. Therefore, values for which BTX had no effect (warning values) were identified. This electrophysiological method can recognise swallowing abnormalities which may affect the outcome of the therapeutic approach to dysphagia with BTX treatment.

Effects of disease duration on the clinical features and brain glucose metabolism in patients with mixed type multiple system atrophy.

PubMed

Lyoo, C H; Jeong, Y; Ryu, Y H; Lee, S Y; Song, T J; Lee, J H; Rinne, J O; Lee, M S

2008-02-01

To study the effect of disease duration on the clinical, neuropsychological and [(18)F]-deoxyglucose (FDG) PET findings in patients with mixed type multiple system atrophy (MSA), this study included 16 controls and 37 mixed-type MSA patients with a shorter than a 3-year history of cerebellar or parkinsonian symptoms. We classified the patients into three groups according to the duration of parkinsonian or cerebellar symptoms (Group I =

Diagnosis of multiple system atrophy

PubMed Central

Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

2017-01-01

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs. PMID:29111419

Distinguishing spinocerebellar ataxia with pure cerebellar manifestation from multiple system atrophy (MSA-C) through saccade profiles.

PubMed

Terao, Yasuo; Fukuda, Hideki; Tokushige, Shin-Ichi; Inomata-Terada, Satomi; Yugeta, Akihiro; Hamada, Masashi; Ugawa, Yoshikazu

2017-01-01

Patients with spinocerebellar ataxia with pure cerebellar presentation (SCD) and multiple system atrophy (MSA-C) show similar symptoms at early stages, although cerebellofugal pathology predominates in SCD, and cerebellopetal pathology in MSA-C. We studied whether saccade velocity profiles, which reflect the accelerating and braking functions of the cerebellum, can differentiate these two disorders. We recorded visually guided (VGS) and memory guided saccades (MGS) in 29 MSA-C patients, 12 SCD patients, and 92 age-matched normal subjects, and compared their amplitude, peak velocity and duration (accelerating and decelerating phases). Hypometria predominated in VGS and MGS of MSA-C, whereas hypometria was less marked in SCD, with hypermetria frequently noted in MGS. Peak velocity was reduced, and deteriorated with advancing disease both in SCD and MSA-C groups at smaller target eccentricities. The deceleration phase was prolonged in SCD compared to MSA-C and normal groups at larger target eccentricities, which deteriorated with advancing disease. Saccades in MSA-C were characterized by a more prominent acceleration deficit and those in SCD by a more prominent braking defect, possibly caused by the cerebellopetal and cerebellofugal pathologies, respectively. Saccade profiles provide important information regarding the accelerating and braking signals of the cerebellum in spinocerebellar ataxia. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Prediction of orthostatic hypotension in multiple system atrophy and Parkinson disease

PubMed Central

Sun, Zhanfang; Jia, Dandan; Shi, Yuting; Hou, Xuan; Yang, Xiaosu; Guo, Jifeng; Li, Nan; Wang, Junling; Sun, Qiying; Zhang, Hainan; Lei, Lifang; Shen, Lu; Yan, Xinxiang; Xia, Kun; Jiang, Hong; Tang, Beisha

2016-01-01

Orthostatic hypotension (OH) is common in multiple system atrophy (MSA) and Parkinson disease (PD), generally assessed through a lying-to-standing orthostatic test. However, standing blood pressure may not be available due to orthostatic intolerance or immobilization for such patients. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were successively measured in supine, sitting, and standing positions in patients with MSA and PD. Receiver operating characteristic analysis was used to evaluate diagnostic performance of the drops of sitting SBP or DBP. OH and severe OH were respectively regarded as “gold standard”. The drops of SBP in standing position were associated with increased disease severity for MSA and correlated with age for PD. In MSA group, drops in sitting SBP ≥ 14 mmHg or DBP ≥ 6 mmHg had highest validity for prediction of OH, and drops in sitting SBP ≥ 18 mmHg or DBP ≥ 8 mmHg for severe OH. In PD group, drops in sitting SBP ≥ 10 mmHg or DBP ≥ 6 mmHg had highest validity for prediction of OH. The lying-to-sitting orthostatic test is an alternative method for detection of OH in MSA and PD, especially when standing BP could not be validly measured due to various reasons. PMID:26867507

Distinctive Features of NREM Parasomnia Behaviors in Parkinson’s Disease and Multiple System Atrophy

PubMed Central

Ratti, Pietro-Luca; Sierra-Peña, Maria; Manni, Raffaele; Simonetta-Moreau, Marion; Bastin, Julien; Mace, Harrison; Rascol, Olivier; David, Olivier

2015-01-01

Objective To characterize parasomnia behaviors on arousal from NREM sleep in Parkinson’s Disease (PD) and Multiple System Atrophy (MSA). Methods From 30 patients with PD, Dementia with Lewy Bodies/Dementia associated with PD, or MSA undergoing nocturnal video-polysomnography for presumed dream enactment behavior, we were able to select 2 PD and 2 MSA patients featuring NREM Parasomnia Behviors (NPBs). We identified episodes during which the subjects seemed to enact dreams or presumed dream-like mentation (NPB arousals) versus episodes with physiological movements (no-NPB arousals). A time-frequency analysis (Morlet Wavelet Transform) of the scalp EEG signals around each NPB and no- NPB arousal onset was performed, and the amplitudes of the spectral frequencies were compared between NPB and no-NPB arousals. Results 19 NPBs were identified, 12 of which consisting of ‘elementary’ NPBs while 7 resembling confusional arousals. With quantitative EEG analysis, we found an amplitude reduction in the 5-6 Hz band 40 seconds before NPBs arousal as compared to no-NPB arousals at F4 and C4 derivations (p<0.01). Conclusions Many PD and MSA patients feature various NREM sleep-related behaviors, with clinical and electrophysiological differences and similarities with arousal parasomnias in the general population. Significance This study help bring to attention an overlooked phenomenon in neurodegenerative diseases. PMID:25756280

Disparate cardio-cerebral vascular modulation during standing in multiple system atrophy and Parkinson disease.

PubMed

Xu, Wei-Hai; Wang, Han; Wang, Bo; Niu, Fu-Sheng; Gao, Shan; Cui, Li-Ying

2009-01-15

The dynamic variance of cerebral blood flow velocity (CBFV), monitored by transcranial doppler (TCD), can reveal the integrated effects of cardio-cerebral vascular autoregulation. We investigated the characteristics of CBFV curve during active standing in multiple system atrophy (MSA), Parkinson's disease (PD) and healthy volunteers. The CBFV curve of middle cerebral arteries was recorded using TCD in 22 patients with probable MSA; 20 PD patients and 20 volunteers matched for age. All individuals started in a supine posture, followed by abrupt standing for 2 min before returning to supine. The features of CBFV curve were compared among the groups. In the healthy volunteers, the CBFV decreased following standing up but quickly rebounded and reached the same or greater level as the supine baseline. Afterwards, the CBFV decreased abruptly to a sustained level, lower than the supine baseline, forming a spike wave that appeared in CBFV curve. This spike wave was present in 5/22 of MSA, significantly less than PD patients (18/20) and volunteers (20/20) (P<0.001). The CBFV decrease after standing showed no significant difference between MSA than PD (9+/-7 vs. 6+/-3 cm/s, P=0.163). The different pattern of CBFV curves during active standing suggests MSA may possess cardio-cerebral vascular modulation different from PD. The clinical value of the CBFV curve in differentiating MSA from PD needs further investigation.

Therapeutic advances in multiple system atrophy and progressive supranuclear palsy.

PubMed

Poewe, Werner; Mahlknecht, Philipp; Krismer, Florian

2015-09-15

Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are relentlessly progressive neurodegenerative diseases leading to severe disability and ultimately death within less than 10 y. Despite increasing efforts in basic and clinical research, effective therapies for these atypical parkinsonian disorders are lacking. Although earlier small clinical studies in MSA and PSP mainly focused on symptomatic treatment, advances in the understanding of the molecular underpinnings of these diseases and in the search for biomarkers have paved the way for the first large and well-designed clinical trials aiming at disease modification. Targets of intervention in these trials have included α-synuclein inclusion pathology in the case of MSA and tau-related mechanisms in PSP. Since 2013, four large randomized, placebo-controlled, double-blind disease-modification trials have been completed and published, using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All of these failed to demonstrate signal efficacy with regard to the primary outcome measures. In addition, two randomized, placebo-controlled, double-blind trials have studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial. This review summarizes the design and the outcomes of these and other smaller trials published since 2013 and attempts to highlight priority areas of future therapeutic research in MSA and PSP. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.

Spatial patterns of progressive brain volume loss after moderate-severe traumatic brain injury

PubMed Central

Jolly, Amy; de Simoni, Sara; Bourke, Niall; Patel, Maneesh C; Scott, Gregory; Sharp, David J

2018-01-01

Abstract Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of MRI. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions; and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 patients with moderate-severe traumatic brain injury (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (1-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterized using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarized regionally and compared with clinical and neuropsychological measures. Patients with traumatic brain injury showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over 1 year was pronounced following traumatic brain injury. Patients with traumatic brain injury lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates were related to memory performance at the end of the follow-up period, as well as to changes in memory performance, prior to multiple comparison correction. In conclusion, traumatic brain injury results in progressive loss of brain tissue volume, which continues for many years post-injury. Atrophy is most prominent in the white matter, but is also more pronounced in cortical sulci compared to gyri. These findings suggest the Jacobian determinant provides a method of quantifying brain atrophy following a traumatic brain injury and is informative in determining the long-term neurodegenerative effects after injury. Power calculations indicate that Jacobian determinant images are an efficient surrogate marker in clinical trials of neuroprotective therapeutics. PMID:29309542

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reed, S.A.; Senf, S.M.; Cornwell, E.W.

Research highlights: {yields} Independent inhibition of Foxo, IKK{alpha} and IKK{beta} activities does not alter muscle fiber size in weight bearing muscles. {yields} Inhibition of Foxo activity plus IKK{alpha} or IKK{beta} activities increases muscle fiber size. {yields} Independent inhibition of Foxo and IKK{beta} activities attenuates cast immobilization-induced muscle fiber atrophy. {yields} Disuse muscle fiber atrophy is abolished by inhibition of Foxo activity plus IKK{alpha} or IKK{beta} activities. -- Abstract: Two transcription factor families that are activated during multiple conditions of skeletal muscle wasting are nuclear factor {kappa}B (NF-{kappa}B) and forkhead box O (Foxo). There is clear evidence that both NF-{kappa}B andmore » Foxo activation are sufficient to cause muscle fiber atrophy and they are individually required for at least half of the fiber atrophy during muscle disuse, but there is no work determining the combined effect of inhibiting these factors during a physiological condition of muscle atrophy. Here, we determined whether inhibition of Foxo activation plus inhibition of NF-{kappa}B activation, the latter by blocking the upstream inhibitor of kappaB kinases (IKK{alpha} and IKK{beta}), would prevent muscle atrophy induced by 7 days of cast immobilization. Results were based on measurements of mean fiber cross-sectional area (CSA) from 72 muscles transfected with 5 different mutant expression plasmids or plasmid combinations. Immobilization caused a 47% decrease in fiber CSA in muscles injected with control plasmids. Fibers from immobilized muscles transfected with dominant negative (d.n.) IKK{alpha}-EGFP, d.n. IKK{beta}-EGFP or d.n. Foxo-DsRed showed a 22%, 57%, and 76% inhibition of atrophy, respectively. Co-expression of d.n. IKK{alpha}-EGFP and d.n. Foxo-DsRed significantly inhibited 89% of the immobilization-induced fiber atrophy. Similarly, co-expression of d.n. IKK{beta}-EGFP and d.n. Foxo-DsRed inhibited the immobilization-induced fiber atrophy by 95%. These findings demonstrate that the combined effects of inhibiting immobilization-induced NF-{kappa}B and Foxo transcriptional activity has an additive effect on preventing immobilization-induced atrophy, indicating that NF-{kappa}B and Foxo have a cumulative effect on atrophy signaling and/or atrophy gene expression.« less

Skeletal Muscle Pathophysiology: The Emerging Role of Spermine Oxidase and Spermidine

PubMed Central

Duranti, Guglielmo; Sabatini, Stefania; Ceci, Roberta; Mariottini, Paolo

2018-01-01

Skeletal muscle comprises approximately 40% of the total body mass. Preserving muscle health and function is essential for the entire body in order to counteract chronic diseases such as type II diabetes, cardiovascular diseases, and cancer. Prolonged physical inactivity, particularly among the elderly, causes muscle atrophy, a pathological state with adverse outcomes such as poor quality of life, physical disability, and high mortality. In murine skeletal muscle C2C12 cells, increased expression of the spermine oxidase (SMOX) enzyme has been found during cell differentiation. Notably, SMOX overexpression increases muscle fiber size, while SMOX reduction was enough to induce muscle atrophy in multiple murine models. Of note, the SMOX reaction product spermidine appears to be involved in skeletal muscle atrophy/hypertrophy. It is effective in reactivating autophagy, ameliorating the myopathic defects of collagen VI-null mice. Moreover, spermidine treatment, if combined with exercise, can affect D-gal-induced aging-related skeletal muscle atrophy. This review hypothesizes a role for SMOX during skeletal muscle differentiation and outlines its role and that of spermidine in muscle atrophy. The identification of new molecular pathways involved in the maintenance of skeletal muscle health could be beneficial in developing novel therapeutic lead compounds to treat muscle atrophy. PMID:29443878

Associations of religious behavior and experiences with extent of regional atrophy in the orbitofrontal cortex during older adulthood

PubMed Central

Hayward, R. David; Owen, Amy D.; Koenig, Harold G.; Steffens, David C.; Payne, Martha E.

2011-01-01

The orbitofrontal cortex (OFC) is a region of the brain that has been empirically linked with religious or spiritual activity, and atrophy in this region has been shown to contribute to serious mental illness in late life. This study used structural magnetic resonance imaging to examine the association between religious or spiritual factors and volume of the orbitalfrontal cortex (OFC). Change in the volume of participants’ left and right OFC was measured longitudinally over a period of two to eight years. Multiple linear regression analyses showed that religious or spiritual factors were related to extent of atrophy in the left OFC. Significantly less atrophy of the left OFC was observed in participants who reported a life-changing religious or spiritual experience during the course of the study, and in members of Protestant religious groups who reported being born-again when entering the study. Significantly greater atrophy of the left OFC was also associated with more frequent participation in public religious worship. No significant relationship was observed between religious or spiritual factors and extent of atrophy in the right OFC. These results support the presence of a long-term relationship between religious or spiritual experience and brain structure, which may have clinical implications. PMID:22611519

Histone Deacetylase 6 Is a FoxO Transcription Factor-dependent Effector in Skeletal Muscle Atrophy*

PubMed Central

Ratti, Francesca; Ramond, Francis; Moncollin, Vincent; Simonet, Thomas; Milan, Giulia; Méjat, Alexandre; Thomas, Jean-Luc; Streichenberger, Nathalie; Gilquin, Benoit; Matthias, Patrick; Khochbin, Saadi; Sandri, Marco; Schaeffer, Laurent

2015-01-01

Skeletal muscle atrophy is a severe condition of muscle mass loss. Muscle atrophy is caused by a down-regulation of protein synthesis and by an increase of protein breakdown due to the ubiquitin-proteasome system and autophagy activation. Up-regulation of specific genes, such as the muscle-specific E3 ubiquitin ligase MAFbx, by FoxO transcription factors is essential to initiate muscle protein ubiquitination and degradation during atrophy. HDAC6 is a particular HDAC, which is functionally related to the ubiquitin proteasome system via its ubiquitin binding domain. We show that HDAC6 is up-regulated during muscle atrophy. HDAC6 activation is dependent on the transcription factor FoxO3a, and the inactivation of HDAC6 in mice protects against muscle wasting. HDAC6 is able to interact with MAFbx, a key ubiquitin ligase involved in muscle atrophy. Our findings demonstrate the implication of HDAC6 in skeletal muscle wasting and identify HDAC6 as a new downstream target of FoxO3a in stress response. This work provides new insights in skeletal muscle atrophy development and opens interesting perspectives on HDAC6 as a valuable marker of muscle atrophy and a potential target for pharmacological treatments. PMID:25516595

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

ClinicalTrials.gov

2017-09-28

Rare Disorders; Undiagnosed Disorders; Disorders of Unknown Prevalence; Cornelia De Lange Syndrome; Prenatal Benign Hypophosphatasia; Perinatal Lethal Hypophosphatasia; Odontohypophosphatasia; Adult Hypophosphatasia; Childhood-onset Hypophosphatasia; Infantile Hypophosphatasia; Hypophosphatasia; Kabuki Syndrome; Bohring-Opitz Syndrome; Narcolepsy Without Cataplexy; Narcolepsy-cataplexy; Hypersomnolence Disorder; Idiopathic Hypersomnia Without Long Sleep Time; Idiopathic Hypersomnia With Long Sleep Time; Idiopathic Hypersomnia; Kleine-Levin Syndrome; Kawasaki Disease; Leiomyosarcoma; Leiomyosarcoma of the Corpus Uteri; Leiomyosarcoma of the Cervix Uteri; Leiomyosarcoma of Small Intestine; Acquired Myasthenia Gravis; Addison Disease; Hyperacusis (Hyperacousis); Juvenile Myasthenia Gravis; Transient Neonatal Myasthenia Gravis; Williams Syndrome; Lyme Disease; Myasthenia Gravis; Marinesco Sjogren Syndrome(Marinesco-Sjogren Syndrome); Isolated Klippel-Feil Syndrome; Frasier Syndrome; Denys-Drash Syndrome; Beckwith-Wiedemann Syndrome; Emanuel Syndrome; Isolated Aniridia; Beckwith-Wiedemann Syndrome Due to Paternal Uniparental Disomy of Chromosome 11; Beckwith-Wiedemann Syndrome Due to Imprinting Defect of 11p15; Beckwith-Wiedemann Syndrome Due to 11p15 Translocation/Inversion; Beckwith-Wiedemann Syndrome Due to 11p15 Microduplication; Beckwith-Wiedemann Syndrome Due to 11p15 Microdeletion; Axenfeld-Rieger Syndrome; Aniridia-intellectual Disability Syndrome; Aniridia - Renal Agenesis - Psychomotor Retardation; Aniridia - Ptosis - Intellectual Disability - Familial Obesity; Aniridia - Cerebellar Ataxia - Intellectual Disability; Aniridia - Absent Patella; Aniridia; Peters Anomaly - Cataract; Peters Anomaly; Potocki-Shaffer Syndrome; Silver-Russell Syndrome Due to Maternal Uniparental Disomy of Chromosome 11; Silver-Russell Syndrome Due to Imprinting Defect of 11p15; Silver-Russell Syndrome Due to 11p15 Microduplication; Syndromic Aniridia; WAGR Syndrome; Wolf-Hirschhorn Syndrome; 4p16.3 Microduplication Syndrome; 4p Deletion Syndrome, Non-Wolf-Hirschhorn Syndrome; Autosomal Recessive Stickler Syndrome; Stickler Syndrome Type 2; Stickler Syndrome Type 1; Stickler Syndrome; Mucolipidosis Type 4; X-linked Spinocerebellar Ataxia Type 4; X-linked Spinocerebellar Ataxia Type 3; X-linked Intellectual Disability - Ataxia - Apraxia; X-linked Progressive Cerebellar Ataxia; X-linked Non Progressive Cerebellar Ataxia; X-linked Cerebellar Ataxia; Vitamin B12 Deficiency Ataxia; Toxic Exposure Ataxia; Unclassified Autosomal Dominant Spinocerebellar Ataxia; Thyroid Antibody Ataxia; Sporadic Adult-onset Ataxia of Unknown Etiology; Spinocerebellar Ataxia With Oculomotor Anomaly; Spinocerebellar Ataxia With Epilepsy; Spinocerebellar Ataxia With Axonal Neuropathy Type 2; Spinocerebellar Ataxia Type 8; Spinocerebellar Ataxia Type 7; Spinocerebellar Ataxia Type 6; Spinocerebellar Ataxia Type 5; Spinocerebellar Ataxia Type 4; Spinocerebellar Ataxia Type 37; Spinocerebellar Ataxia Type 36; Spinocerebellar Ataxia Type 35; Spinocerebellar Ataxia Type 34; Spinocerebellar Ataxia Type 32; Spinocerebellar Ataxia Type 31; Spinocerebellar Ataxia Type 30; Spinocerebellar Ataxia Type 3; Spinocerebellar Ataxia Type 29; Spinocerebellar Ataxia Type 28; Spinocerebellar Ataxia Type 27; Spinocerebellar Ataxia Type 26; Spinocerebellar Ataxia Type 25; Spinocerebellar Ataxia Type 23; Spinocerebellar Ataxia Type 22; Spinocerebellar Ataxia Type 21; Spinocerebellar Ataxia Type 20; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia Type 19/22; Spinocerebellar Ataxia Type 18; Spinocerebellar Ataxia Type 17; Spinocerebellar Ataxia Type 16; Spinocerebellar Ataxia Type 15/16; Spinocerebellar Ataxia Type 14; Spinocerebellar Ataxia Type 13; Spinocerebellar Ataxia Type 12; Spinocerebellar Ataxia Type 11; Spinocerebellar Ataxia Type 10; Spinocerebellar Ataxia Type 1 With Axonal Neuropathy; Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia - Unknown; Spinocerebellar Ataxia - Dysmorphism; Non Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Spectrin-associated Autosomal Recessive Cerebellar Ataxia; Spasticity-ataxia-gait Anomalies Syndrome; Spastic Ataxia With Congenital Miosis; Spastic Ataxia - Corneal Dystrophy; Spastic Ataxia; Rare Hereditary Ataxia; Rare Ataxia; Recessive Mitochondrial Ataxia Syndrome; Progressive Epilepsy and/or Ataxia With Myoclonus as a Major Feature; Posterior Column Ataxia - Retinitis Pigmentosa; Post-Stroke Ataxia; Post-Head Injury Ataxia; Post Vaccination Ataxia; Polyneuropathy - Hearing Loss - Ataxia - Retinitis Pigmentosa - Cataract; Muscular Atrophy - Ataxia - Retinitis Pigmentosa - Diabetes Mellitus; Non-progressive Cerebellar Ataxia With Intellectual Disability; Non-hereditary Degenerative Ataxia; Paroxysmal Dystonic Choreathetosis With Episodic Ataxia and Spasticity; Olivopontocerebellar Atrophy - Deafness; NARP Syndrome; Myoclonus - Cerebellar Ataxia - Deafness; Multiple System Atrophy, Parkinsonian Type; Multiple System Atrophy, Cerebellar Type; Multiple System Atrophy; Maternally-inherited Leigh Syndrome; Machado-Joseph Disease Type 3; Machado-Joseph Disease Type 2; Machado-Joseph Disease Type 1; Lethal Ataxia With Deafness and Optic Atrophy; Leigh Syndrome; Leukoencephalopathy With Mild Cerebellar Ataxia and White Matter Edema; Leukoencephalopathy - Ataxia - Hypodontia - Hypomyelination; Leigh Syndrome With Nephrotic Syndrome; Leigh Syndrome With Leukodystrophy; Leigh Syndrome With Cardiomyopathy; Late-onset Ataxia With Dementia; Intellectual Disability-hyperkinetic Movement-truncal Ataxia Syndrome; Infection or Post Infection Ataxia; Infantile-onset Autosomal Recessive Nonprogressive Cerebellar Ataxia; Infantile Onset Spinocerebellar Ataxia; GAD Ataxia; Hereditary Episodic Ataxia; Gliadin/Gluten Ataxia; Friedreich Ataxia; Fragile X-associated Tremor/Ataxia Syndrome; Familial Paroxysmal Ataxia; Exposure to Medications Ataxia; Episodic Ataxia With Slurred Speech; Episodic Ataxia Unknown Type; Episodic Ataxia Type 7; Episodic Ataxia Type 6; Episodic Ataxia Type 5; Episodic Ataxia Type 4; Episodic Ataxia Type 3; Episodic Ataxia Type 1; Epilepsy and/or Ataxia With Myoclonus as Major Feature; Early-onset Spastic Ataxia-neuropathy Syndrome; Early-onset Progressive Neurodegeneration - Blindness - Ataxia - Spasticity; Early-onset Cerebellar Ataxia With Retained Tendon Reflexes; Early-onset Ataxia With Dementia; Childhood-onset Autosomal Recessive Slowly Progressive Spinocerebellar Ataxia; Dilated Cardiomyopathy With Ataxia; Cataract - Ataxia - Deafness; Cerebellar Ataxia, Cayman Type; Cerebellar Ataxia With Peripheral Neuropathy; Cerebellar Ataxia - Hypogonadism; Cerebellar Ataxia - Ectodermal Dysplasia; Cerebellar Ataxia - Areflexia - Pes Cavus - Optic Atrophy - Sensorineural Hearing Loss; Brain Tumor Ataxia; Brachydactyly - Nystagmus - Cerebellar Ataxia; Benign Paroxysmal Tonic Upgaze of Childhood With Ataxia; Autosomal Recessive Syndromic Cerebellar Ataxia; Autosomal Recessive Spastic Ataxia With Leukoencephalopathy; Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay; Autosomal Recessive Spastic Ataxia - Optic Atrophy - Dysarthria; Autosomal Recessive Spastic Ataxia; Autosomal Recessive Metabolic Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to Repeat Expansions That do Not Encode Polyglutamine; Autosomal Recessive Ataxia, Beauce Type; Autosomal Recessive Ataxia Due to Ubiquinone Deficiency; Autosomal Recessive Ataxia Due to PEX10 Deficiency; Autosomal Recessive Degenerative and Progressive Cerebellar Ataxia; Autosomal Recessive Congenital Cerebellar Ataxia Due to MGLUR1 Deficiency; Autosomal Recessive Congenital Cerebellar Ataxia Due to GRID2 Deficiency; Autosomal Recessive Congenital Cerebellar Ataxia; Autosomal Recessive Cerebellar Ataxia-pyramidal Signs-nystagmus-oculomotor Apraxia Syndrome; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to WWOX Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to TUD Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to KIAA0226 Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome; Autosomal Recessive Cerebellar Ataxia With Late-onset Spasticity; Autosomal Recessive Cerebellar Ataxia Due to STUB1 Deficiency; Autosomal Recessive Cerebellar Ataxia Due to a DNA Repair Defect; Autosomal Recessive Cerebellar Ataxia - Saccadic Intrusion; Autosomal Recessive Cerebellar Ataxia - Psychomotor Retardation; Autosomal Recessive Cerebellar Ataxia - Blindness - Deafness; Autosomal Recessive Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to a Polyglutamine Anomaly; Autosomal Dominant Spinocerebellar Ataxia Due to a Point Mutation; Autosomal Dominant Spinocerebellar Ataxia Due to a Channelopathy; Autosomal Dominant Spastic Ataxia Type 1; Autosomal Dominant Spastic Ataxia; Autosomal Dominant Optic Atrophy; Ataxia-telangiectasia Variant; Ataxia-telangiectasia; Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy; Autosomal Dominant Cerebellar Ataxia Type 4; Autosomal Dominant Cerebellar Ataxia Type 3; Autosomal Dominant Cerebellar Ataxia Type 2; Autosomal Dominant Cerebellar Ataxia Type 1; Autosomal Dominant Cerebellar Ataxia; Ataxia-telangiectasia-like Disorder; Ataxia-intellectual Disability-oculomotor Apraxia-cerebellar Cysts Syndrome; Ataxia-deafness-intellectual Disability Syndrome; Ataxia With Vitamin E Deficiency; Ataxia With Dementia; Ataxia Neuropathy Spectrum; Ataxia - Tapetoretinal Degeneration; Ataxia - Photosensitivity - Short Stature; Ataxia - Pancytopenia; Ataxia - Oculomotor Apraxia Type 1; Ataxia - Hypogonadism - Choroidal Dystrophy; Ataxia - Other; Ataxia - Genetic Diagnosis - Unknown; Acquired Ataxia; Adult-onset Autosomal Recessive Cerebellar Ataxia; Alcohol Related Ataxia; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type II; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Multiple Endocrine Neoplasia, Type IV; Multiple Endocrine Neoplasia, Type 3; Multiple Endocrine Neoplasia (MEN) Syndrome; Multiple Endocrine Neoplasia Type 2B; Multiple Endocrine Neoplasia Type 2A; Atypical Hemolytic Uremic Syndrome; Atypical HUS; Wiedemann-Steiner Syndrome; Breast Implant-Associated Anaplastic Large Cell Lymphoma; Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA); Hemophagocytic Lymphohistiocytosis; Behcet's Disease

The coeliac stomach: gastritis in patients with coeliac disease.

PubMed

Lebwohl, B; Green, P H R; Genta, R M

2015-07-01

Lymphocytic gastritis (LG) is an uncommon entity with varying symptoms and endoscopic appearances. This condition, as well as two forms of H. pylori-negative gastritis [chronic active gastritis (CAG) and chronic inactive gastritis (CIG)], appears to be more common in patients with coeliac disease (CD) based on single-centred studies. To compare the prevalence of LG, CAG and CIG among those with normal duodenal histology (or nonspecific duodenitis) and those with CD, as defined by villous atrophy (Marsh 3). We analysed all concurrent gastric and duodenal biopsy specimens submitted to a national pathology laboratory during a 6-year period. We performed multiple logistic regression to identify independent predictors of each gastritis subtype. Among patients who underwent concurrent gastric and duodenal biopsy (n = 287,503), the mean age was 52 and the majority (67%) were female. Compared to patients with normal duodenal histology, LG was more common in partial villous atrophy (OR: 37.66; 95% CI: 30.16-47.03), and subtotal/total villous atrophy (OR: 78.57; 95% CI: 65.37-94.44). CD was also more common in CAG (OR for partial villous atrophy 1.93; 95% CI: 1.49-2.51, OR for subtotal/total villous atrophy 2.42; 95% CI: 1.90-3.09) and was similarly associated with CIG (OR for partial villous atrophy 2.04; 95% CI: 1.76-2.35, OR for subtotal/total villous atrophy 2.96; 95% CI: 2.60-3.38). Lymphocytic gastritis is strongly associated with coeliac disease, with increasing prevalence correlating with more advanced villous atrophy. Chronic active gastritis and chronic inactive gastritis are also significantly associated with coeliac disease. Future research should measure the natural history of these conditions after treatment with a gluten-free diet. © 2015 John Wiley & Sons Ltd.

The Coeliac Stomach: Gastritis in Patients with Coeliac Disease

PubMed Central

Lebwohl, Benjamin; Green, Peter HR; Genta, Robert M.

2015-01-01

Background Lymphocytic gastritis (LG) is an uncommon entity with varying symptoms and endoscopic appearances. This condition, as well as two forms of H. pylori-negative gastritis (chronic active gastritis [CAG] and chronic inactive gastritis [CIG]), appears to be more common in patients with coeliac disease (CD) based on single-center studies. Aim To compare the prevalence of LG, CAG, and CIG among those with normal duodenal histology (or non-specific duodenitis) and those with CD, as defined by villous atrophy (Marsh 3). Methods We analyzed all concurrent gastric and duodenal biopsy specimens submitted to a national pathology laboratory during a six-year period. We performed multiple logistic regression to identify independent predictors of each gastritis subtype. Results Among patients who underwent concurrent gastric and duodenal biopsy (n=287,503), the mean age was 52 and the majority (67%) was female. Compared to patients with normal duodenal histology, LG was more common inpartial villous atrophy (OR 37.66; 95% CI 30.16–47.03), and subtotal/total villous atrophy (OR 78.57; 95% CI 65.37–94.44). CD was also more common in CAG (OR for partial villous atrophy 1.93; 95%CI 1.49–2.51, OR for subtotal/total villous atrophy 2.42; 95%CI 1.90–3.09) and was similarly associated with CIG (OR for partial villous atrophy 2.04; 95%CI 1.76–2.35, OR for subtotal/total villous atrophy 2.96; 95% CI 2.60–3.38). Conclusion LG is strongly associated with CD, with increasing prevalence correlating with more advanced villous atrophy. CAG and CIG are also significantly associated with CD. Future researchshould measure the natural history of these conditions after treatment with a gluten-free diet. PMID:25973720

Nuclear microscopy in Parkinson's disease

NASA Astrophysics Data System (ADS)

Watt, F.; Lee, T.; Thong, P. S. P.; Tang, S. M.

1995-09-01

Rats have been subjected to unilateral lesioning with the selective neurotoxin 6-OHDA in order to induce Parkinsonism. Analysis using the NUS Nuclear Microscope facility have shown that iron levels are raised by an average of 26% in the lesioned subtantia nigra region of the brain compared with the non-lesioned side. In addition the background tissue level of iron is also elevated by 31% in the lesioned side, indicating that there is a general increase in iron levels as a result of the lesioning. This result is consistent with the other observations that other diseases of the brain are frequently associated with altered iron levels (eg. progressive nuclear palsy, multiple system atrophy, Alzheimers disease, multiple sclerosis).

Deep gray matter volume loss drives disability worsening in multiple sclerosis

PubMed Central

Prados, Ferran; Brownlee, Wallace J.; Altmann, Daniel R.; Tur, Carmen; Cardoso, M. Jorge; De Angelis, Floriana; van de Pavert, Steven H.; Cawley, Niamh; De Stefano, Nicola; Stromillo, M. Laura; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A.; Rovira, Alex; Sastre‐Garriga, Jaume; Vrenken, Hugo; Leurs, Cyra E.; Killestein, Joep; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Wheeler‐Kingshott, Claudia A.M. Gandini; Chard, Declan; Thompson, Alan J.; Alexander, Daniel C.; Barkhof, Frederik; Ciccarelli, Olga

2018-01-01

Objective Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Methods We analyzed 3,604 brain high‐resolution T1‐weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing‐remitting [RRMS], 128 secondary‐progressive [SPMS], and 125 primary‐progressive [PPMS]), over an average follow‐up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow‐up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time‐to‐EDSS progression. Results SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time‐to‐EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow‐up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (–1.45%), PPMS (–1.66%), and RRMS (–1.34%) than CIS (–0.88%) and HCs (–0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (–1.21%) was significantly faster than RRMS (–0.76%), CIS (–0.75%), and HCs (–0.51%). Similarly, the rate of parietal GM atrophy in SPMS (–1.24‐%) was faster than CIS (–0.63%) and HCs (–0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001). Interpretation This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210–222 PMID:29331092

Distinct neurochemical profiles of spinocerebellar ataxias 1, 2, 6, and cerebellar multiple system atrophy.

PubMed

Oz, Gülin; Iltis, Isabelle; Hutter, Diane; Thomas, William; Bushara, Khalaf O; Gomez, Christopher M

2011-06-01

Hereditary and sporadic neurodegenerative ataxias are movement disorders that affect the cerebellum. Robust and objective biomarkers are critical for treatment trials of ataxias. In addition, such biomarkers may help discriminate between ataxia subtypes because these diseases display substantial overlap in clinical presentation and conventional MRI. Profiles of 10-13 neurochemical concentrations obtained in vivo by high field proton magnetic resonance spectroscopy ((1)H MRS) can potentially provide ataxia-type specific biomarkers. We compared cerebellar and brainstem neurochemical profiles measured at 4 T from 26 patients with spinocerebellar ataxias (SCA1, N = 9; SCA2, N = 7; SCA6, N = 5) or cerebellar multiple system atrophy (MSA-C, N = 5) and 15 age-matched healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA) was used to assess disease severity. The patterns of neurochemical alterations relative to controls differed between ataxia types. Myo-inositol levels in the vermis, myo-inositol, total N-acetylaspartate, total creatine, glutamate, glutamine in the cerebellar hemispheres and myo-inositol, total N-acetylaspartate, glutamate in the pons were significantly different between patient groups (Bonferroni corrected p < 0.05). The best MRS predictors were selected by a tree classification procedure and lead to 89% accurate classification of all subjects while the SARA scores overlapped considerably between patient groups. Therefore, this study demonstrated multiple neurochemical alterations in SCAs and MSA-C relative to controls and the potential for these neurochemical levels to differentiate ataxia types. Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high-field MRS as ataxia biomarkers.

Distinct Neurochemical Profiles of Spinocerebellar Ataxias 1, 2, 6, and Cerebellar Multiple System Atrophy

PubMed Central

Öz, Gülin; Iltis, Isabelle; Hutter, Diane; Thomas, William; Bushara, Khalaf O.; Gomez, Christopher M.

2011-01-01

Hereditary and sporadic neurodegenerative ataxias are movement disorders that affect the cerebellum. Robust and objective biomarkers are critical for treatment trials of ataxias. In addition, such biomarkers may help discriminate between ataxia subtypes because these diseases display substantial overlap in clinical presentation and conventional MRI. Profiles of 10–13 neurochemical concentrations obtained in vivo by high field proton magnetic resonance spectroscopy (1H MRS) can potentially provide ataxia-type specific biomarkers. We compared cerebellar and brainstem neurochemical profiles measured at 4 T from 26 patients with spinocerebellar ataxias (SCA1, N=9; SCA2, N=7; SCA6, N=5) or cerebellar multiple system atrophy (MSA-C, N=5) and 15 age-matched healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA) was used to assess disease severity. The patterns of neurochemical alterations relative to controls differed between ataxia types. Myo-inositol levels in the vermis, myo-inositol, total N-acetylaspartate, total creatine, glutamate, glutamine in the cerebellar hemispheres and myo-inositol, total N-acetylaspartate, glutamate in the pons were significantly different between patient groups (Bonferroni corrected p<0.05). The best MRS predictors were selected by a tree classification procedure and lead to 89% accurate classification of all subjects while the SARA scores overlapped considerably between patient groups. Therefore, this study demonstrated multiple neurochemical alterations in SCAs and MSA-C relative to controls and the potential for these neurochemical levels to differentiate ataxia types. Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high-field MRS as ataxia biomarkers. PMID:20838948

Cognitive Implications of Deep Gray Matter Iron in Multiple Sclerosis.

PubMed

Fujiwara, E; Kmech, J A; Cobzas, D; Sun, H; Seres, P; Blevins, G; Wilman, A H

2017-05-01

Deep gray matter iron accumulation is increasingly recognized in association with multiple sclerosis and can be measured in vivo with MR imaging. The cognitive implications of this pathology are not well-understood, especially vis-à-vis deep gray matter atrophy. Our aim was to investigate the relationships between cognition and deep gray matter iron in MS by using 2 MR imaging-based iron-susceptibility measures. Forty patients with multiple sclerosis (relapsing-remitting, n = 16; progressive, n = 24) and 27 healthy controls were imaged at 4.7T by using the transverse relaxation rate and quantitative susceptibility mapping. The transverse relaxation rate and quantitative susceptibility mapping values and volumes (atrophy) of the caudate, putamen, globus pallidus, and thalamus were determined by multiatlas segmentation. Cognition was assessed with the Brief Repeatable Battery of Neuropsychological Tests. Relationships between cognition and deep gray matter iron were examined by hierarchic regressions. Compared with controls, patients showed reduced memory ( P < .001) and processing speed ( P = .02) and smaller putamen ( P < .001), globus pallidus ( P = .002), and thalamic volumes ( P < .001). Quantitative susceptibility mapping values were increased in patients compared with controls in the putamen ( P = .003) and globus pallidus ( P = .003). In patients only, thalamus ( P < .001) and putamen ( P = .04) volumes were related to cognitive performance. After we controlled for volume effects, quantitative susceptibility mapping values in the globus pallidus ( P = .03; trend for transverse relaxation rate, P = .10) were still related to cognition. Quantitative susceptibility mapping was more sensitive compared with the transverse relaxation rate in detecting deep gray matter iron accumulation in the current multiple sclerosis cohort. Atrophy and iron accumulation in deep gray matter both have negative but separable relationships to cognition in multiple sclerosis. © 2017 by American Journal of Neuroradiology.

Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis.

PubMed

Hofstetter, Louis; Naegelin, Yvonne; Filli, Lukas; Kuster, Pascal; Traud, Stefan; Smieskova, Renata; Mueller-Lenke, Nicole; Kappos, Ludwig; Gass, Achim; Sprenger, Till; Penner, Iris-Katharina; Nichols, Thomas E; Vrenken, Hugo; Barkhof, Frederik; Polman, Chris; Radue, Ernst-Wilhelm; Borgwardt, Stefan J; Bendfeldt, Kerstin

2014-02-01

In multiple sclerosis (MS) regional grey matter (GM) atrophy has been associated with disability progression. The aim of this study was to compare regional GM volume changes in relapsing-remitting MS (RRMS) patients with progressive and stable disability, using voxel-based morphometry (VBM). We acquired baseline and 1-year follow-up 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI) data of RRMS patients, using two 1.5-Tesla scanners. Patients were matched pair-wise with respect to age, gender, disease duration, medication, scanner and baseline Expanded Disability Status Scale (EDSS) into 13 pairs, with either progressive EDSS (≥ 1 point change y(-1)) or stable EDSS, as well as into 29 pairs with either progressive Multiple Sclerosis Functional Composite (MSFC) at ≥ 0.25% decrease in y(-1) in any component, or stable MSFC. We analysed longitudinal regional differences in GM volumes in the progressive and stable EDSS and MSFC groups, respectively, using VBM. Significant GM volume reductions occurred in the right precuneus, in the progressive EDSS group. Differential between-group effects occurred in the right precuneus and in the postcentral gyrus. Further longitudinal GM volume reductions occurred in the right orbicular gyrus, in the progressive MSFC group, but no between-group differences were observed (non-stationary cluster-wise inference, all P(corrected) < 0.05). These results suggested a direct association of disability progression and regional GM atrophy in RRMS.

Deficits in memory and visuospatial learning correlate with regional hippocampal atrophy in MS.

PubMed

Longoni, Giulia; Rocca, Maria A; Pagani, Elisabetta; Riccitelli, Gianna C; Colombo, Bruno; Rodegher, Mariaemma; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo

2015-01-01

The hippocampus has a critical role in episodic memory and visuospatial learning and consolidation. We assessed the patterns of whole and regional hippocampal atrophy in a large group of multiple sclerosis (MS) patients, and their correlations with neuropsychological impairment. From 103 MS patients and 28 healthy controls (HC), brain dual-echo and high-resolution 3D T1-weighted images were acquired using a 3.0-Tesla scanner. All patients underwent a neuropsychological assessment of hippocampal-related cognitive functions, including Paired Associate Word Learning, Short Story, delayed recall of Rey-Osterrieth Complex Figure and Paced Auditory Serial Attention tests. The hippocampi were manually segmented and volumes derived. Regional atrophy distribution was assessed using a radial mapping analysis. Correlations between hippocampal atrophy and clinical, neuropsychological and MRI metrics were also evaluated. Hippocampal volume was reduced in MS patients vs HC (p < 0.001 for both right and hippocampus). In MS patients, radial atrophy affected CA1 subfield and subiculum of posterior hippocampus, bilaterally. The dentate hilus (DG:H) of the right hippocampal head was also affected. Regional hippocampal atrophy correlated with brain T2 and T1 lesion volumes, while no correlation was found with disability. Damage to the CA1 and subiculum was significantly correlated to the performances at hippocampal-targeted neuropsychological tests. These results show that hippocampal subregions have a different vulnerability to MS-related damage, with a relative sparing of the head of the left hippocampus. The assessment of regional hippocampal atrophy may help explain deficits of specific cognitive functions in MS patients, including memory and visuospatial abilities.

Extensive distribution of glial cytoplasmic inclusions in an autopsied case of multiple system atrophy with a prolonged 18-year clinical course.

PubMed

Masui, Kenta; Nakata, Yukako; Fujii, Naoki; Iwaki, Toru

2012-02-01

We describe herein an autopsied case of multiple system atrophy (MSA) with prolonged clinical course of 18 years, and evaluate the extent of neurodegeneration and glial cytoplasmic inclusions (GCIs) in the entire brain of this rare case. A 64-year-old woman presented with typical neurological symptoms and imaging features of MSA. Thereafter, she became bedridden, and breathing was assisted through a tracheostomy for 12 years. She died at the age of 82 after 18 years from the initial symptom. Post mortem examination revealed severe neurodegeneration in the inferior olive, pontine nuclei, substantia nigra, locus ceruleus, putamen and cerebellum. Notably, phosphorylated α-synuclein (p-α-syn)-positive GCIs were found in these areas, but their number was very low. In contrast, the density of GCIs was much higher in such regions as the tectum/tegmentum of the brainstem, pyramidal tracts, neocortices and limbic system, which usually contain a small number of GCIs. Another constituent of GCIs, ubiquitin (Ub) and Ub-associated autophagy substrate p62, were also positive in some GCIs, and distribution of Ub/p62 immunoreactivity was proportionate to that of p-α-syn+ GCIs despite the very long duration of the disease. Furthermore, this case had complicated hypoxic encephalopathy, but p-α-syn+ GCIs were also found in the damaged white matter, indicating the contribution of α-syncleinopathy as well as hypoxic effect to the secondary myelin and axonal loss in the white matter. Together, this rare case suggests the contribution of the disease duration to the prevalence of GCIs, and the possible involvement of the limbic system in extensive-stage disease. © 2011 Japanese Society of Neuropathology.

Baroreflex buffering and susceptibility to vasoactive drugs

NASA Technical Reports Server (NTRS)

Jordan, Jens; Tank, Jens; Shannon, John R.; Diedrich, Andre; Lipp, Axel; Schroder, Christoph; Arnold, Guy; Sharma, Arya M.; Biaggioni, Italo; Robertson, David;

Bone Marrow-Derived Mesenchymal Stem Cell Therapy as a Candidate Disease-Modifying Strategy in Parkinson's Disease and Multiple System Atrophy

PubMed Central

Park, Hyun Jung

2009-01-01

Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases representative of α-synucleinopathies characterized pathologically by α-synuclein-abundant Lewy bodies and glial cytoplasmic inclusions, respectively. Embryonic stem cells, fetal mesencephalic neurons, and neural stem cells have been introduced as restorative strategies in PD animals and patients, but ethical and immunological problems as well as the serious side effects of tumorigenesis and disabling dyskinesia have limited clinical application of these stem cells. Meanwhile, cell therapy using mesenchymal stem cells (MSCs) is attractive clinically because these cells are free from ethical and immunological problems. MSCs are present in adult bone marrow and represent <0.01% of all nucleated bone marrow cells. MSCs are themselves capable of multipotency, differentiating under appropriate conditions into chondrocytes, skeletal myocytes, and neurons. According to recent studies, the neuroprotective effect of MSCs is mediated by their ability to produce various trophic factors that contribute to functional recovery, neuronal cell survival, and stimulation of endogenous regeneration and by immunoregulatory properties that not only inhibit nearly all cells participating in the immune response cell-cell-contact-dependent mechanism, but also release various soluble factors associated with immunosuppressive activity. However, the use of MSCs as neuroprotectives in PD and MSA has seldom been studied. Here we comprehensively review recent advances in the therapeutic roles of MSCs in PD and MSA, especially focusing on their neuroprotective properties and use in disease-modifying therapeutic strategies. PMID:19513327

Leukocyte glutamate dehydrogenase activity in patients with degenerative neurological disorders.

PubMed Central

Aubby, D; Saggu, H K; Jenner, P; Quinn, N P; Harding, A E; Marsden, C D

1988-01-01

Leukocyte glutamate dehydrogenase (GDH) activity was measured in 39 normal subjects, 32 neurological controls, 66 patients with progressive ataxic disorders, 32 with multiple system atrophy, 40 with Parkinson's disease, eight with Steele-Richardson-Olszewski syndrome, eight with juvenile Parkinsonism and four with the dystonia-Parkinsonism syndrome. GDH activity was reproducible to within 10% in leukocyte pellets stored at -70 degrees C for up to 9 months, and did not vary with sex or age in control subjects. There was marked variation in the relative proportions of heat stable and heat labile forms of GDH between control subjects and on repeated assay in the same subject. Total leukocyte GDH activity was similar in normal subjects and neurological controls. Mean total GDH activity was reduced in all patient groups by between 15 to 29% compared with controls. Fourteen patients had total GDH activity below 50% of the control mean, but low values were not specific for any one disease (five had ataxic disorders, four Parkinson's disease, three multiple system atrophy, one juvenile Parkinsonism, and one dystonia-Parkinsonism). The heat labile fraction of GDH represented about 20% of total activity in control subjects, and 27% in the patients with reduced total GDH activity. Thus low GDH activity was not disease-specific in this study, and the heat-labile GDH fraction was not selectively affected. "Reduced" leucocyte GDH activity in some patients may represent no more than the lower end of a normal distribution. PMID:3204397

Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death.

PubMed

Reimer, Lasse; Vesterager, Louise Buur; Betzer, Cristine; Zheng, Jin; Nielsen, Lærke Dalsgaard; Kofoed, Rikke Hahn; Lassen, Louise Berkhoudt; Bølcho, Ulrik; Paludan, Søren Riis; Fog, Karina; Jensen, Poul Henning

2018-07-01

Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy comprise a group of neurodegenerative diseases termed synucleinopathies. Synucleinopathie are, characterized by presence of inclusion bodies in degenerating brain cells which contain aggregated α-synuclein phosphorylated on Ser129. Although the inflammation-associated serine-threonine kinase, PKR (EIF2AK2), promotes cellular protection against infection, we demonstrate a pro-degenerative role of activated PKR in an α-synuclein-dependent cell model of multiple system atrophy, where inhibition and silencing of PKR decrease cellular degeneration. In vitro phosphorylation demonstrates that PKR can directly bind and phosphorylate monomeric and filamenteous α-synuclein on Ser129. Inhibition and knockdown of PKR reduce Ser129 phosphorylation in different models (SH-SY5Y ASYN cells, OLN-AS7 cells, primary mouse hippocampal neurons, and acute brain slices), while overexpression of constitutively active PKR increases Ser129 α-syn phosphorylation. Treatment with pre-formed α-synuclein fibrils, proteostatic stress-promoting MG-132 and known PKR activators, herpes simplex virus-1-∆ICP34.5 and LPS, as well as PKR inducer, IFN-β-1b, lead to increased levels of phosphorylated Ser129 α-synuclein that is completely blocked by simultaneous PKR inhibition. These results reveal a direct link between PKR and the phosphorylation and toxicity of α-synuclein, and they support that neuroinflammatory processes play a role in modulating the pathogenicity of α-synuclein. Copyright © 2018 Elsevier Inc. All rights reserved.

Reduced orexin immunoreactivity in Perry syndrome and multiple system atrophy.

PubMed

Mishima, Takayasu; Kasanuki, Koji; Koga, Shunsuke; Castanedes-Casey, Monica; Wszolek, Zbigniew K; Tsuboi, Yoshio; Dickson, Dennis W

2017-09-01

Orexin is a neuropeptide that plays a key role in maintaining a state of arousal, and possibly associates with sleep apnea syndrome (SAS). Reduced orexin immunoreactivity has been reported in various neurologic conditions such as narcolepsy, Alzheimer's disease, Lewy body disease and multiple system atrophy (MSA); however, there has been no report investigating orexin in Perry syndrome, a rare hereditary neurodegenerative disease characterized by four clinical cardinal signs (parkinsonism, depression/apathy, weight loss, and central hypoventilation). Perry syndrome patients frequently have sleep disturbances, including SAS and insomnia. We evaluated orexin immunoreactivity in Perry syndrome. Using imaging analysis, we quantitatively assessed orexin immunoreactivity in the nucleus basalis of Meynert in three Perry syndrome cases, as well as five cases of frontotemporal lobar degeneration with motor neuron disease, five cases of MSA and five age-matched controls. For these cases, antemortem clinical information on sleep disturbances has been reviewed. In Perry syndrome and MSA, there was reduction of orexin immunoreactivity compared with controls (Perry syndrome: p = 0.020, MSA: p < 0.001). In contrast, FTLD-MND did not have significant reduction of orexin immunoreactivity. Two out of three cases of Perry syndrome had SAS confirmed by polysomnography. This is the first report assessing orexin immunoreactivity in Perry syndrome, and it showed significant reduction, similar to select neurodegenerative diseases, such as MSA. Further analysis with more cases will be needed to elucidate the specific mechanism of orexin loss in these disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Diagnosis of multiple system atrophy.

PubMed

Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

2018-05-01

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Association between serum uric acid level and multiple system atrophy: A meta-analysis.

PubMed

Zhang, Xi; Liu, De-Shan; An, Chun-Yao; Liu, Yu-Zhao; Liu, Xiao-Hong; Zhang, Fang; Ning, Lu-Ning; Li, Chang-Ling; Ma, Chun-Mei; Hu, Rui-Ting

2018-06-01

Lower serum uric acid (UA) levels are considered to be related to the risk to develop many neurodegenerative disorders. However, the association between serum UA level and multiple system atrophy (MSA) remains controversial. The aim of this meta-analysis was to evaluate the relationship between serum UA level and MSA. PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched for eligible studies. Standardized mean difference (SMD) and 95% confidence intervals (95% CI) were calculated in a fixed-effects model or a random-effects model when appropriate. Subgroup analyses were carried out based on gender. A total of 6 eligible studies involving 547 MSA patients and 637 healthy individuals were identified. Meta-analysis results revealed that individuals with MSA had lower sera levels of UA as compared with healthy controls (pooled SMD is -0.51, 95%CI: -0.88 to -0.14; p = 0.006). The subgroup analysis to detect sex differences showed that the pooled SMD was -0.61 (95% CI: -0.82 to -0.40; p < 0.0001) for males and -0.22 (95% CI: -0.55 to 0.10; p = 0.18) for females compared with healthy controls. Our meta-analysis revealed that lower serum level of UA is associated with an increased risk of MSA and the relationship is significant in men but not in women. Copyright © 2018 Elsevier B.V. All rights reserved.

Physiological and functional failure in chronic obstructive pulmonary disease, congestive heart failure and cancer: a debilitating intersection of sarcopenia, cachexia and breathlessness.

PubMed

Dudgeon, Deborah; Baracos, Vickie E

2016-09-01

Loss of skeletal muscle mass and cachexia are important manifestations of chronic obstructive pulmonary disease and have been associated with breathlessness, functional limitation and poor prognosis. A number of other life-limiting illnesses, including cancer and chronic heart failure as well as acute conditions seen in ICU such as sepsis, are characteristically associated with cachexia and sarcopenia. These conditions may have respiratory muscle atrophy of sufficient magnitude to contribute to the development of breathlessness and associated functional limitation. The purpose of this review is to summarize findings related to a direct role for severe respiratory muscle wasting in the etiology of breathlessness in advanced, life limiting illness. Localized wasting of respiratory muscles appears to be part of systemic wasting of skeletal muscles, driven by deconditioning, nutritional insufficiencies and inflammation, and because of disease-specific factors (tumor factors and exacerbations), anabolic insufficiency, autonomic dysfunction, drugs (such as corticosteroids and chemotherapy agents), mechanical ventilation and comorbidities. Marked morphological and biochemical abnormalities have been noted in diaphragm muscle biopsies. Older patients with multiple comorbidities associated with muscle loss and cachexia are likely to be at elevated risk of respiratory muscle atrophy and functional loss, because of the presence of multiple, interacting etiologic factors.

A rare case of short stature: Say Meyer syndrome.

PubMed

Karthik, T S; Prasad, N Rajendra; Rani, P Radha; Maheshwari, Rushikesh; Reddy, P Amaresh; Chakradhar, B V S; Menon, Bindu

2013-10-01

Say Meyer syndrome is rare X linked condition characterized by developmental delay, short stature and metopic suture synostosis. We are reporting a case of Say Meyer syndrome presented to our hospital for short stature and developmental delay at age 3½ years. A 3½-year-old boy presented to our hospital for decreased growth velocity from the age of 1 year. History revealed the boy had a birth weight of 2.3 kg, had an episode of seizures in the neonatal period. He was born to non-consanguineous marriage. He had global developmental delay and there was a lack of bowel and bladder control. History did not reveal any hearing or visual impairment. No history of any chronic systemic illnesses. Magnetic resonance imaging (MRI) brain revealed mild diffuse frontotemporal atrophy with multiple irregular gliotic areas in bilateral frontal lobes. Diffuse white matter volume loss in bilateral cerebral hemispheres. Diffuse thinning of corpus callosum. Diffuse periventricular hyper intensity on T2W and fluid attenuated inversion recovery sequences. Say Meyer syndrome is rare X linked condition characterized by developmental delay, short stature and metopic suture synostosis. Characteristic MRI brain findings include diffuse frontotemporal atrophy with multiple gliotic areas in frontal lobes. Diffuse white matter volume loss in bilateral cerebral hemispheres.

Grey matter damage in progressive multiple sclerosis versus amyotrophic lateral sclerosis: a voxel-based morphometry MRI study.

PubMed

Tavazzi, Eleonora; Laganà, Maria Marcella; Bergsland, Niels; Tortorella, Paola; Pinardi, Giovanna; Lunetta, Christian; Corbo, Massimo; Rovaris, Marco

2015-03-01

Primary progressive multiple sclerosis (PPMS) and amyotrophic lateral sclerosis (ALS) seem to share some clinical and pathological features. MRI studies revealed the presence of grey matter (GM) atrophy in both diseases, but no comparative data are available. The objective was to compare the regional patterns of GM tissue loss in PPMS and ALS with voxel-based morphometry (VBM). Eighteen PPMS patients, 20 ALS patients, and 31 healthy controls (HC) were studied with a 1.5 Tesla scanner. VBM was performed to assess volumetric GM differences with age and sex as covariates. Threshold-free cluster enhancement analysis was used to obtain significant clusters. Group comparisons were tested with family-wise error correction for multiple comparisons (p < 0.05) except for HC versus MND which was tested at a level of p < 0.001 uncorrected and a cluster threshold of 20 contiguous voxels. Compared to HC, ALS patients showed GM tissue reduction in selected frontal and temporal areas, while PPMS patients showed a widespread bilateral GM volume decrease, involving both deep and cortical regions. Compared to ALS, PPMS patients showed tissue volume reductions in both deep and cortical GM areas. This preliminary study confirms that PPMS is characterized by a more diffuse cortical and subcortical GM atrophy than ALS and that, in the latter condition, brain damage is present outside the motor system. These results suggest that PPMS and ALS may share pathological features leading to GM tissue loss.

Comparative analysis of Lacistema pubescens and dexamethasone on topical treatment of skin inflammation in a chronic disease model and side effects.

PubMed

da Silva, Josiane M; Conegundes, Jéssica L M; Pinto, Nícolas C C; Mendes, Renata F; Castañon, Maria Christina M N; Scio, Elita

2018-04-01

This study aimed to evaluate the chronic topical anti-inflammatory activity of the pharmaceutical formulation ProHLP containing the hexane fraction of Lacistema pubescens (HLP). It was also investigated the possible cutaneous and systemic adverse effects of HLP and ProHLP in mice when compared to dexamethasone. The chronic topical anti-inflammatory activity was determined by croton oil multiple application-induced mouse ear oedema model. Histopathological analyses of ear tissue samples sensitized with croton oil were performed. Cutaneous atrophy induced by HLP and topical glucocorticoid treatments and excision skin wounds model to evidenced possible adverse reactions were also determined. ProHLP significantly reduced the mice ear oedema and considerably accelerated the wound-healing process. Also, HLP did not lead cutaneous atrophy and preserved the clinical aspect of the thymus, adrenal and spleen, unlike dexamethasone. The results suggested that ProHLP is an efficient and safer pharmaceutical formulation to treat chronic inflammatory diseases. © 2018 Royal Pharmaceutical Society.

Localized atrophy of the thalamus and slowed cognitive processing speed in MS patients.

PubMed

Bergsland, Niels; Zivadinov, Robert; Dwyer, Michael G; Weinstock-Guttman, Bianca; Benedict, Ralph Hb

2016-09-01

Deep gray matter (DGM) atrophy is common in multiple sclerosis (MS), but no studies have investigated surface-based structure changes over time with respect to healthy controls (HCs). Moreover, the relationship between cognition and the spatio-temporal evolution of DGM atrophy is poorly understood. To explore DGM structural differences between MS and HCs over time in relation to neuropsychological (NP) outcomes. The participants were 44 relapsing-remitting and 20 secondary progressive MS patients and 22 HCs. All were scanned using 3T magnetic resonance imaging (MRI) at baseline and 3-year follow-up. NP examination emphasized consensus standard tests of processing speed and memory. We performed both volumetric and shape analysis of DGM structures and assessed their relationships with cognition. Compared to HCs, MS patients presented with significantly smaller DGM volumes. For the thalamus and caudate, differences in shape were mostly localized along the lateral ventricles. NP outcomes were related to both volume and shape of the DGM structures. Over 3 years, decreased cognitive processing speed was related to localized atrophy on the anterior and superior surface of the left thalamus. These findings highlight the role of atrophy in the anterior nucleus of the thalamus and its relation to cognitive decline in MS. © The Author(s), 2015.

99mTc-d,l-HMPAO and SPECT of the brain in normal aging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waldemar, G.; Hasselbalch, S.G.; Andersen, A.R.

1991-05-01

Single photon emission computed tomography (SPECT) with 99mTc-d,l-hexamethylpropyleneamine oxime (99mTc-d,l-HMPAO) was used to determine global and regional CBF in 53 healthy subjects aged 21-83 years. For the whole group, global CBF normalized to the cerebellum was 86.4% +/- 8.4 (SD). The contribution of age, sex, and atrophy to variations in global CBF was studied using stepwise multiple regression analysis. There was a significant negative correlation of global CBF with subjective ratings of cortical atrophy, but not with ratings of ventricular size, Evans ratio, sex, or age. In a subgroup of 33 subjects, in whom volumetric measurements of atrophy were performed,more » cortical atrophy was the only significant determinant for global CBF, accounting for 27% of its variance. Mean global CBF as measured with the 133Xe inhalation technique and SPECT was 54 +/- 9 ml/100 g/min and did not correlate significantly with age. There was a preferential decline of CBF in the frontal cortex with advancing age. The side-to-side asymmetry of several regions of interest increased with age. A method was described for estimation of subcortical CBF, which decreased with advancing cortical atrophy. The relative area of the subcortical low-flow region increased with age. These results are useful in distinguishing the effects of age and simple atrophy from disease effects, when the 99mTc-d,l-HMPAO method is used.« less

Abdominal rectus muscle atrophy and midline shift after colostomy creation.

PubMed

Timmermans, Lucas; Deerenberg, Eva B; van Dijk, Sven M; Lamme, Bas; Koning, Anton H; Kleinrensink, Gert-Jan; Jeekel, Johannes; Lange, Johan F

2014-04-01

Incisional hernia (IH) can be attributed to multiple factors. The presence of a parastomal hernia has shown to be a risk factor for IH after midline laparotomy. Our hypothesis is that this increased risk of IH may be caused by changes in biomechanical forces, such as midline shift to the contralateral side of the colostomy owing to decreased restraining forces at the site of the colostomy, and left abdominal rectus muscle (ARM) atrophy owing to intercostal nerve damage. Patients were selected if they underwent end-colostomy via open operation between 2004 and 2011. Patients were eligible if computed tomography (CT) had been performed postoperatively. If available, preoperative CTs were collected for case-control analyses. Midline shift was measured using V-scope application in the I-space, a CAVE-like virtual reality system. For the ARM atrophy hypothesis, measurements of ARM were performed at the level of colostomy, and 3 and 8 cm cranial and caudal of the colostomy. Postoperative CT were available for 77 patients; of these patients, 30 also had a preoperative CT. Median follow-up was 19 months. A mean shift to the right side was identified after preoperative and postoperative comparison; from -1.3 ± 4.6 to 2.1 ± 9.3 (P = .043). Furthermore, during rectus muscle measurements, a thinner left ARM was observed below the level of colostomy. Creation of a colostomy alters the abdominal wall. Atrophy of the left ARM was seen caudal to the level of the colostomy, and a midline shift to the right side was evident on CT. These changes may explain the increased rate of IH after colostomy creation. Copyright © 2014 Mosby, Inc. All rights reserved.

Hypogravity-induced atrophy of rat soleus and extensor digitorum longus muscles

NASA Technical Reports Server (NTRS)

Riley, D. A.; Ellis, S.; Slocum, G. R.; Satyanarayana, T.; Bain, J. L.; Sedlak, F. R.

1987-01-01

Prolonged exposure of humans to hypogravity causes weakening of their skeletal muscles. This problem was studied in rats exposed to hypogravity for 7 days aboard Spacelab 3. Hindlimb muscles were harvested 12-16 hours postflight for histochemical, biochemical, and ultrastructural analyses. The majority of the soleus and extensor digitorum longus fibers exhibited simple cell shrinkage. However, approximately 1% of the fibers in flight soleus muscles appeared necrotic. Flight muscle fibers showed increased glycogen, lower subsarcolemmal staining for mitochondrial enzymes, and fewer subsarcolemmal mitochondria. During atrophy, myofibrils were eroded by multiple focal losses of myofilaments; lysosomal autophagy was not evident. Tripeptidylaminopeptidase and calcium-activated protease activities of flight soleus fibers were significantly increased, implying a role in myofibril breakdown. Simple fiber atrophy appears to account for muscle weakening during spaceflight, but fiber necrosis is also a contributing factor.

Femoral neuropathy due to patellar dislocation in a theatrical and jazz dancer: a case report.

PubMed

Shin, Chris S; Davis, Brian A

2005-06-01

This case report describes a teenage female, high-level modern dancer who suffered multiple left patellar dislocations. Her history is atypical in that after her fifth dislocation, her recovery was hindered secondary to persistent weakness and atrophy of her quadriceps out of proportion to disuse alone. Electrodiagnostic studies and magnetic resonance imaging showed evidence of a subacute femoral neuropathy correlating chronologically with her most recent patellar dislocation. This case suggests that further diagnostic study may be warranted in patients with persistent quadriceps weakness or atrophy after a patellar dislocation, because this may suggest the presence of a femoral neuropathy. This is important because the strength training goals and precautions differ in disuse atrophy and a neuropathy. We believe this is the first reported case of a femoral neuropathy associated with the mechanism of a patellar dislocation.

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study

PubMed Central

Geerlings, Mirjam I.; Sigurdsson, Sigurdur; Eiriksdottir, Gudny; Garcia, Melissa E.; Harris, Tamara B.; Sigurdsson, Thordur; Gudnason, Vilmundur; Launer, Lenore J.

2014-01-01

Background To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. Methods Within the population-based AGES-Reykjavik Study 4,354 persons (mean age 76±5 years, 58% women) without dementia had a 1.5Tesla brain MRI. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the MINI International Neuropsychiatric Interview. Results Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy (B=−1.25%; 95%CI −2.05 to −0.44%), including more gray and white matter atrophy in most lobes as well as more atrophy of the hippocampus and thalamus. Participants with current, first onset, MDD also had more brain atrophy (B=−1.62%; 95%CI −3.30 to 0.05%), while those remitted did not (B=0.06%; 95%CI −0.54 to 0.66%). Conclusion In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD, was associated with widespread gray and white matter brain atrophy. Prospective studies should examine whether MDD is a consequence of or contributes to brain volume loss and development of dementia. PMID:22647536

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study.

PubMed

Geerlings, M I; Sigurdsson, S; Eiriksdottir, G; Garcia, M E; Harris, T B; Sigurdsson, T; Gudnason, V; Launer, L J

2013-02-01

To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. Within the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 4354 persons (mean age 76 ± 5 years, 58% women) without dementia had a 1.5-T brain magnetic resonance imaging (MRI) scan. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview (MINI). Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy [B = -1.25%, 95% confidence interval (CI) -2.05 to -0.44], including more gray- and white-matter atrophy in most lobes, and also more atrophy of the hippocampus and thalamus. Participants with current, first-onset MDD also had more brain atrophy (B = -1.62%, 95% CI -3.30 to 0.05) whereas those remitted did not (B = 0.06%, 95% CI -0.54 to 0.66). In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD was associated with widespread gray- and white-matter brain atrophy. Prospective studies should examine whether MDD is a consequence of, or contributes to, brain volume loss and development of dementia.

[REM sleep behavior disorders in Parkinson's disease].

PubMed

Liashenko, E A; Poluéktov, M G; Levin, O S

2014-01-01

The article presents a literature review on REM sleep behavior disorder (RBD). The loss of REM atonia of sleep, such that patients act out the contents of their dreams, is described. The most important implication of research into this area is that patients with idiopathic RBD are at very high risk of developing synuclein-mediated neurodegenerative disease (Parkinson's disease, dementia with Lewy bodies and multiple system atrophy), with risk estimates that approximate 40-65% at 10 years. Thus, RBD is a reliable marker of prodromal synucleinopathy that open possibilities for neuroprotective therapy.

4H Leukodystrophy: A Brain Magnetic Resonance Imaging Scoring System.

PubMed

Vrij-van den Bos, Suzanne; Hol, Janna A; La Piana, Roberta; Harting, Inga; Vanderver, Adeline; Barkhof, Frederik; Cayami, Ferdy; van Wieringen, Wessel N; Pouwels, Petra J W; van der Knaap, Marjo S; Bernard, Geneviève; Wolf, Nicole I

2017-06-01

4H (hypomyelination, hypodontia and hypogonadotropic hypogonadism) leukodystrophy (4H) is an autosomal recessive hypomyelinating white matter (WM) disorder with neurologic, dental, and endocrine abnormalities. The aim of this study was to develop and validate a magnetic resonance imaging (MRI) scoring system for 4H. A scoring system (0-54) was developed to quantify hypomyelination and atrophy of different brain regions. Pons diameter and bicaudate ratio were included as measures of cerebral and brainstem atrophy, and reference values were determined using controls. Five independent raters completed the scoring system in 40 brain MRI scans collected from 36 patients with genetically proven 4H. Interrater reliability (IRR) and correlations between MRI scores, age, gross motor function, gender, and mutated gene were assessed. IRR for total MRI severity was found to be excellent (intraclass correlation coefficient: 0.87; 95% confidence interval: 0.80-0.92) but varied between different items with some (e.g., myelination of the cerebellar WM) showing poor IRR. Atrophy increased with age in contrast to hypomyelination scores. MRI scores (global, hypomyelination, and atrophy scores) significantly correlated with clinical handicap ( p  < 0.01 for all three items) and differed between the different genotypes. Our 4H MRI scoring system reliably quantifies hypomyelination and atrophy in patients with 4H, and MRI scores reflect clinical disease severity. Georg Thieme Verlag KG Stuttgart · New York.

Reduced modulation of scanpaths in response to task demands in posterior cortical atrophy.

PubMed

Shakespeare, Timothy J; Pertzov, Yoni; Yong, Keir X X; Nicholas, Jennifer; Crutch, Sebastian J

2015-02-01

A difficulty in perceiving visual scenes is one of the most striking impairments experienced by patients with the clinico-radiological syndrome posterior cortical atrophy (PCA). However whilst a number of studies have investigated perception of relatively simple experimental stimuli in these individuals, little is known about multiple object and complex scene perception and the role of eye movements in posterior cortical atrophy. We embrace the distinction between high-level (top-down) and low-level (bottom-up) influences upon scanning eye movements when looking at scenes. This distinction was inspired by Yarbus (1967), who demonstrated how the location of our fixations is affected by task instructions and not only the stimulus' low level properties. We therefore examined how scanning patterns are influenced by task instructions and low-level visual properties in 7 patients with posterior cortical atrophy, 8 patients with typical Alzheimer's disease, and 19 healthy age-matched controls. Each participant viewed 10 scenes under four task conditions (encoding, recognition, search and description) whilst eye movements were recorded. The results reveal significant differences between groups in the impact of test instructions upon scanpaths. Across tasks without a search component, posterior cortical atrophy patients were significantly less consistent than typical Alzheimer's disease patients and controls in where they were looking. By contrast, when comparing search and non-search tasks, it was controls who exhibited lowest between-task similarity ratings, suggesting they were better able than posterior cortical atrophy or typical Alzheimer's disease patients to respond appropriately to high-level needs by looking at task-relevant regions of a scene. Posterior cortical atrophy patients had a significant tendency to fixate upon more low-level salient parts of the scenes than controls irrespective of the viewing task. The study provides a detailed characterisation of scene perception abilities in posterior cortical atrophy and offers insights into the mechanisms by which high-level cognitive schemes interact with low-level perception. Copyright © 2015 Elsevier Ltd. All rights reserved.

Impairment of visuospatial/visuoconstructional skills in multiple sclerosis patients: the correlation with regional lesion load and subcortical atrophy.

PubMed

Marasescu, R; Cerezo Garcia, M; Aladro Benito, Y

2016-04-01

About 20% to 26% of patients with multiple sclerosis (MS) show alterations in visuospatial/visuoconstructive (VS-VC) skills even though temporo-parieto-occipital impairment is a frequent finding in magnetic resonance imaging. No studies have specifically analysed the relationship between these functions and lesion volume (LV) in these specific brain areas. To evaluate the relationship between VS-VC impairment and magnetic resonance imaging temporo-parieto-occipital LV with subcortical atrophy in patients with MS. Of 100 MS patients undergoing a routine neuropsychological evaluation, 21 were selected because they displayed VS-VC impairments in the following tests: Incomplete picture, Block design (WAIS-III), and Rey-Osterrieth complex figure test. We also selected 13 MS patients without cognitive impairment (control group). Regional LV was measured in FLAIR and T1-weighted images using a semiautomated method; subcortical atrophy was measured by bicaudate ratio and third ventricle width. Partial correlations (controlling for age and years of school) and linear regression analysis were employed to analyse correlations between magnetic resonance imaging parameters and cognitive performance. All measures of LV and brain atrophy were significantly higher in patients with cognitive impairment. Regional LV, bicaudate ratio, and third ventricle width are significantly and inversely correlated with cognitive performance; the strongest correlation was between third ventricle width and VC performance (Block design: P=.001; Rey-Osterrieth complex figure: P<.000). In the multivariate analysis, third ventricle width only had a significant effect on performance of VC tasks (Block design: P=.000; Rey-Osterrieth complex figure: P=.000), and regional FLAIR VL was linked to the VS task (Incomplete picture; P=.002). Measures of subcortical atrophy explain the variations in performance on visuocostructive tasks, and regional FLAIR VL measures are linked to VS tasks. Copyright © 2015 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Localized grey matter damage in early primary progressive multiple sclerosis contributes to disability.

PubMed

Khaleeli, Z; Cercignani, M; Audoin, B; Ciccarelli, O; Miller, D H; Thompson, A J

2007-08-01

Disability in primary progressive multiple sclerosis (PPMS) has been correlated with damage to the normal appearing brain tissues. Magnetization transfer ratio (MTR) and volume changes indicate that much of this damage occurs in the normal appearing grey matter, but the clinical significance of this remains uncertain. We aimed to localize these changes to distinct grey matter regions, and investigate the clinical impact of the MTR changes. 46 patients with early PPMS and 23 controls underwent MT and high-resolution T1-weighted imaging. Patients were scored on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite and subtests (Nine-Hole Peg Test, Timed Walk Test, Paced Auditory Serial Addition Test [PASAT]). Grey matter volume and MTR were compared between patients and controls, adjusting for age. Mean MTR for significant regions within the motor network and in areas relevant to PASAT performance were correlated with appropriate clinical scores, adjusting for grey matter volume. Patients showed reduced MTR and atrophy in the right pre- and left post-central gyri, right middle frontal gyrus, left insula, and thalamus bilaterally. Reduced MTR without significant atrophy occurred in the left pre-central gyrus, left superior frontal gyri, bilateral superior temporal gyri, right insula and visual cortex. Higher EDSS correlated with lower MTR in the right primary motor cortex (BA 4). In conclusion, localized grey matter damage occurs in early PPMS, and MTR change is more widespread than atrophy. Damage demonstrated by reduced MTR is clinically eloquent.

Gray matter trophism, cognitive impairment, and depression in patients with multiple sclerosis.

PubMed

Pravatà, Emanuele; Rocca, Maria A; Valsasina, Paola; Riccitelli, Gianna C; Gobbi, Claudio; Comi, Giancarlo; Falini, Andrea; Filippi, Massimo

2017-12-01

Cognitive impairment and depression frequently affects patients with multiple sclerosis (MS). However, the relationship between the occurrence of depression and cognitive impairment and the development of cortical atrophy has not been fully elucidated yet. To investigate the association of cortical and deep gray matter (GM) volume with depression and cognitive impairment in MS. Three-dimensional (3D) T1-weighted scans were obtained from 126 MS patients and 59 matched healthy controls. Cognitive impairment was assessed using the Brief Repeatable Battery of Neuropsychological Tests and depression with the Montgomery-Asberg Depression Rating Scale (MADRS). Using FreeSurfer and FIRST software, we assessed cortical thickness (CTh) and deep GM volumetry. Magnetic resonance imaging (MRI) variables explaining depression and cognitive impairment were investigated using factorial and classification analysis. Multivariate regression models correlated GM abnormalities with symptoms severity. Compared with controls, MS patients exhibited widespread bilateral cortical thinning involving all brain lobes. Depressed MS showed selective CTh decrease in fronto-temporal regions, whereas cognitive impairment MS exhibited widespread fronto-parietal cortical and subcortical GM atrophy. Frontal cortical thinning was the best predictor of depression ( C-statistic = 0.7), whereas thinning of the right precuneus and high T2 lesion volume best predicted cognitive impairment ( C-statistic = 0.8). MADRS severity correlated with right entorhinal cortex thinning, whereas cognitive impairment severity correlated with left entorhinal and thalamus atrophy. MS-related depression is linked to circumscribed CTh changes in areas deputed to emotional behavior, whereas cognitive impairment is correlated with cortical and subcortical GM atrophy of circuits involved in cognition.

A novel ubiquitin-binding protein ZNF216 functioning in muscle atrophy

PubMed Central

Hishiya, Akinori; Iemura, Shun-ichiro; Natsume, Tohru; Takayama, Shinichi; Ikeda, Kyoji; Watanabe, Ken

2006-01-01

The ubiquitin–proteasome system (UPS) is critical for specific degradation of cellular proteins and plays a pivotal role on protein breakdown in muscle atrophy. Here, we show that ZNF216 directly binds polyubiquitin chains through its N-terminal A20-type zinc-finger domain and associates with the 26S proteasome. ZNF216 was colocalized with the aggresome, which contains ubiquitinylated proteins and other UPS components. Expression of Znf216 was increased in both denervation- and fasting-induced muscle atrophy and upregulated by expression of constitutively active FOXO, a master regulator of muscle atrophy. Mice deficient in Znf216 exhibited resistance to denervation-induced atrophy, and ubiquitinylated proteins markedly accumulated in neurectomized muscle compared to wild-type mice. These data suggest that ZNF216 functions in protein degradation via the UPS and plays a crucial role in muscle atrophy. PMID:16424905

Spinal Muscular Atrophy (SMA)

MedlinePlus

... kids of the same age or have trouble lifting things. Kids with SMA can develop scoliosis (a ... Nervous System Your Muscles Wheelchairs Scoliosis Steven's Story: Power Player Kyphosis Muscular Dystrophy Spinal Muscular Atrophy: Steven's ...

Feasibility and Efficacy of Intra‐Arterial Administration of Mesenchymal Stem Cells in an Animal Model of Double Toxin‐Induced Multiple System Atrophy

PubMed Central

Na Kim, Ha; Yeol Kim, Dong; Hee Oh, Se; Sook Kim, Hyung; Suk Kim, Kyung

2017-01-01

Abstract Multiple system atrophy (MSA) is a sporadic neurodegenerative disease of the central and autonomic nervous system. Because no drug treatment consistently benefits MSA patients, neuroprotective strategy using mesenchymal stem cells (MSCs) has a lot of concern for the management of MSA. In this study, we investigated the safety and efficacy of intra‐arterial administration of MSCs via internal carotid artery (ICA) in an animal model of MSA. The study was composed of feasibility test using a ×10 and ×50 of a standard dose of MSCs (4 × 107 MSCs) and efficacy test using a ×0.2, ×2, and ×20 of the standard dose. An ultrasonic flow meter and magnetic resonance imaging (MRI) showed that no cerebral ischemic lesions with patent ICA blood flow was were observed in animals receiving a ×10 of the standard dose of MSCs. However, no MSA animals receiving a ×50 of the standard dose survived. In efficacy test, animals injected with a ×2 of the standard dose increased nigrostriatal neuronal survival relative to a ×0.2 or ×20 of the standard dose. MSA animals receiving MSCs at ×0.2 and ×2 concentrations of the standard dose exhibited a significant reduction in rotation behavior relative to ×20 of the standard dose of MSCs. Cerebral ischemic lesions on MRI were only observed in MSA animals receiving a ×20 of the standard dose. The present study revealed that if their concentration is appropriate, intra‐arterial injection of MSCs is safe and exerts a neuroprotective effect on striatal and nigral neurons with a coincidental improvement in motor behavior. Stem Cells Translational Medicine 2017;6:1424–1433 PMID:28296268

'Prion-like' propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum.

PubMed

Sargent, Dorian; Verchère, Jérémy; Lazizzera, Corinne; Gaillard, Damien; Lakhdar, Latifa; Streichenberger, Nathalie; Morignat, Eric; Bétemps, Dominique; Baron, Thierry

2017-10-01

The M83 transgenic mouse is a model of human synucleinopathies that develops severe motor impairment correlated with accumulation of the pathological Ser129-phosphorylated α-synuclein (α-syn P ) in the brain and spinal cord. M83 disease can be accelerated by intracerebral inoculation of brain extracts from sick M83 mice. This has also recently been described using peripheral routes, injecting recombinant preformed α-syn fibrils into the muscle or the peritoneum. Here, we inoculated homozygous and/or hemizygous M83 neonates via the intraperitoneal and/or intracerebral routes with two different brain extracts: one from sick M83 mice inoculated with brain extract from other sick M83 mice, and the other derived from a human multiple system atrophy source passaged in M83 mice. Detection of α-syn P using ELISA and western blot confirmed the disease in mice. The distribution of α-syn P in the central nervous system was similar, independently of the inoculum or inoculation route, consistent with previous studies describing M83 disease. ELISA tests revealed higher levels of α-syn P in homozygous than in hemizygous sick M83 mice, at least after IC inoculation. Interestingly, the immunoreactivity of α-syn P detected by ELISA was significantly lower in M83 mice inoculated with the multiple system atrophy inoculum than in M83 mice inoculated with the M83 inoculum, at the first two passages. 'Prion-like' propagation of the synucleinopathy up to the clinical disease was accelerated by both intracerebral and intraperitoneal inoculations of brain extracts from sick mice. This acceleration, however, depends on the levels of α-syn expression by the mouse and the type of inoculum. © 2017 International Society for Neurochemistry.

Cytokine profiling in the prefrontal cortex of Parkinson's Disease and Multiple System Atrophy patients.

PubMed

Rydbirk, Rasmus; Elfving, Betina; Andersen, Mille Dahl; Langbøl, Mia Aggergaard; Folke, Jonas; Winge, Kristian; Pakkenberg, Bente; Brudek, Tomasz; Aznar, Susana

2017-10-01

Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are neurodegenerative diseases characterized neuropathologically by alpha-synuclein accumulation in brain cells. This accumulation is hypothesized to contribute to constitutive neuroinflammation, and to participate in the neurodegeneration. Cytokines, which are the main inflammatory signalling molecules, have been identified in blood and cerebrospinal fluid of PD patients, but studies investigating the human brain levels are scarce. It is documented that neurotrophins, necessary for survival of brain cells and known to interact with cytokines, are altered in the basal ganglia of PD patients. In regards to MSA, no major study has investigated brain cytokine or neurotrophin protein expression. Here, we measured protein levels of 18 cytokines (IL-2, 4-8, 10, 12, 13, 17, G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1α and 1β, TNF-α) and 5 neurotrophins (BDNF, GDNF, bFGF, PDGF-BB, VEGF) in the dorsomedial prefrontal cortex in brains of MSA and PD patients and control subjects. We found altered expression of IL-2, IL-13, and G-CSF, but no differences in neurotrophin levels. Further, in MSA patients we identified increased mRNA levels of GSK3β that is involved in neuroinflammatory pathways. Lastly, we identified increased expression of the neurodegenerative marker S100B, but not CRP, in PD and MSA patients, indicating local rather than systemic inflammation. Supporting this, in both diseases we observed increased MHC class II + and CD45 + positive cells, and low numbers of infiltrating CD3 + cells. In conclusion, we identified neuroinflammatory responses in PD and MSA which seems more widespread in the brain than neurotrophic changes. Copyright © 2017 Elsevier Inc. All rights reserved.

3D Maps from Multiple MRI Illustrate Changing Atrophy Patterns as Subjects Progress from MCI to AD

PubMed Central

Whitwell, Jennifer L; Przybelski, Scott; Weigand, Stephen D; Knopman, David S; Boeve, Bradley F; Petersen, Ronald C; Jack, Clifford R

2009-01-01

Summary Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to conversion to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately three years before conversion to AD, the second scan approximately one year before conversion, and the third scan at the time of conversion from aMCI to AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were three years before conversion was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were one year before conversion. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had converted to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least three years before conversion to AD. These results also suggest that 3-dimensional patterns of grey matter atrophy may help to predict the time to conversion in subjects with aMCI. PMID:17533169

Gray Matter Atrophy Is Primarily Related to Demyelination of Lesions in Multiple Sclerosis: A Diffusion Tensor Imaging MRI Study.

PubMed

Tóth, Eszter; Szabó, Nikoletta; Csete, Gergõ; Király, András; Faragó, Péter; Spisák, Tamás; Bencsik, Krisztina; Vécsei, László; Kincses, Zsigmond T

2017-01-01

Objective: Cortical pathology, periventricular demyelination, and lesion formation in multiple sclerosis (MS) are related (Hypothesis 1). Factors in the cerebrospinal fluid close to these compartments could possibly drive the parallel processes. Alternatively, the cortical atrophy could be caused by remote axonal transection (Hypothesis 2). Since MRI can differentiate between demyelination and axon loss, we used this imaging modality to investigate the correlation between the pattern of diffusion parameter changes in the periventricular- and deep white matter and the gray matter atrophy. Methods: High-resolution T1-weighted, FLAIR, and diffusion MRI images were acquired in 52 RRMS patients and 50 healthy, age-matched controls. We used EDSS to estimate the clinical disability. We used Tract Based Spatial Statistics to compare diffusion parameters (fractional anisotropy, mean, axial, and radial diffusivity) between groups. We evaluated global brain, white, and gray matter atrophy with SIENAX. Averaged, standard diffusion parameters were calculated in four compartment: periventricular lesioned and normal appearing white matter, non-periventricular lesioned and normal appearing white matter. PLS regression was used to identify which diffusion parameter and in which compartment best predicts the brain atrophy and clinical disability. Results: In our diffusion tensor imaging study compared to controls we found extensive alterations of fractional anisotropy, mean and radial diffusivity and smaller changes of axial diffusivity (maximal p > 0.0002) in patients that suggested demyelination in the lesioned and in the normal appearing white matter. We found significant reduction in total brain, total white, and gray matter (patients: 718.764 ± 14.968, 323.237 ± 7.246, 395.527 ± 8.050 cm 3 , controls: 791.772 ± 22.692, 355.350 ± 10.929, 436.422 ± 12.011 cm 3 ; mean ± SE), ( p < 0.015; p < 0.0001; p < 0.009; respectively) of patients compared to controls. The PLS analysis revealed a combination of demyelination-like diffusion parameters (higher mean and radial diffusivity in patients) in the lesions and in the non-lesioned periventricular white matter, which best predicted the gray matter atrophy ( p < 0.001). Similarly, EDSS was best predicted by the radial diffusivity of the lesions and the non-lesioned periventricular white matter, but axial diffusivity of the periventricular lesions also contributed significantly ( p < 0.0001). Interpretation: Our investigation showed that gray matter atrophy and white matter demyelination are related in MS but white matter axonal loss does not significantly contribute to the gray matter pathology.

Characterization of disuse skeletal muscle atrophy and the efficacy of a novel muscle atrophy countermeasure during spaceflight and simulated microgravity

NASA Astrophysics Data System (ADS)

Hanson, Andrea Marie

Humans are an integral part of the engineered systems that will enable return to the Moon and eventually travel to Mars. Major advancements in countermeasure development addressing deleterious effects of microgravity and reduced gravity on the musculoskeletal system need to be made to ensure mission safety and success. The primary objectives of this dissertation are to advance the knowledge and understanding of skeletal muscle atrophy, and support development of novel countermeasures for disuse atrophy to enable healthy long-duration human spaceflight. Models simulating microgravity and actual spaceflight were used to examine the musculoskeletal adaptations during periods of unloading. Myostatin inhibition, a novel anti-atrophy drug therapy, and exercise were examined as a means of preventing and recovering from disuse atrophy. A combination of assays was used to quantify adaptation responses to unloading and examine efficacy of the countermeasures. Body and muscle masses were collected to analyze systemic changes due to treatments. Hindlimb strength and individual muscle forces were measured to demonstrate functional adaptations to treatments. Muscle fiber morphology and myosin heavy chain (MHC) expression was examined to identify adaptations at the cellular level. Protein synthesis signals insulin-like growth factor-1 (IGF-1), Akt, and p70s6 kinase; and the degradation signals Atrogin-1 and MuRF-1 were examined to identify adaptations at the molecular level that ultimately lead to muscle hypertrophy and atrophy. A time course study provided a thorough characterization of the adaptation of skeletal muscle during unloading in C57BL/6 mice, and baseline data for comparison to and evaluation of subsequent studies. Time points defining the on-set and endpoints of disuse muscle atrophy were identified to enable characterization of rapid vs. long-term responses of skeletal muscle to hindlimb suspension. Unloading-induced atrophy primarily resulted from increased protein degradation at early time points that predominantly affected slow-twitch muscle fibers. A second study examined the use of exercise as a means of recovery from disuse atrophy. Contrary to previous reports, a short duration of exercise following disuse provided a functional benefit to contractile mechanisms and increased resistance to fatigue---possibly due to increased expression of fast-twitch fibers. Two additional studies examined the efficacy of a myostatin inhibitor in combination with hindlimb unloading and in spaceflight. Myostatin inhibition increased expression of markers within the muscle synthesis pathway in both models. The myostatin inhibitors were potent enough for the skeletal muscles to overcome the atrophying effects of musculoskeletal unloading as demonstrated by increased mass and strength. Myostatin inhibition is demonstrated to be a very promising and effective treatment for disuse muscle atrophy that may benefit astronauts and patients with muscle wasting diseases. This dissertation provides the first analyses of an unloading model in combination with a myostatin inhibitor as a countermeasure for skeletal muscle disuse atrophy while exploring the specific roles of muscle function, morphology, and translational signaling pathways.

Localized hippocampus measures are associated with Alzheimer pathology and cognition independent of total hippocampal volume.

PubMed

Carmichael, Owen; Xie, Jing; Fletcher, Evan; Singh, Baljeet; DeCarli, Charles

2012-06-01

Hippocampal injury in the Alzheimer's disease (AD) pathological process is region-specific and magnetic resonance imaging (MRI)-based measures of localized hippocampus (HP) atrophy are known to detect region-specific changes associated with clinical AD, but it is unclear whether these measures provide information that is independent of that already provided by measures of total HP volume. Therefore, this study assessed the strength of association between localized HP atrophy measures and AD-related measures including cerebrospinal fluid (CSF) amyloid beta and tau concentrations, and cognitive performance, in statistical models that also included total HP volume as a covariate. A computational technique termed localized components analysis (LoCA) was used to identify 7 independent patterns of HP atrophy among 390 semiautomatically delineated HP from baseline magnetic resonance imaging of participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Among cognitively normal participants, multiple measures of localized HP atrophy were significantly associated with CSF amyloid concentration, while total HP volume was not. In addition, among all participants, localized HP atrophy measures and total HP volume were both independently and additively associated with CSF tau concentration, performance on numerous neuropsychological tests, and discrimination between normal, mild cognitive impairment (MCI), and AD clinical diagnostic groups. Together, these results suggest that regional measures of hippocampal atrophy provided by localized components analysis may be more sensitive than total HP volume to the effects of AD pathology burden among cognitively normal individuals and may provide information about HP regions whose deficits may have especially profound cognitive consequences throughout the AD clinical course. Copyright © 2012 Elsevier Inc. All rights reserved.

[A case of an anti-Ma2 antibody-positive patient presenting with variable CNS symptoms mimicking multiple system atrophy with a partial response to immunotherapy].

PubMed

Shiraishi, Wataru; Iwanaga, Yasutaka; Yamamoto, Akifumi

2015-01-01

A 70-year-old man with a 5-month history of progressive bradykinesia of the bilateral lower extremities was admitted to our hospital. At the age of 64, he underwent proximal gastrectomy for gastric cancer. He also had a history of subacute combined degeneration of the spinal cord since the age of 67, which was successfully treated with vitamin B12 therapy. Four weeks before admission to our hospital, he admitted himself to his former hospital complaining of walking difficulty. Two weeks later, however, his symptoms progressed rapidly; he was immobilized for two weeks and did not respond to the vitamin therapy. On admission to our hospital, he showed moderate paralysis of the lower extremities, cog-wheel rigidity of the four extremities, and dystonic posture of his left hand. He also showed orthostatic hypotension and vesicorectal disorders. Blood examination and cerebrospinal fluid analysis revealed no remarkable abnormalities. Electroencephalography showed frontal dominant, high voltage, sharp waves. His brain and spinal MRI revealed no notable abnormalities. We suspected autoimmune disease and commenced one course of intravenous methylprednisolone therapy, resulting in improvement of the parkinsonism and orthostatic hypotension. Based on these results, we investigated possible neural antigens and detected anti-Ma2 antibody. In addition to limbic encephalitis, anti-Ma2 antibody-positive neural disorders are characterized by rapid eye movement sleep behavior disorders or parkinsonism. Here, we report an anti-Ma2 antibody positive patient presenting variable CNS symptoms mimicking multiple system atrophy, who responded to immunotherapy.

Speech disorders reflect differing pathophysiology in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy.

PubMed

Rusz, Jan; Bonnet, Cecilia; Klempíř, Jiří; Tykalová, Tereza; Baborová, Eva; Novotný, Michal; Rulseh, Aaron; Růžička, Evžen

2015-01-01

Although speech disorder is frequently an early and prominent clinical feature of Parkinson's disease (PD) as well as atypical parkinsonian syndromes (APS) such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), there is a lack of objective and quantitative evidence to verify whether any specific speech characteristics allow differentiation between PD, PSP and MSA. Speech samples were acquired from 77 subjects including 15 PD, 12 PSP, 13 MSA and 37 healthy controls. The accurate differential diagnosis of dysarthria subtypes was based on the quantitative acoustic analysis of 16 speech dimensions. Dysarthria was uniformly present in all parkinsonian patients but was more severe in PSP and MSA than in PD. Whilst PD speakers manifested pure hypokinetic dysarthria, ataxic components were more affected in MSA whilst PSP subjects demonstrated severe deficits in hypokinetic and spastic elements of dysarthria. Dysarthria in PSP was dominated by increased dysfluency, decreased slow rate, inappropriate silences, deficits in vowel articulation and harsh voice quality whereas MSA by pitch fluctuations, excess intensity variations, prolonged phonemes, vocal tremor and strained-strangled voice quality. Objective speech measurements were able to discriminate between APS and PD with 95% accuracy and between PSP and MSA with 75% accuracy. Dysarthria severity in APS was related to overall disease severity (r = 0.54, p = 0.006). Dysarthria with various combinations of hypokinetic, spastic and ataxic components reflects differing pathophysiology in PD, PSP and MSA. Thus, motor speech examination may provide useful information in the evaluation of these diseases with similar manifestations.

Serum creatinine is associated with the prevalence but not disease progression of multiple system atrophy in Chinese population.

PubMed

Cao, Bei; Guo, XiaoYan; Chen, Ke; Song, Wei; Huang, Rui; Wei, QianQian; Zhao, Bi; Shang, Hui-Fang

2016-03-01

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Creatine, which is converted to creatinine, has an anti-oxidative effect. Our aim is to clarify the correlations between creatinine and the occurrence as well as the progression of MSA. A total of 115 patients with probable MSA and 115 age- and gender-matched healthy controls were included in the study. The serum creatinine level of all patients and controls were evaluated and compared. The mean age of MSA patients was 58.18 ± 8.67 years and the mean disease duration was 2.85 ± 1.71 years. The creatinine level of MSA patients was significantly lower than that of healthy controls (P < 0.0001). The occurrence of MSA was decreased in the highest creatinine quartiles compared with the lowest creatinine quartiles. In a gender-specific analysis, patients with the highest quartiles and second quartiles of creatinine level had decreased occurrence than patients with the lowest quartile in females, but not in males. The serum level of creatinine was not found correlated with the mean rate of annualised changes, neither with other independent factors, such as age, body mass index (BMI), sex, Unified MSA Rating Scale (UMSARS) scores and disease duration at the initial visit in patients with MSA. High level of serum creatinine may be associated with a low occurrence of MSA in Chinese population, especially in female. However, serum creatinine does not deteriorate or ameliorate the progression of MSA.

Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure

NASA Technical Reports Server (NTRS)

Benarroch, E. E.; Smithson, I. L.; Low, P. A.; Parisi, J. E.

1998-01-01

The ventrolateral portion of the intermediate reticular formation of the medulla (ventrolateral medulla, VLM), including the C1/A1 groups of catecholaminergic neurons, is thought to be involved in control of sympathetic cardiovascular outflow, cardiorespiratory interactions, and reflex control of vasopressin release. As all these functions are affected in patients with multiple systems atrophy (MSA) with autonomic failure, we sought to test the hypothesis that catecholaminergic (tyrosine hydroxylase [TH]-positive) neurons of the VLM are depleted in these patients. Medullas were obtained at autopsy from 4 patients with MSA with prominent autonomic failure and 5 patients with no neurological disease. Patients with MSA had laboratory evidence of severe adrenergic sudomotor and cardiovagal failure. Tissue was immersion fixed in 2% paraformaldehyde at 4 degrees C for 24 hours and cut into 1-cm blocks in the coronal plane from throughout the medulla. Serial 50-microm sections were collected and one section every 300 microm was stained for TH. There was a pronounced depletion of TH neurons in the rostral VLM in all cases of MSA. There was also significant reduction of TH neurons in the caudal VLM in 3 MSA patients compared with 3 control subjects. In 2 MSA cases and in 2 control subjects, the thoracic spinal cord was available for study. There was also depletion of TH fibers and sympathetic preganglionic neurons (SPNs) in the 2 MSA cases examined. Thus, depletion of catecholaminergic neurons in the VLM may provide a substrate for some of the autonomic and endocrine manifestations of MSA.

Stress-induced brain activity, brain atrophy, and clinical disability in multiple sclerosis

PubMed Central

Weygandt, Martin; Meyer-Arndt, Lil; Behrens, Janina Ruth; Wakonig, Katharina; Bellmann-Strobl, Judith; Ritter, Kerstin; Scheel, Michael; Brandt, Alexander U.; Labadie, Christian; Hetzer, Stefan; Gold, Stefan M.; Paul, Friedemann; Haynes, John-Dylan

2016-01-01

Prospective clinical studies support a link between psychological stress and multiple sclerosis (MS) disease severity, and peripheral stress systems are frequently dysregulated in MS patients. However, the exact link between neurobiological stress systems and MS symptoms is unknown. To evaluate the link between neural stress responses and disease parameters, we used an arterial-spin–labeling functional MRI stress paradigm in 36 MS patients and 21 healthy controls. Specifically, we measured brain activity during a mental arithmetic paradigm with performance-adaptive task frequency and performance feedback and related this activity to disease parameters. Across all participants, stress increased heart rate, perceived stress, and neural activity in the visual, cerebellar and insular cortex areas compared with a resting condition. None of these responses was related to cognitive load (task frequency). Consistently, although performance and cognitive load were lower in patients than in controls, stress responses did not differ between groups. Insula activity elevated during stress compared with rest was negatively linked to impairment of pyramidal and cerebral functions in patients. Cerebellar activation was related negatively to gray matter (GM) atrophy (i.e., positively to GM volume) in patients. Interestingly, this link was also observed in overlapping areas in controls. Cognitive load did not contribute to these associations. The results show that our task induced psychological stress independent of cognitive load. Moreover, stress-induced brain activity reflects clinical disability in MS. Finally, the link between stress-induced activity and GM volume in patients and controls in overlapping areas suggests that this link cannot be caused by the disease alone. PMID:27821732

Affective symptoms in multiple system atrophy and Parkinson's disease: response to levodopa therapy

PubMed Central

Fetoni, V; Soliveri, P; Monza, D; Testa, D; Girotti, F

1999-01-01

The objective was to determine the extent to which psychiatric disturbances (especially mood disorders) generally considered poor prognostic factors, are present in patients with striatonigral (SND) type multiple system atrophy (MSA) compared with patients with idiopathic Parkinson's disease (IPD).
The Hamilton depression scale (HAM-D), brief psychiatric rating scale (BPRS), and Unified Parkinson's disease rating scale (UPDRS) were administered to clinically probable non-demented patients with SND-type MSA and patients with IPD matched for age and motor disability, at baseline and after receiving levodopa.
At baseline total HAM-D score was greater in patients with IPD. Overall, BPRS score did not differ between the two groups; however, patients with IPD scored higher on anxiety items of the BPRS, and patients with MSA had higher scores on the item indicating blunted affect. After levodopa, both groups improved significantly in UPDRS and HAM-D total scores (just significant for patients with MSA). Patients with IPD improved significantly in total BPRS score but patients with MSA did not.
At baseline patients with IPD were more depressed and anxious than patients with MSA who, by contrast, showed blunted affect. After levodopa, depression and anxiety of patients with IPD improved significantly whereas the affective detachment of patients with MSA did not change. Major neuronal loss in the caudate and ventral striatum, which are part of the lateral orbitofrontal and limbic circuits, may be responsible for the blunted affect not responsive to levodopa therapy found in patients with MSA.

 PMID:10201434

Heterozygous genotype at codon 129 correlates with prolonged disease course in Heidenhain variant sporadic CJD: case report.

PubMed

Townley, Ryan A; Dawson, Elliot T; Drubach, Daniel A

2018-02-01

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains.

Glossitis of Military Working Dogs in South Vietnam: Histopathologic Observations

DTIC Science & Technology

1974-05-31

atrophy of lingual papillae. In man, atrophic lingual changes are usually associated with systemic cause’s such as pellagra, sprue, pernicious anemia...missing in many instances where each papilla had not com- pletely atrophied . This ohservation was especially char- acteristic of filiform papillae...most often existed in regions of papillary atrophy , it also occurred in adjacent regions with normal papillae. In areas of hemorrhage, endo

The association of cognitive impairment with gray matter atrophy and cortical lesion load in clinically isolated syndrome.

PubMed

Diker, Sevda; Has, Arzu Ceylan; Kurne, Aslı; Göçmen, Rahşan; Oğuz, Kader Karlı; Karabudak, Rana

2016-11-01

Multiple sclerosis can impair cognition from the early stages and has been shown to be associated with gray matter damage in addition to white matter pathology. To investigate the profile of cognitive impairment in clinically isolated syndrome (CIS), and the contribution of cortical inflammation, cortical and deep gray matter atrophy, and white matter lesions to cognitive decline. Thirty patients with clinically isolated syndrome and twenty demographically- matched healthy controls underwent neuropsychologic assessment through the Rao Brief Repeatable Battery, and brain magnetic resonance imaging with double inversion recovery using a 3T scanner. Patients with clinically isolated syndrome performed significantly worse than healthy controls on tests that evaluated verbal memory, visuospatial learning and memory, and verbal fluency. Significant deep gray matter atrophy was found in the patients but cortical volume was not lower than the controls. Visual memory tests correlated with the volume of the hippocampus, cerebral white matter and deep gray matter structures and with cerebellar cortical atrophy. Cortical or white matter lesion load did not affect cognitive test results. In our patients with CIS, it was shown that cognitive impairment was mainly related to cerebral white matter, cerebellar cortical and deep gray matter atrophy, but not with cortical inflammation, at least in the early stage of disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.

PubMed

Stephen, Joshi; Nampoothiri, Sheela; Vinayan, K P; Yesodharan, Dhanya; Remesh, Preetha; Gahl, William A; Malicdan, May Christine V

2018-05-16

Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy. The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy. Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.

HYDRA: Revealing heterogeneity of imaging and genetic patterns through a multiple max-margin discriminative analysis framework.

PubMed

Varol, Erdem; Sotiras, Aristeidis; Davatzikos, Christos

2017-01-15

Multivariate pattern analysis techniques have been increasingly used over the past decade to derive highly sensitive and specific biomarkers of diseases on an individual basis. The driving assumption behind the vast majority of the existing methodologies is that a single imaging pattern can distinguish between healthy and diseased populations, or between two subgroups of patients (e.g., progressors vs. non-progressors). This assumption effectively ignores the ample evidence for the heterogeneous nature of brain diseases. Neurodegenerative, neuropsychiatric and neurodevelopmental disorders are largely characterized by high clinical heterogeneity, which likely stems in part from underlying neuroanatomical heterogeneity of various pathologies. Detecting and characterizing heterogeneity may deepen our understanding of disease mechanisms and lead to patient-specific treatments. However, few approaches tackle disease subtype discovery in a principled machine learning framework. To address this challenge, we present a novel non-linear learning algorithm for simultaneous binary classification and subtype identification, termed HYDRA (Heterogeneity through Discriminative Analysis). Neuroanatomical subtypes are effectively captured by multiple linear hyperplanes, which form a convex polytope that separates two groups (e.g., healthy controls from pathologic samples); each face of this polytope effectively defines a disease subtype. We validated HYDRA on simulated and clinical data. In the latter case, we applied the proposed method independently to the imaging and genetic datasets of the Alzheimer's Disease Neuroimaging Initiative (ADNI 1) study. The imaging dataset consisted of T1-weighted volumetric magnetic resonance images of 123 AD patients and 177 controls. The genetic dataset consisted of single nucleotide polymorphism information of 103 AD patients and 139 controls. We identified 3 reproducible subtypes of atrophy in AD relative to controls: (1) diffuse and extensive atrophy, (2) precuneus and extensive temporal lobe atrophy, as well some prefrontal atrophy, (3) atrophy pattern very much confined to the hippocampus and the medial temporal lobe. The genetics dataset yielded two subtypes of AD characterized mainly by the presence/absence of the apolipoprotein E (APOE) ε4 genotype, but also involving differential presence of risk alleles of CD2AP, SPON1 and LOC39095 SNPs that were associated with differences in the respective patterns of brain atrophy, especially in the precuneus. The results demonstrate the potential of the proposed approach to map disease heterogeneity in neuroimaging and genetic studies. Copyright © 2016 Elsevier Inc. All rights reserved.

Sudden Death: An Uncommon Occurrence in Dementia with Lewy Bodies.

PubMed

Molenaar, Joery P; Wilbers, Joyce; Aerts, Marjolein B; Leijten, Quinten H; van Dijk, Jan G; Esselink, Rianne A; Bloem, Bastiaan R

2016-01-01

We present a 75-year-old woman with dementia and parkinsonism who developed severe orthostatic hypotension and eventually died. Autopsy revealed extensive Lewy body formation in the midbrain, limbic system, intermediate spinal cord, and medulla oblongata. Furthermore, a vast amount of Lewy bodies was seen in the paravertebral sympathetic ganglia which likely explained the severe autonomic failure. We speculate that this autonomic failure caused sudden death through dysregulation of respiration or heart rhythm, reminiscent of sudden death in multiple system atrophy (MSA). Clinicians should be aware of this complication in patients presenting with parkinsonism and autonomic dysfunction, and that sudden death may occur in dementia with Lewy bodies (DLB) as it does in MSA.

Neurocysticercosis (NCC) with Hydrocephalus, Optic Atrophy and Vision Loss: A Rare Presentation.

PubMed

Chaudhary, Nagendra; Mahato, Shyam Kumar; Khan, Salamat; Pathak, Santosh; Bhatia, B D

2015-02-01

Neurocysticercosis (NCC) is one of the most common parasitic infestations (Taenia solium) of central nervous system (CNS) in children. Seizures are the common presenting symptoms. Hydrocephalus and optic atrophy are rare complications which may require neurosurgical interventions. We report a case of NCC with hydrocephalus and bilateral optic atrophy associated with vision loss in a Nepalese patient who improved with anti-parasitic therapy followed by ventriculo-peritoneal (VP) shunting.

Corpus callosal atrophy and associations with cognitive impairment in Parkinson disease

PubMed Central

Bledsoe, Ian O.; Merkitch, Doug; Dinh, Vy; Bernard, Bryan; Stebbins, Glenn T.

2017-01-01

Objective: To investigate atrophy of the corpus callosum on MRI in Parkinson disease (PD) and its relationship to cognitive impairment. Methods: One hundred patients with PD and 24 healthy control participants underwent clinical and neuropsychological evaluations and structural MRI brain scans. Participants with PD were classified as cognitively normal (PD-NC; n = 28), having mild cognitive impairment (PD-MCI; n = 47), or having dementia (PDD; n = 25) by Movement Disorder Society criteria. Cognitive domain (attention/working memory, executive function, memory, language, visuospatial function) z scores were calculated. With the use of FreeSurfer image processing, volumes for total corpus callosum and its subsections (anterior, midanterior, central, midposterior, posterior) were computed and normalized by total intracranial volume. Callosal volumes were compared between participants with PD and controls and among PD cognitive groups, covarying for age, sex, and PD duration and with multiple comparison corrections. Regression analyses were performed to evaluate relationships between callosal volumes and performance in cognitive domains. Results: Participants with PD had reduced corpus callosum volumes in midanterior and central regions compared to healthy controls. Participants with PDD demonstrated decreased callosal volumes involving multiple subsections spanning anterior to posterior compared to participants with PD-MCI and PD-NC. Regional callosal atrophy predicted cognitive domain performance such that central volumes were associated with the attention/working memory domain; midposterior volumes with executive function, language, and memory domains; and posterior volumes with memory and visuospatial domains. Conclusions: Notable volume loss occurs in the corpus callosum in PD, with specific neuroanatomic distributions in PDD and relationships of regional atrophy to different cognitive domains. Callosal volume loss may contribute to clinical manifestations of PD cognitive impairment. PMID:28235816

[SCA6 presenting parkinsonism without ataxia--A case report].

PubMed

Takeshima, Shinichi; Takeda, Ikuko; Kobatake, Keitaro; Yamashita, Toru; Abe, Koji; Kuriyama, Masaru

2015-01-01

A 57-year-old man was admitted to our hospital because of bradykinesia. He was diagnosed with Parkinson disease (Hoehn and Yahr grade 2) and administered levodopa at the maximum dose of 800 mg. However, his condition did not improve. While his symptoms were responsive to levodopa therapy, the sensitivity to the drug was poor. Brain MRI revealed atrophy of the upper vermis and cerebral hemispheres, and brain SPECT revealed low perfusion in both parietal lobes. I(123)-metaiodobenzylguanidine scintigraphy showed a decrease in the heart/mediastinum ratio. Striatal dopamine transporter (DAT) density was evaluated using I(123)-FP-CIT. The patient showed moderately reduced DAT density, which suggested nigrostriatal dopaminergic damage. His mother was found to have pure cerebellar ataxia without parkinsonism, and her two siblings also had celebellar type of multiple system atrophy (MSA-C) and progressive supranuclear palsy, respectively. Genetic testing revealed that the patient, his mother and the uncle with MSA-C had spinocerebellar ataxia type 6 (SCA6). SCA6 presenting parkinsonism without ataxia is very rare and important for the pathomechanism of disease.

Severe gastritis decreases success rate of Helicobacter pylori eradication.

PubMed

Kalkan, Ismail Hakki; Sapmaz, Ferdane; Güliter, Sefa; Atasoy, Pınar

2016-05-01

In several studies, different risk factors other than antibiotic resistance have been documented with Helicobacter pylori eradication failure. We aimed in this study to investigate the relationship of gastric density of H. pylori, the occurrence/degree of gastric atrophy, and intestinal metaplasia (IM) with success rate of H. pylori eradication. Two hundred consecutive treatment naive patients who received bismuth containing standart quadruple treatment due to H. pylori infection documented by histopathological examination of two antral or two corpal biopsies entered this retrospective study. The updated Sydney system was used to grade the activity of gastritis, density of H. pylori colonization, atrophy, and IM. Stages III and IV of operative link for gastritis assessment (OLGA) or the operative link on gastric intestinal metaplasia assessment (OLGIM) stages was considered as severe gastritis. H. pylori eradication was determined via stool H. pylori antigen test performed 4 weeks after the end of therapy. The presence of gastric atrophy and IM was significantly higher in patients with eradication failure (p = 0.001 and 0.01, respectively). Severe gastritis (OLGA III-IV and OLGIM III-IV) rates were higher in eradication failure group. A multiple linear regression analysis showed that OLGA and OLGIM stages were to be independent risk factors for eradication failure (p = 0.03 and 0.01, respectively). Our results suggested that histopathologically severe gastritis may cause H. pylori eradication failure. In addition, we found that H. pylori density was not a risk factor for treatment failure in patients who receive quadruple treatment.

Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.

PubMed

Tong, Junchao; Rathitharan, Gausiha; Meyer, Jeffrey H; Furukawa, Yoshiaki; Ang, Lee-Cyn; Boileau, Isabelle; Guttman, Mark; Hornykiewicz, Oleh; Kish, Stephen J

2017-09-01

See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and 'turnover' of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson's disease, also distinguishes astrocyte behaviour in Parkinson's disease from that in the two 'Parkinson-plus' conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Abnormal subcortical nuclei shapes in patients with type 2 diabetes mellitus.

PubMed

Chen, Ji; Zhang, Junxiang; Liu, Xuebing; Wang, Xiaoyang; Xu, Xiangjin; Li, Hui; Cao, Bo; Yang, Yanqiu; Lu, Jingjing; Chen, Ziqian

2017-10-01

Type 2 diabetes mellitus (T2DM) increases the risk of brain atrophy and dementia. We aimed to elucidate deep grey matter (GM) structural abnormalities and their relationships with T2DM cognitive deficits by combining region of interest (ROI)-based volumetry, voxel-based morphometry (VBM) and shape analysis. We recruited 23 T2DM patients and 24 age-matched healthy controls to undergo T1-weighted structural MRI scanning. Images were analysed using the three aforementioned methods to obtain deep GM structural shapes and volumes. Biochemical and cognitive assessments were made and were correlated with the resulting metrics. Shape analysis revealed that T2DM is associated with focal atrophy in the bilateral caudate head and dorso-medial part of the thalamus. ROI-based volumetry only detected thalamic volume reduction in T2DM when compared to the controls. No significant between-group differences were found by VBM. Furthermore, a worse performance of cognitive processing speed correlated with more severe GM atrophy in the bilateral dorso-medial part of the thalamus. Also, the GM volume in the bilateral dorso-medial part of the thalamus changed negatively with HbA 1c . Shape analysis is sensitive in identifying T2DM deep GM structural abnormalities and their relationships with cognitive impairments, which may greatly assist in clarifying the neural substrate of T2DM cognitive dysfunction. • Type 2 diabetes mellitus is accompanied with brain atrophy and cognitive dysfunction • Deep grey matter structures are essential for multiple cognitive processes • Shape analysis revealed local atrophy in the dorso-medial thalamus and caudatum in patients • Dorso-medial thalamic atrophy correlated to cognitive processing speed slowing and high HbA1c. • Shape analysis has advantages in unraveling neural substrates of diabetic cognitive deficits.

The Evolution of and Risk Factors for Neck Muscle Atrophy and Weakness in Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy

PubMed Central

Zhang, Lu-Lu; Mao, Yan-Ping; Zhou, Guan-Qun; Tang, Ling-Long; Qi, Zhen-Yu; Lin, Li; Yao, Ji-Jin; Ma, Jun; Lin, Ai-Hua; Sun, Ying

2015-01-01

Abstract The aim of this study was to investigate the evolution of sternocleidomastoid muscle (SCM) atrophy in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT), and the relationship between SCM atrophy and neck weakness. Data were retrospectively analyzed from 223 biopsy-proven NPC patients with no distant metastasis who underwent IMRT with or without chemotherapy. The volume of SCM was measured on pretreatment magnetic resonance imaging (MRI), and MRIs were conducted 1, 2, and 3 years after the completion of IMRT. Change in SCM volume was calculated and classified using the late effects of normal tissues–subjective, objective, management, and analytic system. The grade of neck muscle weakness, classified by the Common Terminology Criteria for Adverse Events V 3.0, was measured 3 years after the completion of IMRT. The average SCM atrophy ratio was −10.97%, −18.65%, and −22.25% at 1, 2, and 3 years postirradiation, respectively. Multivariate analysis indicated N stage and the length of time after IMRT were independent prognostic variables. There were significant associations between the degree of SCM atrophy and neck weakness. Radical IMRT can cause significant SCM atrophy in NPC patients. A more advanced N stage was associated with more severe SCM atrophy, but no difference was observed between N2 and N3. SCM atrophy progresses over time during the 3 years following IMRT. Grade of SCM atrophy is significantly associated with neck weakness. PMID:26252307

The Evolution of and Risk Factors for Neck Muscle Atrophy and Weakness in Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy: A Retrospective Study in an Endemic Area.

PubMed

Zhang, Lu-Lu; Mao, Yan-Ping; Zhou, Guan-Qun; Tang, Ling-Long; Qi, Zhen-Yu; Lin, Li; Yao, Ji-Jin; Ma, Jun; Lin, Ai-Hua; Sun, Ying

2015-08-01

The aim of this study was to investigate the evolution of sternocleidomastoid muscle (SCM) atrophy in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT), and the relationship between SCM atrophy and neck weakness.Data were retrospectively analyzed from 223 biopsy-proven NPC patients with no distant metastasis who underwent IMRT with or without chemotherapy. The volume of SCM was measured on pretreatment magnetic resonance imaging (MRI), and MRIs were conducted 1, 2, and 3 years after the completion of IMRT. Change in SCM volume was calculated and classified using the late effects of normal tissues-subjective, objective, management, and analytic system. The grade of neck muscle weakness, classified by the Common Terminology Criteria for Adverse Events V 3.0, was measured 3 years after the completion of IMRT.The average SCM atrophy ratio was -10.97%, -18.65%, and -22.25% at 1, 2, and 3 years postirradiation, respectively. Multivariate analysis indicated N stage and the length of time after IMRT were independent prognostic variables. There were significant associations between the degree of SCM atrophy and neck weakness.Radical IMRT can cause significant SCM atrophy in NPC patients. A more advanced N stage was associated with more severe SCM atrophy, but no difference was observed between N2 and N3. SCM atrophy progresses over time during the 3 years following IMRT. Grade of SCM atrophy is significantly associated with neck weakness.

Correlation between white matter damage and gray matter lesions in multiple sclerosis patients.

PubMed

Han, Xue-Mei; Tian, Hong-Ji; Han, Zheng; Zhang, Ce; Liu, Ying; Gu, Jie-Bing; Bakshi, Rohit; Cao, Xia

2017-05-01

We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. We analyzed the correlation between fractional anisotropy values and changes in whole-brain gray matter volume. The participants included 20 patients with relapsing-remitting multiple sclerosis and 20 healthy volunteers as controls. All subjects underwent head magnetic resonance imaging and diffusion tensor imaging. Our results revealed that fractional anisotropy values decreased and gray matter volumes were reduced in the genu and splenium of corpus callosum, left anterior thalamic radiation, hippocampus, uncinate fasciculus, right corticospinal tract, bilateral cingulate gyri, and inferior longitudinal fasciculus in multiple sclerosis patients. Gray matter volumes were significantly different between the two groups in the right frontal lobe (superior frontal, middle frontal, precentral, and orbital gyri), right parietal lobe (postcentral and inferior parietal gyri), right temporal lobe (caudate nucleus), right occipital lobe (middle occipital gyrus), right insula, right parahippocampal gyrus, and left cingulate gyrus. The voxel sizes of atrophic gray matter positively correlated with fractional anisotropy values in white matter association fibers in the patient group. These findings suggest that white matter fiber bundles are extensively injured in multiple sclerosis patients. The main areas of gray matter atrophy in multiple sclerosis are the frontal lobe, parietal lobe, caudate nucleus, parahippocampal gyrus, and cingulate gyrus. Gray matter atrophy is strongly associated with white matter injury in multiple sclerosis patients, particularly with injury to association fibers.

Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy.

PubMed

Puska, Gina; Lutz, Mirjam I; Molnar, Kinga; Regelsberger, Günther; Ricken, Gerda; Pirker, Walter; Laszlo, Lajos; Kovacs, Gabor G

2018-06-01

Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of α-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/α-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated α-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of α-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with α-synuclein pre-aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated α-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated α-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of α-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous α-synuclein in MSA. Copyright © 2018 Elsevier Inc. All rights reserved.

A single-layer network unsupervised feature learning method for white matter hyperintensity segmentation

NASA Astrophysics Data System (ADS)

Vijverberg, Koen; Ghafoorian, Mohsen; van Uden, Inge W. M.; de Leeuw, Frank-Erik; Platel, Bram; Heskes, Tom

2016-03-01

Cerebral small vessel disease (SVD) is a disorder frequently found among the old people and is associated with deterioration in cognitive performance, parkinsonism, motor and mood impairments. White matter hyperintensities (WMH) as well as lacunes, microbleeds and subcortical brain atrophy are part of the spectrum of image findings, related to SVD. Accurate segmentation of WMHs is important for prognosis and diagnosis of multiple neurological disorders such as MS and SVD. Almost all of the published (semi-)automated WMH detection models employ multiple complex hand-crafted features, which require in-depth domain knowledge. In this paper we propose to apply a single-layer network unsupervised feature learning (USFL) method to avoid hand-crafted features, but rather to automatically learn a more efficient set of features. Experimental results show that a computer aided detection system with a USFL system outperforms a hand-crafted approach. Moreover, since the two feature sets have complementary properties, a hybrid system that makes use of both hand-crafted and unsupervised learned features, shows a significant performance boost compared to each system separately, getting close to the performance of an independent human expert.

Different patterns of longitudinal brain and spinal cord changes and their associations with disability progression in NMO and MS.

PubMed

Liu, Yaou; Duan, Yunyun; Huang, Jing; Ren, Zhuoqiong; Liu, Zheng; Dong, Huiqing; Weiler, Florian; Hahn, Horst K; Shi, Fu-Dong; Butzkueven, Helmut; Barkhof, Frederik; Li, Kuncheng

2018-01-01

To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression. We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS. MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non-progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow-up showed association with clinical disability in NMO. Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS. • Spinal cord atrophy progression was observed in NMO. • Spinal cord atrophy changes were associated with disability progression in NMO. • Brain lesion and atrophy were related to disability progression in MS.

Microcystic macular oedema in optic neuropathy: case series and literature review.

PubMed

Kessel, Line; Hamann, Steffen; Wegener, Marianne; Tong, Jessica; Fraser, Clare L

2018-05-25

Cavitations in the inner nuclear layer associated with severe optic atrophy and loss of retinal ganglion cells have clinically been termed microcystic macular oedema (MME). We describe a case series of MME in patients of all ages but predominantly younger patients with a wide range of optic atrophies ranging from acute onset optic disc drusen associated ischemic optic neuropathy to slowly progressive disease as glaucoma. There were no physical distinctions between MME in different causes of optic atrophy suggesting a common causative mechanism. We reviewed the literature on MME and it appears that MME is associated with more severe visual loss, and is more common in hereditary optic neuropathies and neuro-myelitis optica spectrum disease rather than in patients with optic atrophy secondary to multiple sclerosis and glaucoma. Three main causative mechanisms have been proposed, including increased vitreal traction on the macular as the ganglion cells are lost. Others have suggested that trans-synaptic loss of cells in the inner nuclear layer causes formation of empty spaces or cavities. Finally, some have hypothesized a disturbance in the fluid homeostasis of the inner retina as Müller cells are lost or their function is impaired. There are no known treatments of MME. In conclusion, MME seems to be a marker of severe optic nerve atrophy irrespective of the underlying cause. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

76 FR 40445 - Qualification of Drivers; Exemption Applications; Vision

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-08

...). Matthew K. Hagge Mr. Hagge, 31, has had optic atrophy in his right eye since 2007 due to multiple sclerosis. The visual acuity in his right eye is 20/250 and in his left eye, 20/20. Following an examination...

Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage.

PubMed

Filippi, Massimo; Rocca, Maria A; Pagani, Elisabetta; De Stefano, Nicola; Jeffery, Douglas; Kappos, Ludwig; Montalban, Xavier; Boyko, Alexei N; Comi, Giancarlo

2014-08-01

In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration. 1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM. Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated patients, but not in laquinimod-treated patients. WM NAA/Cr tended to increase with laquinimod and decrease with placebo at 24 months (p=0.179). Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMS patients. The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis

PubMed Central

Deppe, Michael; Marinell, Jasmin; Krämer, Julia; Duning, Thomas; Ruck, Tobias; Simon, Ole J.; Zipp, Frauke; Wiendl, Heinz; Meuth, Sven G.

2014-01-01

Objective White matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increases if WMV decreases and the cortical surface area remains constant. Methods In total, 95 participants were enrolled: 30 patients with early and advanced relapsing–remitting MS; 30 age-matched control subjects; 30 patients with Alzheimer's disease (AD) and 5 patients with clinically isolated syndrome (CIS). Results 29/30 MS and 5/5 CIS patients showed lower WMV than expected from their intracranial volume (average reduction 13.0%, P < 10− 10), while the cortical surface area showed no significant differences compared with controls. The estimated WMV reductions were correlated with an increase in cortical curvature (R = 0.62, P = 0.000001). Discriminant analysis revealed that the curvature increase was highly specific for the MS and CIS groups (96.7% correct assignments between MS and control groups) and was significantly correlated with reduction of white matter fractional anisotropy, as determined by diffusion tensor imaging and the Expanded Disability Status Scale. As expected by the predominant gray and WM degeneration in AD, no systematic curvature increase was observed in AD. Conclusion Whole-brain-averaged cortical extrinsic curvature appears to be a specific and quantitative marker for a WMV–cortex disproportionality and allows us to assess “pure” WMA without being confounded by intracranial volume. WMA seems to be a characteristic symptom in early MS and can already occur in patients with CIS and should thus be considered in future MS research and clinical studies. PMID:25610761

[Histological changes of gastric atrophy and intestinal metaplasia after Helicobacter pylori eradication].

PubMed

Lee, Yonggu; Jeon, Yong Cheol; Koo, Tai Yeon; Cho, Hyun Seok; Byun, Tae Jun; Kim, Tae Yeob; Lee, Hang Lak; Eun, Chang Soo; Lee, Oh Young; Han, Dong Soo; Sohn, Joo Hyun; Yoon, Byung Chul

2007-11-01

Long-term Helicobater pylori infection results in atrophic gastritis and intestinal metaplasia, and increases the risk of gastric cancer. However, it is still controversial that eradication of H. pylori improves atrophy or metaplasia. Therefore, we investigated histological changes after the H. pylori eradication in patients with atrophy or metaplasia. One hundred seven patients who received successful eradication of H. pylori infection in Hanyang University, Guri Hospital from March 2001 to April 2006, were enrolled. Antral biopsy was taken before the eradication to confirm the H. pylori infection and grade of atrophy or metaplasia by updated Sydney System. After a certain period of time, antral biopsy was repeatedly taken to confirm the eradication and investigate histological changes of atrophy or metaplasia. Mean age of the patients was 55.3+/-11.3, and average follow-up period was 28.7+/-13.9 months. Endoscopic diagnosis included gastric ulcer, duodenal ulcer, non-ulcer antral gastritis. Atrophy was observed in 41 of 91 and their average score was 0.73+/-0.92. After the eradication of H. pylori, atrophy was improved (0.38+/-0.70, p=0.025). However, metaplasia which was observed in 49 of 107, did not significantly improve during the follow-up period. Newly developed atrophy (7 of 38) or metaplasia (18 of 49) was observed in patients who without atrophy or metaplasia initially. Their average scores were slightly lower than those of cases with pre-existing atrophy or metaplasia without statistical significance. After the eradication of H. pylori infection, atrophic gastritis may be improved, but change of intestinal metaplasia is milder and may take longer duration for improvement.

Fingolimod inhibits brain atrophy and promotes brain-derived neurotrophic factor in an animal model of multiple sclerosis.

PubMed

Smith, Paul A; Schmid, Cindy; Zurbruegg, Stefan; Jivkov, Magali; Doelemeyer, Arno; Theil, Diethilde; Dubost, Valérie; Beckmann, Nicolau

2018-05-15

Longitudinal brain atrophy quantification is a critical efficacy measurement in multiple sclerosis (MS) clinical trials and the determination of No Evidence of Disease Activity (NEDA). Utilising fingolimod as a clinically validated therapy we evaluated the use of repeated brain tissue volume measures during chronic experimental autoimmune encephalomyelitis (EAE) as a new preclinical efficacy measure. Brain volume changes were quantified using magnetic resonance imaging (MRI) at 7 Tesla and correlated to treatment-induced brain derived neurotrophic factor (BDNF) measured in blood, cerebrospinal fluid, spinal cord and brain. Serial brain MRI measurements revealed slow progressive brain volume loss in vehicle treated EAE mice despite a stable clinical score. Fingolimod (1 mg/kg) significantly ameliorated brain tissue atrophy in the cerebellum and striatum when administered from established EAE disease onwards. Fingolimod-dependent tissue preservation was associated with induction of BDNF specifically within the brain and co-localized with neuronal soma. In contrast, therapeutic teriflunomide (3 mg/kg) treatment failed to inhibit CNS autoimmune mediated brain degeneration. Finally, weekly anti-IL-17A antibody (15 mg/kg) treatment was highly efficacious and preserved whole brain, cerebellum and striatum volume. Fingolimod-mediated BDNF increases within the CNS may contribute to limiting progressive tissue loss during chronic neuroinflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

Diagnostic accuracy of apparent diffusion coefficient and 123I-metaiodobenzylguanidine for differentiation of multiple system atrophy and Parkinson's disease.

PubMed

Umemura, Atsushi; Oeda, Tomoko; Hayashi, Ryutaro; Tomita, Satoshi; Kohsaka, Masayuki; Yamamoto, Kenji; Sawada, Hideyuki

2013-01-01

It is often hard to differentiate Parkinson's disease (PD) and parkinsonian variant of multiple system atrophy (MSA-P), especially in the early stages. Cardiac sympathetic denervation and putaminal rarefaction are specific findings for PD and MSA-P, respectively. We investigated diagnostic accuracy of putaminal apparent diffusion coefficient (ADC) test for MSA-P and (123)I-metaiodobenzylguanidine (MIBG) scintigram for PD, especially in early-stage patients. The referral standard diagnosis of PD and MSA-P were the diagnostic criteria of the United Kingdom Parkinson's Disease Society Brain Bank Criteria and the second consensus criteria, respectively. Based on the referral standard criteria, diagnostic accuracy [area under the receiver-operator characteristic curve (AUC), sensitivity and specificity] of the ADC and MIBG tests was estimated retrospectively. Diagnostic accuracy of these tests performed within 3 years of symptom onset was also investigated. ADC and MIBG tests were performed on 138 patients (20 MSA and 118 PD). AUC was 0.95 and 0.83 for the ADC and MIBG tests, respectively. Sensitivity and specificity were 85.0% and 89.0% for MSA-P diagnosis by ADC test and 67.0% and 80.0% for PD diagnosis by MIBG test. When these tests were restricted to patients with disease duration ≤ 3 years, the sensitivity and specificity were 75.0% and 91.4% for the ADC test (MSA-P diagnosis) and 47.7% and 92.3% for the MIBG test (PD diagnosis). Both tests were useful in differentiating between PD and MSA-P, even in the early stages. In early-stage patients, elevated putaminal ADC was a diagnostic marker for MSA-P. Despite high specificity of the MIBG test, careful neurological history and examinations were required for PD diagnosis because of possible false-negative results.

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

PubMed Central

Bassil, Fares; Fernagut, Pierre-Olivier; Bezard, Erwan; Pruvost, Alain; Leste-Lasserre, Thierry; Hoang, Quyen Q.; Ringe, Dagmar; Petsko, Gregory A.; Meissner, Wassilios G.

2016-01-01

Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation. PMID:27482103

Critical appraisal of clinical trials in multiple system atrophy: Toward better quality.

PubMed

Castro Caldas, Ana; Levin, Johannes; Djaldetti, Ruth; Rascol, Olivier; Wenning, Gregor; Ferreira, Joaquim J

2017-10-01

Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although many clinical trials have been conducted, there is still no treatment that cures the disease or slows its progression. We sought to assess the clinical trials, methodology, and quality of reporting of clinical trails conducted in MSA patients. We conducted a systematic review of all trials with at least 1 MSA patient subject to any pharmacological/nonpharmacological interventions. Two independent reviewers evaluated the methodological characteristics and quality of reporting of trials. A total of 60 clinical trials were identified, including 1375 MSA patients. Of the trials, 51% (n = 31) were single-arm studies. A total of 28% (n = 17) had a parallel design, half of which (n = 13) were placebo controlled. Of the studies, 8 (13.3%) were conducted in a multicenter setting, 3 of which were responsible for 49.3% (n = 678) of the total included MSA patients. The description of primary outcomes was unclear in 60% (n = 40) of trials. Only 10 (16.7%) clinical trials clearly described the randomization process. Blinding of the participants, personnel, and outcome assessments were at high risk of bias in the majority of studies. The number of dropouts/withdrawals was high (n = 326, 23.4% among the included patients). Overall, the design and quality of reporting of the reviewed studies is unsatisfactory. The most frequent clinical trials were small and single centered. Inadequate reporting was related to the information on the randomization process, sequence generation, allocation concealment, blinding of participants, and sample size calculations. Although improved during the recent years, methodological quality and trial design need to be optimized to generate more informative results. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience.

PubMed

Mathias, Christopher J

2008-03-01

Neurogenic orthostatic hypotension is a cardinal feature of generalised autonomic failure and commonly is the presenting sign in patients with primary autonomic failure. Orthostatic hypotension can result in considerable morbidity and even mortality and is a major management problem in disorders such as pure autonomic failure, multiple system atrophy and also in Parkinson's disease. Treatment is ideally two pronged, using non-pharmacological and pharmacological measures. Drug treatment ideally is aimed at restoring adequate amounts of the neurotransmitter noradrenaline. This often is not achievable because of damage to sympathetic nerve terminals, to autonomic ganglia or to central autonomic networks. An alternative is the use of sympathomimetics (that mimic the effects of noradrenaline, but are not identical to noradrenaline), in addition to other agents that target physiological mechanisms that contribute to blood pressure control.L-threo-dihydroxyphenyslerine (Droxidopa) is a pro-drug which has a structure similar to noradrenaline, but with a carboxyl group. It has no pressor effects in this form. It can be administered orally, unlike noradrenaline, and after absorption is converted by the enzyme dopa decarboxylase into noradrenaline thus increasing levels of the neurotransmitter which is identical to endogenous noradrenaline. Experience in Caucasians and in Europe is limited mainly to patients with dopamine beta hydroxylase deficiency. This review focuses on two studies performed in Europe, and provides information on its efficacy, tolerability and safety in patients with pure autonomic failure, multiple system atrophy and Parkinson's disease. It also addresses the issue of whether addition of dopa decarboxylase inhibitors, when combined with l-dopa in the treatment of the motor deficit in Parkinson's disease, impairs the pressor efficacy of Droxidopa.

3-Hz postural tremor in multiple system atrophy cerebellar type (MSA-C)-a static posturography study.

PubMed

Li, Xiaodi; Wang, Yuzhou; Wang, Zhanhang; Xu, Yan; Zheng, Wenhua

2018-01-01

The objective of the study is to evaluate postural dysfunction of multiple system atrophy-parkinsonian type (MSA-P) and cerebellar type (MSA-C) by static posturography exam. A total of 29 MSA-P patients, 40 MSA-C patients, and 23 healthy controls (HC) were recruited and engaged in a sensory organization test (SOT). The amplitude of the postural sway was measured and transformed into energy value by Fourier analyzer. SOT scores, frequency of falls and typical 3-Hz postural tremors during the four stance tasks, and energy value in three different frequency bands were recorded and compared. Compared with HC, SOT scores were significantly lower in MSA groups (P < 0.01). Compared with MSA-P, the vestibular scores were further reduced in MSA-C patients (P < 0.05). Falls were more frequent in MSA groups, especially in SOT4 task (foam surface with eyes closed) or in MSA-C group (P < 0.05). Typical 3-Hz postural tremor was observed in 97.5% MSA-C patients, in 24.1% MSA-P patients but in none of the HC (P < 0.05). Compared with HC, much more energy was consumed in every task, every direction, and nearly every frequency band in MSA groups. Energy value of MSA-C group was significantly higher than that of MSA-P, especially in higher frequency band (2 ~ 20 Hz) or in more difficult stance tasks (SOT 3 ~ 4, foam surface with eyes open or closed) (P < 0.05). Both MSA-P and MSA-C were characterized by severe static postural dysfunction. However, typical 3-Hz postural tremor was predominant in MSA-C and was very useful in the differential diagnosis between MSA-P and MSA-C.

Evaluation of autonomic functions of patients with multiple system atrophy and Parkinson's disease by head-up tilt test.

PubMed

Watano, Chikako; Shiota, Yuri; Onoda, Keiichi; Sheikh, Abdullah Md; Mishima, Seiji; Nitta, Eri; Yano, Shozo; Yamaguchi, Shuhei; Nagai, Atsushi

2018-02-01

The aim of this study was to evaluate the autonomic neural function in Parkinson's disease (PD) and multiple system atrophy (MSA) with head-up tilt test and spectral analysis of cardiovascular parameters. This study included 15 patients with MSA, 15 patients with PD, and 29 healthy control (HC) subjects. High frequency power of the RR interval (RR-HF), the ratio of low frequency power of RR interval to RR-HF (RR-LF/HF) and LF power of systolic BP were used to evaluate parasympathetic, cardiac sympathetic and vasomotor sympathetic functions, respectively. Both patients with PD and MSA showed orthostatic hypotension and lower parasympathetic function (RR-HF) at tilt position as compared to HC subjects. Cardiac sympathetic function (RR-LF/HF) was significantly high in patients with PD than MSA at supine position. RR-LF/HF tended to increase in MSA and HC, but decreased in PD by tilting. Consequently, the change of the ratio due to tilting (ΔRR-LF/HF) was significantly lower in patients with PD than in HC subjects. Further analysis showed that compared to mild stage of PD, RR-LF/HF at the supine position was significantly higher in advanced stage. By tilting, it was increased in mild stage and decreased in the advanced stage of PD, causing ΔRR-LF/HF to decrease significantly in the advanced stage. Thus, we demonstrated that spectral analysis of cardiovascular parameters is useful to identify sympathetic and parasympathetic disorders in MSA and PD. High cardiac sympathetic function at the supine position, and its reduction by tilting might be a characteristic feature of PD, especially in the advanced stage.

Anle138b Partly Ameliorates Motor Deficits Despite Failure of Neuroprotection in a Model of Advanced Multiple System Atrophy

PubMed Central

Fellner, Lisa; Kuzdas-Wood, Daniela; Levin, Johannes; Ryazanov, Sergey; Leonov, Andrei; Griesinger, Christian; Giese, Armin; Wenning, Gregor K.; Stefanova, Nadia

2016-01-01

The neurodegenerative disorder multiple system atrophy (MSA) is characterized by autonomic failure, cerebellar ataxia and parkinsonism in any combination associated with predominantly oligodendroglial α-synuclein (α-syn) aggregates (glial cytoplasmic inclusions = GCIs). To date, there is no effective disease modifying therapy. Previous experiments have shown that the aggregation inhibitor anle138b reduces neurodegeneration, as well as behavioral deficits in both transgenic and toxin mouse models of Parkinson's disease (PD). Here we analyzed whether anle138b improves motor skills and reduces neuronal loss, as well as oligodendroglial α-syn aggregation in the PLP-α-syn transgenic mouse challenged with the mitochondrial toxin 3-nitropropionic acid (3-NP) to model full-blown MSA. Following 1 month of treatment with anle138b, MSA mice showed signs of motor improvement affecting stride length, but not pole, grip strength, and beam test performance. Loss of dopaminergic nigral neurons and Purkinje cells was not attenuated and GCI density remained unchanged. These data suggest that the pathology in transgenic PLP-α-syn mice receiving 3-NP might be too advanced to detect significant effects of anle138b treatment on neuronal loss and intracytoplasmic α-syn inclusion bodies. However, the partial motor amelioration may indicate potential efficacy of anle138b treatment that may be mediated by its actions on α-syn oligomers or may reflect improvement of neuronal dysfunction in neural at risk populations. Further studies are required to address the efficacy of anle138b in transgenic α-syn models of early-stage MSA and in the absence of additional toxin application. PMID:27013960

Association of TNF-α rs1799964 and IL-1β rs16944 polymorphisms with multiple system atrophy in Chinese Han population.

PubMed

Zhou, Xin; Wang, Chunrong; Chen, Zhao; Peng, Yun; Peng, Huirong; Hou, Xuan; Ye, Wei; Qiu, Rong; Xia, Kun; Tang, Beisha; Jiang, Hong

2018-01-07

Recent evidence suggested that several single nucleotide polymorphisms (SNPs) of inflammation-related genes (TNF-α rs1799964, IL-1α rs1800587, IL-1β rs16944, IL-8 rs4073, ICAM-1 rs5498) were associated with multiple system atrophy (MSA). Herein, we conducted this case-control study to evaluate the possible correlation between the five SNPs related to inflammation and MSA in Chinese Han population. We recruited 154 sporadic patients with MSA and 223 health controls in this study. All subjects were genotyped for the five SNPs using polymerase chain reaction amplification and Sanger sequencing. TNF-α rs1799964, genotype distribution and minor allele frequency (MAF) showed significant differences between patients and controls, which might illustrate the minor allele C may increase the risk for MSA (genotype, P = 0.006, OR = 1.245, 95% CI = [1.066-1.455]; allele, P = 0.001, OR = 1.887, 95% CI = [1.303-2.733]). For rs16944, patients carrying AA genotype showed a nearly 5-year early age at onset (AAO) than GG genotype (50.52 ± 7.45 years vs. 54.90 ± 7.21 years, P = 0.037). No differences were found in genotype distribution and MAF of the five SNPs between patients with MSA with predominant cerebellar ataxia (MSA-C) and with predominant Parkinsonism (MSA-P). Our study suggests that rs1799964 of TNF-α may act as a risk factor for MSA and the IL-1β rs16944 might be a genetic factor that modifies the AAO in MSA. Moreover, the exact mechanism of neuroinflammatory response in MSA deserves further exploration.

Neuropsychological and clinical heterogeneity of cognitive impairment in patients with multiple system atrophy.

PubMed

Barcelos, Lorena Broseghini; Saad, Flávia; Giacominelli, Carla; Saba, Roberta Arb; de Carvalho Aguiar, Patrícia Maria; Silva, Sonia Maria Azevedo; Borges, Vanderci; Bertolucci, Paulo Henrique Ferreira; Ferraz, Henrique Ballalai

2018-01-01

We evaluated neuropsychological tests to compare cognitive impairment between two types of multiple system atrophy: predominant parkinsonism (MSA-P) and predominant cerebellar ataxia (MSA-C). This cross-sectional study included 14 patients diagnosed with MSA: four with MSA-C and ten with MSA-P. Presence of motor symptoms was determined by using the Unified Rating MSA Scale (URMSAS). Non-motor symptoms were evaluated by the Short Form Health Survey (SF-36), Scales for Outcomes in Parkinson's disease Autonomic (SCOPA-AUT), Hospital Anxiety and Depression Scale (HADS), and Beck Depression Inventory (BDI). Neuropsychological tests were used to evaluate general cognition, verbal and visual memory, working memory, constructional ability, visuospatial, language, and executive function. The median age of the patients was 62 years, median disease duration was 3.5 years, and median education level was 10 years. The median Mini-Mental State Examination (MMSE) score was 26.5 points, and median Mattis Dementia Rating Scale (MDRS) score was 131.5. We compared the continuous data between the two MSA subtypes and observed that bodily pain reported in the quality of life questionnaire, SF-36, was worse in MSA-P (p<0.05), and attention function evaluated by MDRS was significantly lower in MSA-C than MSA-P (p<0.05). Our comparative study of cognitive impairment in MSA-P and MSA-C showed that both groups had impaired executive and visuospatial functions, while the attention deficit was predominant only in MSA-C. These findings support the concept that cognitive deficit originates from striatofrontal dysfunction and cerebellar degeneration. Our study also suggests that cognitive impairment is relevant in MSA, and clinical neurologists should not neglect evaluation of these aspects in their daily clinical practice. Copyright © 2017. Published by Elsevier B.V.

Contrasting actions of pressor agents in severe autonomic failure

NASA Technical Reports Server (NTRS)

Jordan, J.; Shannon, J. R.; Biaggioni, I.; Norman, R.; Black, B. K.; Robertson, D.

1998-01-01

BACKGROUND: Orthostatic hypotension is the most disabling symptom of autonomic failure. The choice of a pressor agent is largely empiric, and it would be of great value to define predictors of a response. PATIENTS AND METHODS: In 35 patients with severe orthostatic hypotension due to multiple system atrophy or pure autonomic failure, we determined the effect on seated systolic blood pressure (SBP) of placebo, phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin (50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg). In a subgroup of patients, we compared the pressor effect of midodrine (5 mg) with the effect of phenylpropanolamine (12.5 mg). RESULTS: There were no significant differences in the pressor responses between patients with multiple system atrophy or pure autonomic failure. When compared with placebo, the pressor response was significant for phenylpropanolamine, yohimbine, and indomethacin. In a subgroup of patients, we confirmed that this pressor effect of phenylpropanolamine, yohimbine, and indomethacin corresponded to a significant increase in standing SBP. The pressor responses to ibuprofen, caffeine, and methylphenidate were not significantly different from placebo. Phenylpropanolamine and midodrine elicited similar pressor responses. There were no significant associations between drug response and autonomic function testing, postprandial hypotension, or plasma catecholamine levels. CONCLUSIONS: We conclude that significant increases in systolic blood pressure can be obtained in patients with orthostatic hypotension due to primary autonomic failure with phenylpropanolamine in low doses or yohimbine or indomethacin in moderate doses. The response to a pressor agent cannot be predicted by autonomic function testing or plasma catecholamines. Therefore, empiric testing with a sequence of medications, based on the risk of side effects in the individual patient and the probability of a response, is a useful approach.

Profile of cognitive impairment and underlying pathology in multiple system atrophy.

PubMed

Koga, Shunsuke; Parks, Adam; Uitti, Ryan J; van Gerpen, Jay A; Cheshire, William P; Wszolek, Zbigniew K; Dickson, Dennis W

2017-03-01

The objectives of this study were to elucidate any potential association between α-synuclein pathology and cognitive impairment and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients. To do this, we analyzed the clinical and pathologic features in autopsy-confirmed MSA patients. We retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semiquantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer's disease, hippocampal sclerosis, and cerebrovascular pathology. Of 102 patients, 33 (32%) were documented to have cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal-subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, 8 patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia. The cognitive deficits observed in this study were more evident on neuropsychological assessment than with cognitive screens. Based on these findings, we recommend that clinicians consider more in-depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, a greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Association of metallothionein-III with oligodendroglial cytoplasmic inclusions in multiple system atrophy.

PubMed

Pountney, D L; Dickson, T C; Power, J H T; Vickers, J C; West, A J; Gai, W P

2011-01-01

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterised by Parkinsonian and autonomic symptoms and by widespread intracytoplasmic inclusion bodies in oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are comprised of 9-10 nm filaments rich in the protein alpha-synuclein, also found in neuronal inclusion bodies associated with Parkinson's disease. Metallothioneins (MTs) are a class of low-molecular weight (6-7 kDa), cysteine-rich metal-binding proteins the expression of which is induced by heavy metals, glucocorticoids, cytokines and oxidative stress. Recent studies have shown a role for the ubiquitously expressed MT-I/II isoforms in the brain following a variety of stresses, whereas, the function of the brain-specific MT isoform, MT-III, is less clear. MT-III and MT-I/II immunostaining of post-mortem tissue in MSA and normal control human brains showed that the number of MT-III-positive cells is significantly increased in MSA in visual cortex, whereas MT-I/II isoforms showed no significant difference in the distribution of immunopositive cells in MSA compared to normal tissue. GCIs were immunopositive for MT-III, but were immunonegative for the MT-I/II isoforms. Immunofluorescence double labelling showed the co-localisation of alpha-synuclein and MT-III in GCIs in MSA tissue. In isolated GCIs, transmission electron microscopy demonstrated MT-III immunogold labelling of the amorphous material surrounding alpha-synuclein filaments in GCIs. High-molecular weight MT-III species in addition to MT-III monomer were detected in GCIs by Western analysis of the detergent-solubilised proteins of purified GCIs. These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments.

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

PubMed

Pigna, Eva; Renzini, Alessandra; Greco, Emanuela; Simonazzi, Elena; Fulle, Stefania; Mancinelli, Rosa; Moresi, Viviana; Adamo, Sergio

2018-02-24

Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.

Droxidopa in neurogenic orthostatic hypotension

PubMed Central

Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto

2015-01-01

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy, pure autonomic failure and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise blood pressure by acting at the neurovascular junction to increase vascular tone. This review summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials. PMID:26092297

Droxidopa in neurogenic orthostatic hypotension.

PubMed

Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto

2015-01-01

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure (BP) on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise BP by acting at the neurovascular junction to increase vascular tone. This article summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials.

Three-Dimensional Culture Model of Skeletal Muscle Tissue with Atrophy Induced by Dexamethasone.

PubMed

Shimizu, Kazunori; Genma, Riho; Gotou, Yuuki; Nagasaka, Sumire; Honda, Hiroyuki

2017-06-15

Drug screening systems for muscle atrophy based on the contractile force of cultured skeletal muscle tissues are required for the development of preventive or therapeutic drugs for atrophy. This study aims to develop a muscle atrophy model by inducing atrophy in normal muscle tissues constructed on microdevices capable of measuring the contractile force and to verify if this model is suitable for drug screening using the contractile force as an index. Tissue engineered skeletal muscles containing striated myotubes were prepared on the microdevices for the study. The addition of 100 µM dexamethasone (Dex), which is used as a muscle atrophy inducer, for 24 h reduced the contractile force significantly. An increase in the expression of Atrogin-1 and MuRF-1 in the tissues treated with Dex was established. A decrease in the number of striated myotubes was also observed in the tissues treated with Dex. Treatment with 8 ng/mL Insulin-like Growth Factor (IGF-I) for 24 h significantly increased the contractile force of the Dex-induced atrophic tissues. The same treatment, though, had no impact on the force of the normal tissues. Thus, it is envisaged that the atrophic skeletal muscle tissues induced by Dex can be used for drug screening against atrophy.

Three-Dimensional Culture Model of Skeletal Muscle Tissue with Atrophy Induced by Dexamethasone

PubMed Central

Shimizu, Kazunori; Genma, Riho; Gotou, Yuuki; Nagasaka, Sumire; Honda, Hiroyuki

2017-01-01

Drug screening systems for muscle atrophy based on the contractile force of cultured skeletal muscle tissues are required for the development of preventive or therapeutic drugs for atrophy. This study aims to develop a muscle atrophy model by inducing atrophy in normal muscle tissues constructed on microdevices capable of measuring the contractile force and to verify if this model is suitable for drug screening using the contractile force as an index. Tissue engineered skeletal muscles containing striated myotubes were prepared on the microdevices for the study. The addition of 100 µM dexamethasone (Dex), which is used as a muscle atrophy inducer, for 24 h reduced the contractile force significantly. An increase in the expression of Atrogin-1 and MuRF-1 in the tissues treated with Dex was established. A decrease in the number of striated myotubes was also observed in the tissues treated with Dex. Treatment with 8 ng/mL Insulin-like Growth Factor (IGF-I) for 24 h significantly increased the contractile force of the Dex-induced atrophic tissues. The same treatment, though, had no impact on the force of the normal tissues. Thus, it is envisaged that the atrophic skeletal muscle tissues induced by Dex can be used for drug screening against atrophy. PMID:28952535

Predictors of vision impairment in Multiple Sclerosis.

PubMed

Sanchez-Dalmau, Bernardo; Martinez-Lapiscina, Elena H; Pulido-Valdeolivas, Irene; Zubizarreta, Irati; Llufriu, Sara; Blanco, Yolanda; Sola-Valls, Nuria; Sepulveda, Maria; Guerrero, Ana; Alba, Salut; Andorra, Magi; Camos, Anna; Sanchez-Vela, Laura; Alfonso, Veronica; Saiz, Albert; Villoslada, Pablo

2018-01-01

Visual impairment significantly alters the quality of life of people with Multiple Sclerosis (MS). The objective of this study was to identify predictors (independent variables) of visual outcomes, and to define their relationship with neurological disability and retinal atrophy when assessed by optical coherence tomography (OCT). We performed a cross-sectional analysis of 119 consecutive patients with MS, assessing vision using high contrast visual acuity (LogMar), 2.5% and 1.25% low contrast visual acuity (Sloan charts), and color vision (Hardy-Rand-Rittler plates). Quality of vision is a patient reported outcome based on an individual's unique perception of his or her vision and was assessed with the Visual Functioning Questionnaire-25 (VFQ-25) with the 10 neuro-ophthalmologic items. MS disability was assessed using the expanded disability status scale (EDSS), the MS functional composite (MSFC) and the brief repetitive battery-neuropsychology (BRB-N). Retinal atrophy was assessed using spectral domain OCT, measuring the thickness of the peripapillar retinal nerve fiber layer (pRNFL) and the volume of the ganglion cell plus inner plexiform layer (GCIPL). The vision of patients with MS was impaired, particularly in eyes with prior optic neuritis. Retinal atrophy (pRNFL and GCIPL) was closely associated with impaired low contrast vision and color vision, whereas the volume of the GCIPL showed a trend (p = 0.092) to be associated with quality of vision. Multiple regression analysis revealed that EDSS was an explanatory variable for high contrast vision after stepwise analysis, GCIPL volume for low contrast vision, and GCIPL volume and EDSS for color vision. The explanatory variables for quality of vision were high contrast vision and color vision. In summary, quality of vision in MS depends on the impairment of high contrast visual acuity and color vision due to the disease.

Small Molecular Weight Soybean Protein-Derived Peptides Nutriment Attenuates Rat Burn Injury-Induced Muscle Atrophy by Modulation of Ubiquitin-Proteasome System and Autophagy Signaling Pathway.

PubMed

Zhao, Fen; Yu, Yonghui; Liu, Wei; Zhang, Jian; Liu, Xinqi; Liu, Lingying; Yin, Huinan

2018-03-21

This article describes results of the effect of dietary supplementation with small molecular weight soybean protein-derived peptides on major rat burn injury-induced muscle atrophy. As protein nutrients have been previously implicated to play an important role in improving burn injury outcomes, optimized more readily absorbed small molecular weight soybean protein-derived peptides were evaluated. Thus, the quantity, sodium dodecyl sulfate polyacrylamide-gel electrophoresis patterns, molecular weight distribution, and composition of amino acids of the prepared peptides were analyzed, and a major full-thickness 30% total body surface area burn-injury rat model was utilized to assess the impact of supplementation with soybean protein-derived peptides on initial systemic inflammatory responses as measured by interferon-gamma (IFN-γ), chemokine (C-C motif) ligand 2 (CCL2, also known as MCP-1), chemokine (C-C motif) ligand 7 (CCL7, also known as MCP-3), and generation of muscle atrophy as measured by tibialis anterior muscle (TAM) weight relative to total body weight. Induction of burn injury-induced muscle atrophy ubiquitin-proteasome system (UPS) signaling pathways in effected muscle tissues was determined by Western blot protein expression measurements of E3 ubiquitin-protein ligase TRIM-63 (TRIM63, also known as MuRF1) and F-box only protein 32 (FBXO32, also known as atrogin-1 or MAFbx). In addition, induction of burn injury-induced autophagy signaling pathways associated with muscle atrophy in effected muscle tissues was assessed by immunohistochemical analysis as measured by microtubule-associated proteins 1 light chain 3 (MAP1LC3, or commonly abbreviated as LC3) and beclin-1 (BECN1) expression, as well as relative induction of cytoplasmic-liberated form of MAP1LC3 (LC3-I) and phagophore and autophagosome membrane-bound form of MAP1LC3 (LC3-II), and BECN1 protein expression by Western blot analysis. Nutrient supplementation with small molecular weight soybean protein-derived peptides resulted a significant reduction in burn injury-induced inflammatory markers, muscle atrophy, induction of TRIM63 and FBXO32 muscle atrophy signaling pathways, and induction of autophagy signaling pathways LC3 and BECN1 associated with muscle atrophy. These results implicated that small molecular weight soybean-derived peptides dietary supplementation could be used as an adjunct therapy in burn injury management to reduce the development or severity of muscle atrophy for improved burn patient outcomes.

Importance of Multimodal MRI in Characterizing Brain Tissue and Its Potential Application for Individual Age Prediction.

PubMed

Cherubini, Andrea; Caligiuri, Maria Eugenia; Peran, Patrice; Sabatini, Umberto; Cosentino, Carlo; Amato, Francesco

2016-09-01

This study presents a voxel-based multiple regression analysis of different magnetic resonance image modalities, including anatomical T1-weighted, T2(*) relaxometry, and diffusion tensor imaging. Quantitative parameters sensitive to complementary brain tissue alterations, including morphometric atrophy, mineralization, microstructural damage, and anisotropy loss, were compared in a linear physiological aging model in 140 healthy subjects (range 20-74 years). The performance of different predictors and the identification of the best biomarker of age-induced structural variation were compared without a priori anatomical knowledge. The best quantitative predictors in several brain regions were iron deposition and microstructural damage, rather than macroscopic tissue atrophy. Age variations were best resolved with a combination of markers, suggesting that multiple predictors better capture age-induced tissue alterations. The results of the linear model were used to predict apparent age in different regions of individual brain. This approach pointed to a number of novel applications that could potentially help highlighting areas particularly vulnerable to disease.

The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting.

PubMed

Bhatnagar, S; Kumar, A

2012-01-01

The occurrence of skeletal muscle atrophy, a devastating complication of a large number of disease states and inactivity/disuse conditions, provides a never ending quest to identify novel targets for its therapy. Proinflammatory cytokines are considered the mediators of muscle wasting in chronic diseases; however, their role in disuse atrophy has just begun to be elucidated. An inflammatory cytokine, tumor necrosis factor (TNF)- like weak inducer of apoptosis (TWEAK), has recently been identified as a potent inducer of skeletal muscle wasting. TWEAK activates various proteolytic pathways and stimulates the degradation of myofibril protein both in vitro and in vivo. Moreover, TWEAK mediates the loss of skeletal muscle mass and function in response to denervation, a model of disuse atrophy. Adult skeletal muscle express very low to minimal levels of TWEAK receptor, Fn14. Specific catabolic conditions such as denervation, immobilization, or unloading rapidly increase the expression of Fn14 in skeletal muscle which in turn stimulates the TWEAK activation of various catabolic pathways leading to muscle atrophy. In this article, we have discussed the emerging roles and the mechanisms of action of TWEAK-Fn14 system in skeletal muscle with particular reference to different models of muscle atrophy and injury and its potential to be used as a therapeutic target for prevention of muscle loss.

Caribbean parkinsonism and other atypical parkinsonian disorders.

PubMed

Tolosa, Eduardo; Calandrella, Daniela; Gallardo, Marisol

2004-05-01

Atypical parkinsonism (AP) is a term applied to disorders characterized by parkinsonism that evolves rapidly, with poor or transient response to levodopa, or has other associated features such as early falls and postural instability, early autonomic failure, supranuclear gaze palsy, pyramidal or cerebellar signs, alien hand syndrome or severe ideomotor apraxia. The most common AP are multiple system atrophy, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Other APs include Caribbean parkinsonism (CP) and parkinsonism-dementia complex of Guam (PDC). In this review we provide an update in etiology, neuropathology, diagnosis and treatment of atypical parkinsonian disorders associated with protein tau deposit, also known as tauopathies.

Gray Matter Pathology in MS: Neuroimaging and Clinical Correlations

PubMed Central

Honce, Justin Morris

2013-01-01

It is abundantly clear that there is extensive gray matter pathology occurring in multiple sclerosis. While attention to gray matter pathology was initially limited to studies of autopsy specimens and biopsies, the development of new MRI techniques has allowed assessment of gray matter pathology in vivo. Current MRI techniques allow the direct visualization of gray matter demyelinating lesions, the quantification of diffuse damage to normal appearing gray matter, and the direct measurement of gray matter atrophy. Gray matter demyelination (both focal and diffuse) and gray matter atrophy are found in the very earliest stages of multiple sclerosis and are progressive over time. Accumulation of gray matter damage has substantial impact on the lives of multiple sclerosis patients; a growing body of the literature demonstrates correlations between gray matter pathology and various measures of both clinical disability and cognitive impairment. The effect of disease modifying therapies on the rate accumulation of gray matter pathology in MS has been investigated. This review focuses on the neuroimaging of gray matter pathology in MS, the effect of the accumulation of gray matter pathology on clinical and cognitive disability, and the effect of disease-modifying agents on various measures of gray matter damage. PMID:23878736

Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity.

PubMed

Alves, Gilberto Sousa; Oertel Knöchel, Viola; Knöchel, Christian; Carvalho, André Férrer; Pantel, Johannes; Engelhardt, Eliasz; Laks, Jerson

2015-01-01

Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD) and may reflect primary or secondary circuitry degeneration (i.e., due to cortical atrophy). The interpretation of diffusion tensor imaging (DTI) eigenvectors, known as multiple indices, may provide new insights into the main pathological models supporting primary or secondary patterns of WM disruption in AD, the retrogenesis, and Wallerian degeneration models, respectively. The aim of this review is to analyze the current literature on the contribution of DTI multiple indices to the understanding of AD neuropathology, taking the retrogenesis model as a reference for discussion. A systematic review using MEDLINE, EMBASE, and PUBMED was performed. Evidence suggests that AD evolves through distinct patterns of WM disruption, in which retrogenesis or, alternatively, the Wallerian degeneration may prevail. Distinct patterns of WM atrophy may be influenced by complex interactions which comprise disease status and progression, fiber localization, concurrent risk factors (i.e., vascular disease, gender), and cognitive reserve. The use of DTI multiple indices in addition to other standard multimodal methods in dementia research may help to determine the contribution of retrogenesis hypothesis to the understanding of neuropathological hallmarks that lead to AD.

[A case of chronic multifocal myositis].

PubMed

Maruyama, T; Kondo, K; Tabata, K; Yanagisawa, N

1992-11-01

A 61-year-old civil engineer began to have slowly progressive muscle atrophy in the right shoulder and the left arm at 56 years of age. Muscle wasting became manifest in the left thigh at 59 years and in the right thigh at 60 years. He had mild difficulty in climbing and descending stairs. On examination, although he had notable muscle atrophy in the right trapezius and proximal muscles in the upper and lower extremities, his muscle strength was relatively well preserved. The muscle atrophy was asymmetrical; the right periscapular region and the left upper and lower extremities were more markedly atrophic. In addition, multiple foci of the striking muscle atrophy were noted in the upper trunk and the proximal limb muscles. Fasciculation was not present. Deep tendon reflexes were normal with no pathologic reflexes. Except for a moderately elevated serum creatine kinase level of 709 Ul/l (normal 40-170) and mildly elevated serum myoglobin level of 100 ng/ml (normal < 60), no laboratory tests showed abnormal values suggesting an inflammatory process. Motor and sensory nerve conduction velocities were within normal limits. Electromyography disclosed myopathic and neuropathic changes. Computed tomography (CT) of skeletal muscles showed asymmetrical muscle atrophy and patchy low-density foci. In biopsied left quadriceps and right gastrocnemius muscles which showed partially low density on CT, there was marked variation in muscle fiber size, with necrotic and regenerating fibers, an increased number of centrally placed nuclei, and interstitial fibrosis. There were numerous foci of mononuclear inflammatory cellular infiltration, especially around the blood vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Artificial urinary sphincter revision for urethral atrophy: Comparing single cuff downsizing and tandem cuff placement.

PubMed

Linder, Brian J; Viers, Boyd R; Ziegelmann, Matthew J; Rivera, Marcelino E; Elliott, Daniel S

2017-01-01

To compare outcomes for single urethral cuff downsizing versus tandem cuff placement during artificial urinary sphincter (AUS) revision for urethral atrophy. We identified 1778 AUS surgeries performed at our institution from 1990-2014. Of these, 406 were first AUS revisions, including 69 revisions for urethral atrophy. Multiple clinical and surgical variables were evaluated for potential association with device outcomes following revision, including surgical revision strategy (downsizing a single urethral cuff versus placing tandem urethral cuffs). Of the 69 revision surgeries for urethral atrophy at our institution, 56 (82%) were tandem cuff placements, 12 (18%) were single cuff downsizings and one was relocation of a single cuff. When comparing tandem cuff placements and single cuff downsizings, the cohorts were similar with regard to age (p=0.98), body-mass index (p=0.95), prior pelvic radiation exposure (p=0.73) and length of follow-up (p=0.12). Notably, there was no difference in 3-year overall device survival compared between single cuff and tandem cuff revisions (60% versus 76%, p=0.94). Likewise, no significant difference was identified for tandem cuff placement (ref. single cuff) when evaluating the risk of any tertiary surgery (HR 0.95, 95% CI 0.32-4.12, p=0.94) or urethral erosion/device infection following revision (HR 0.79, 95% CI 0.20-5.22, p=0.77). There was no significant difference in overall device survival in patients undergoing single cuff downsizing or tandem cuff placement during AUS revision for urethral atrophy. Copyright® by the International Brazilian Journal of Urology.

PROGNOSTIC VALUE OF SHAPE-DESCRIPTIVE FACTORS FOR THE PROGRESSION OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PubMed

Pfau, Maximilian; Lindner, Moritz; Goerdt, Lukas; Thiele, Sarah; Nadal, Jennifer; Schmid, Matthias; Schmitz-Valckenberg, Steffen; Sadda, SriniVas R; Holz, Frank G; Fleckenstein, Monika

2018-05-16

To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in geographic atrophy progression in previously unknown patients and 39.1% in patients with previous observation. These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for geographic atrophy progression. However, a substantial part of the remaining variation in geographic atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

Histological characteristics following a long-term nitrate-rich diet in miniature pigs with parotid atrophy

PubMed Central

Xia, Dengsheng; Qu, Xingmin; Tran, Simon D; Schmidt, Laura L; Qin, Lizheng; Zhang, Chunmei; Cui, Xiuyu; Deng, Dajun; Wang, Songlin

2015-01-01

The aim of this study was to investigate the histological characteristics following a 2-year nitrate-rich diet in miniature pigs with parotid atrophy. Using averages collected data from three time points at 6, 12, and 24 months following the induction of parotid gland atrophy, salivary nitrate levels of the nitrate-diet parotid-atrophied group (17.3±3.9 ng/µl) were close to those of the control group (19.6±5.1 ng/µl). Compared to the control group, the nitrate-diet group had significantly higher nitrate levels in blood (P < 0.05) and urine (P < 0.001). Histological and electron microscopy analyses showed no abnormalities in the organs of experimental or control animals. No significant differences on apoptosis rate were found in liver and kidney tissues between the standard- and nitrate-diet groups. Therefore, dietary nitrate supplementation could restore salivary nitrate levels. High-dose nitrate loading for 2 years had no observed systemic toxicity in miniature pigs with parotid atrophy. PMID:26261499

Childhood optic atrophy.

PubMed

Mudgil, A V; Repka, M X

2000-02-01

To determine the causes, and relative incidence of the common causes, of optic nerve atrophy in children under 10 years old and to compare prevalent aetiologies with those given in previous studies. The Wilmer Information System database was searched to identify all children, diagnosed between 1987 and 1997 with optic atrophy, who were under 10 years old at diagnosis. The medical records of these children were reviewed retrospectively A total of 272 children were identified, Complications from premature birth were the most frequent aetiology of optic atrophy (n = 44, 16%); 68% of these premature infants having a history of intraventricular haemorrhage. Tumour was the second most common aetiology (n = 40, 15%). The most frequent tumour was pilocytic astrocytoma (50%), followed by craniopharyngioma (17%). Hydrocephalus, unrelated to tumour, was the third most common aetiology (n = 26, 10%). In 114 cases (42%), the cause of optic atrophy became manifest in the perinatal period and/or could be attributed to adverse events in utero. A cause was not determined in 4% of cases. In the last decade, prematurity and hydrocephalus appear to have become important causes of optic atrophy in childhood. This trend is probably the result of improved survival of infants with extremely low birth weight.

Constitutive activation of MAPK cascade in acute quadriplegic myopathy.

PubMed

Di Giovanni, Simone; Molon, Annamaria; Broccolini, Aldobrando; Melcon, Gisela; Mirabella, Massimiliano; Hoffman, Eric P; Servidei, Serenella

2004-02-01

Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)-beta/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-beta receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-beta pathway in myofibers. The acute stimulation of the TGF-beta/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients.

Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge.

PubMed

Cash, David M; Frost, Chris; Iheme, Leonardo O; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B; Pennec, Xavier; Pierson, Ronald K; Gunter, Jeffrey L; Senjem, Matthew L; Jack, Clifford R; Guizard, Nicolas; Fonov, Vladimir S; Collins, D Louis; Modat, Marc; Cardoso, M Jorge; Leung, Kelvin K; Wang, Hongzhi; Das, Sandhitsu R; Yushkevich, Paul A; Malone, Ian B; Fox, Nick C; Schott, Jonathan M; Ourselin, Sebastien

2015-12-01

Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated "direct" measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the distribution of atrophy rates in the Alzheimer's disease (AD) and control groups and of required sample sizes to detect a 25% treatment effect, in relation to healthy ageing, with 95% significance and 80% power over follow-up periods of 6, 12, and 24months. Uncertainty in these estimates, and head-to-head comparisons between techniques, were carried out using the bootstrap. The lateral ventricles provided the most stable measurements, followed by the brain. The hippocampi had much more variability across participants, likely because of differences in segmentation protocol and less distinct boundaries. Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity. The resulting annualized rates of change derived from the model ranged from, for whole brain: -1.4% to -2.2% (AD) and -0.35% to -0.67% (control), for ventricles: 4.6% to 10.2% (AD) and 1.2% to 3.4% (control), and for hippocampi: -1.5% to -7.0% (AD) and -0.4% to -1.4% (control). There were large and statistically significant differences in the sample size requirements between many of the techniques. The lowest sample sizes for each of these structures, for a trial with a 12month follow-up period, were 242 (95% CI: 154 to 422) for whole brain, 168 (95% CI: 112 to 282) for ventricles, 190 (95% CI: 146 to 268) for left hippocampi, and 158 (95% CI: 116 to 228) for right hippocampi. This analysis represents one of the most extensive statistical comparisons of a large number of different atrophy measurement techniques from around the globe. The challenge data will remain online and publicly available so that other groups can assess their methods. Copyright © 2015. Published by Elsevier Inc.

Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge

PubMed Central

Cash, David M.; Frost, Chris; Iheme, Leonardo O.; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B.; Pennec, Xavier; Pierson, Ronald K.; Gunter, Jeffrey L.; Senjem, Matthew L.; Jack, Clifford R.; Guizard, Nicolas; Fonov, Vladimir S.; Collins, D. Louis; Modat, Marc; Cardoso, M. Jorge; Leung, Kelvin K.; Wang, Hongzhi; Das, Sandhitsu R.; Yushkevich, Paul A.; Malone, Ian B.; Fox, Nick C.; Schott, Jonathan M.; Ourselin, Sebastien

2015-01-01

Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated “direct” measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the distribution of atrophy rates in the Alzheimer's disease (AD) and control groups and of required sample sizes to detect a 25% treatment effect, in relation to healthy ageing, with 95% significance and 80% power over follow-up periods of 6, 12, and 24 months. Uncertainty in these estimates, and head-to-head comparisons between techniques, were carried out using the bootstrap. The lateral ventricles provided the most stable measurements, followed by the brain. The hippocampi had much more variability across participants, likely because of differences in segmentation protocol and less distinct boundaries. Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity. The resulting annualized rates of change derived from the model ranged from, for whole brain: − 1.4% to − 2.2% (AD) and − 0.35% to − 0.67% (control), for ventricles: 4.6% to 10.2% (AD) and 1.2% to 3.4% (control), and for hippocampi: − 1.5% to − 7.0% (AD) and − 0.4% to − 1.4% (control). There were large and statistically significant differences in the sample size requirements between many of the techniques. The lowest sample sizes for each of these structures, for a trial with a 12 month follow-up period, were 242 (95% CI: 154 to 422) for whole brain, 168 (95% CI: 112 to 282) for ventricles, 190 (95% CI: 146 to 268) for left hippocampi, and 158 (95% CI: 116 to 228) for right hippocampi. This analysis represents one of the most extensive statistical comparisons of a large number of different atrophy measurement techniques from around the globe. The challenge data will remain online and publicly available so that other groups can assess their methods. PMID:26275383

Comparison of Fundus Autofluorescence Between Fundus Camera and Confocal Scanning Laser Ophthalmoscope–based Systems

PubMed Central

Park, Sung Pyo; Siringo, Frank S.; Pensec, Noelle; Hong, In Hwan; Sparrow, Janet; Barile, Gaetano; Tsang, Stephen H.; Chang, Stanley

2015-01-01

BACKGROUND AND OBJECTIVE To compare fundus autofluorescence (FAF) imaging via fundus camera (FC) and confocal scanning laser ophthalmoscope (cSLO). PATIENTS AND METHODS FAF images were obtained with a digital FC (530 to 580 nm excitation) and a cSLO (488 nm excitation). Two authors evaluated correlation of autofluorescence pattern, atrophic lesion size, and image quality between the two devices. RESULTS In 120 eyes, the autofluorescence pattern correlated in 86% of lesions. By lesion subtype, correlation rates were 100% in hemorrhage, 97% in geographic atrophy, 82% in flecks, 75% in drusen, 70% in exudates, 67% in pigment epithelial detachment, 50% in fibrous scars, and 33% in macular hole. The mean lesion size in geographic atrophy was 4.57 ± 2.3 mm2 via cSLO and 3.81 ± 1.94 mm2 via FC (P < .0001). Image quality favored cSLO in 71 eyes. CONCLUSION FAF images were highly correlated between the FC and cSLO. Differences between the two devices revealed contrasts. Multiple image capture and confocal optics yielded higher image contrast with the cSLO, although acquisition and exposure time was longer. PMID:24221461

Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program

PubMed Central

Hindi, Sajedah M.; Mishra, Vivek; Bhatnagar, Shephali; Tajrishi, Marjan M.; Ogura, Yuji; Yan, Zhen; Burkly, Linda C.; Zheng, Timothy S.; Kumar, Ashok

2014-01-01

Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and TNF-like weak inducer of apoptosis (TWEAK)-Fn14 system are key regulators of skeletal muscle mass in various catabolic states. While the activation of TWEAK-Fn14 signaling causes muscle wasting, PGC-1α preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1α and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1α and mitochondrial content (∼50%) in skeletal muscle. Levels of PGC-1α are significantly increased in skeletal muscle of TWEAK-knockout (KO) and Fn14-KO mice compared to wild-type mice on denervation. Transgenic (Tg) overexpression of PGC-1α inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1α inhibited the TWEAK-induced activation of NF-κB (∼50%) and dramatically reduced (∼90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1α also prevented the inducible expression of Fn14 in denervated skeletal muscle. Collectively, our study demonstrates that TWEAK induces muscle atrophy through repressing the levels of PGC-1α. Overexpression of PGC-1α not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.—Hindi, S. M., Mishra, V., Bhatnagar, S., Tajrishi, M. M., Ogura, Y., Yan, Z., Burkly, L. C., Zheng, T. S., Kumar, A. Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program. PMID:24327607

Heart rate variability regression and risk of sudden unexpected death in epilepsy.

PubMed

Galli, Alessio; Lombardi, Federico

2017-02-01

The exact mechanisms of sudden unexpected death in epilepsy remain elusive, despite there is consensus that SUDEP is associated with severe derangements in the autonomic control to vital functions as breathing and heart rate regulation. Heart rate variability (HRV) has been advocated as biomarker of autonomic control to the heart. Cardiac dysautonomia has been found in diseases where other branches of the autonomous nervous system are damaged, as Parkinson disease and multiple system atrophy. In this perspective, an impaired HRV not only is a risk factor for sudden cardiac death mediated by arrhythmias, but also a potential biomarker for monitoring a progressive decline of the autonomous nervous system. This slope may lead to an acute imbalance of the regulatory pathways of vital functions after seizure and then to SUDEP. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.

PubMed

Kim, Gloria; Chu, Renxin; Yousuf, Fawad; Tauhid, Shahamat; Stazzone, Lynn; Houtchens, Maria K; Stankiewicz, James M; Severson, Christopher; Kimbrough, Dorlan; Quintana, Francisco J; Chitnis, Tanuja; Weiner, Howard L; Healy, Brian C; Bakshi, Rohit

2017-11-01

The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml (-1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.

Cognitive performance in multiple sclerosis: the contribution of intellectual enrichment and brain MRI measures.

PubMed

Santangelo, Gabriella; Bisecco, Alvino; Trojano, Luigi; Sacco, Rosaria; Siciliano, Mattia; d'Ambrosio, Alessandro; Della Corte, Marida; Lavorgna, Luigi; Bonavita, Simona; Tedeschi, Gioacchino; Gallo, Antonio

2018-05-26

Cognitive reserve (CR) is a construct that originates from the observation of poor correspondence between brain damage and clinical symptoms. The aim of the study was to investigate the association between cognitive reserve (CR), brain reserve (BR) and cognitive functions and to evaluate whether CR might attenuate/moderate the negative impact of brain atrophy and lesion load on cognitive functions in multiple sclerosis (MS). To achieve these aims, ninety-eight relapsing-remitting MS patients underwent the brief repeatable battery of neuropsychological tests and Stroop test (ST). CR was assessed by vocabulary-based estimate of lifetime intellectual enrichment. All patients underwent a 3T MRI to assess T2-lesion load and atrophy measures, including normalized gray matter and white matter (nWMV) volumes. The BR was evaluated by maximal lifetime brain volume expressed by intracranial volume (ICV). Hierarchical regressions were used to investigate whether higher BR and/or CR is related to better cognitive performances after controlling for potentially confounding factors. The ICV was not associated with any cognitive tests. Intellectual enrichment was positively associated with performance on tests assessing memory, attention and information processing speed, verbal fluency and inhibitory control. Significant relationship between nWMV and ST was moderated by intellectual enrichment. In conclusion, the findings suggested that CR seems to mitigate cognitive dysfunction in MS patients and can reduce the negative impact of brain atrophy on inhibitory control, relevant for integrity of instrumental activities of daily living.

Longitudinal and cross-sectional structural magnetic resonance imaging correlates of AV-1451 uptake.

PubMed

Das, Sandhitsu R; Xie, Long; Wisse, Laura E M; Ittyerah, Ranjit; Tustison, Nicholas J; Dickerson, Bradford C; Yushkevich, Paul A; Wolk, David A

2018-06-01

We examined the relationship between in vivo estimates of tau deposition as measured by 18 F-AV-1451 tau positron emission tomography imaging and cross-sectional cortical thickness, as well as rates of antecedent cortical thinning measured from magnetic resonance imaging in individuals with and without evidence of cerebral amyloid in 63 participants from the Alzheimer's Disease Neuroimaging Initiative study, including 32 cognitively normal individuals (mean age 74 years), 27 patients with mild cognitive impairment (mean age 76.8 years), and 4 patients diagnosed with Alzheimer's disease (mean age 80 years). We hypothesized that structural measures would correlate with 18 F-AV-1451 in a spatially local manner and that this correlation would be stronger for longitudinal compared to cross-sectional measures of cortical thickness and in those with cerebral amyloid versus those without. Cross-sectional and longitudinal estimates of voxelwise atrophy were made from whole brain maps of cortical thickness and rates of thickness change. In amyloid-β-positive individuals, the correlation of voxelwise atrophy across the whole brain with a summary measure of medial temporal lobe (MTL) 18 F-AV-1451 uptake demonstrated strong local correlations in the MTL with longitudinal atrophy that was weaker in cross-sectional analysis. Similar effects were seen in correlations between 31 bilateral cortical regions of interest. In addition, several nonlocal correlations between atrophy and 18 F-AV-1451 uptake were observed, including association between MTL atrophy and 18 F-AV-1451 uptake in parietal lobe regions of interest such as the precuneus. Amyloid-β-negative individuals only showed weaker correlations in data uncorrected for multiple comparisons. While these data replicate previous reports of associations between 18 F-AV-1451 uptake and cross-sectional structural measures, the current results demonstrate a strong relationship with longitudinal measures of atrophy. These data support the notion that in vivo measures of tau pathology are tightly linked to the rate of neurodegenerative change. Copyright © 2018 Elsevier Inc. All rights reserved.

Counteracting Muscle Atrophy using Galvanic Stimulation of the Vestibular System

NASA Technical Reports Server (NTRS)

Fox, Robert A.; Polyakov, Igor

1999-01-01

The unloading of weight bearing from antigravity muscles during space flight produces significant muscle atrophy and is one of the most serious health problems facing the space program. Various exercise regimens have been developed and used either alone or in combination with pharmacological techniques to ameliorate this atrophy, but no effective countermeasure exists for this problem. The research in this project was conducted to evaluate the potential use of vestibular galvanic stimulation (VGS) to prevent muscle atrophy resulting from unloading of weight bearing from antigravity muscles. This approach was developed based on two concepts related to the process of maintaining the status of the anti-gravity neuromuscular system. These two premises are: (1) The "tone," or bias on spinal motorneurons is affected by vestibular projections that contribute importantly to maintaining muscle health and status. (2) VGS can be used to modify the excitability, or 'tone' of motorneuron of antigravity muscles. Thus, the strategy is to use VGS to modify the gain of vestibular projections to antigravity muscles and thereby change the general status of these muscles.

Factors to improve the interobserver agreement for gastric atrophy and intestinal metaplasia: consensus of definition and criteria.

PubMed

Kim, Sung Sun; Kook, Myeong-Cherl; Shin, Ok-Ran; Kim, Hee Sung; Bae, Han-Ik; Seo, An Na; Park, Do Youn; Choi, Il Ju; Kim, Young-Il; Nam, Byung Ho; Kim, Sohee

2018-04-01

Intestinal metaplasia and atrophy of the gastric mucosa are associated with Helicobacter pylori infection and are considered premalignant lesions. The updated Sydney system is used for these parameters, but experienced pathologists and consensus processes are required for interobserver agreement. We sought to determine the influence of the consensus process on the assessment of intestinal metaplasia and atrophy. Two study sets were used: consensus and validation. The consensus set was circulated and five gastrointestinal pathologists evaluated them independently using the updated Sydney system. The consensus of the definitions was then determined at the first consensus meeting. The same set was recirculated to determine the effect of the consensus. The second consensus meeting was held to standardise the grading criteria and the validation set was circulated to determine the influence. Two additional circulations were performed to assess the maintainance of consensus and intraobserver variability. Interobserver agreement of intestinal metaplasia and atrophy was improved through the consensus process (intestinal metaplasia: baseline κ = 0.52 versus final κ = 0.68, P = 0.006; atrophy: baseline κ = 0.19 versus final κ = 0.43, P < 0.001). Higher interobserver agreement in atrophy was observed after consensus regarding the definition (pre-consensus: κ = 0.19 versus post-consensus: κ = 0.34, P = 0.001). There was improved interobserver agreement in intestinal metaplasia after standardisation of the grading criteria (pre-standardisation: κ = 0.56 versus post-standardisation: κ = 0.71, P = 0.010). This study suggests that interobserver variability regarding intestinal metaplasia and atrophy may result from lack of a precise definition and fine criteria, and can be reduced by consensus of definition and standardisation of grading criteria. © 2017 John Wiley & Sons Ltd.

Extending the range of differential diagnosis of chronic traumatic encephalopathy of the boxer: Insights from a case report

PubMed Central

Caixeta, Leonardo; Dangoni, Iron; de Sousa, Rafael Dias; Soares, Pedro Paulo Dias; Mendonça, Andreia Costa Rabelo

2018-01-01

ABSTRACT Sports activities associated with repetitive cranial trauma have become a fad and are popular in gyms and even among children. It is important to consistently characterize the consequences of such sports activities in order to better advise society on the real risks to the central nervous system. We present the case of a former boxer reporting cognitive and behavioral symptoms that began six years after his retirement as a boxer, evolving progressively with parkinsonian and cerebellar features suggestive of probable chronic traumatic encephalopathy (CTE). Using our case as a paradigm, we extended the range of differential diagnosis of CTE, including corticobasal degeneration, multiple system atrophy, vitamin B12 deficiency, neurosyphilis, frontotemporal dementia and Alzheimer’s disease. PMID:29682240

Imaging spinal cord atrophy in progressive myelopathies: HTLV-I-associated neurological disease (HAM/TSP) and multiple sclerosis (MS).

PubMed

Azodi, Shila; Nair, Govind; Enose-Akahata, Yoshimi; Charlip, Emily; Vellucci, Ashley; Cortese, Irene; Dwyer, Jenifer; Billioux, B Jeanne; Thomas, Chevaz; Ohayon, Joan; Reich, Daniel S; Jacobson, Steven

2017-11-01

Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers. Spinal cord cross-sectional area was measured in individuals (24 healthy controls [HCs], 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 relapsing-remitting MS [RRMS], 17 secondary progressive MS [SPMS], and 40 primary progressive MS [PPMS]) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross-sectional area regions at the C2 to C3, C4 to C5, and T4 to T9 levels. In 2 HAM/TSP patients, spinal cord cross-sectional area was measured over 3 years. All spinal cord regions are thinner in HAM/TSP (56 mm 2 [standard deviation, 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (Expanded Disability Status Scale [p = 0.009] and Instituto de Pesquisas de Cananeia [p = 0.03]) and CD8 + T-cell frequency (p = 0.04) correlate with T4 to T9 spinal cord cross-sectional area in HAM/TSP. Higher cerebrospinal fluid HTLV-1 proviral load (p = 0.01) was associated with thinner spinal cord cross-sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning. Group average spinal cord cross-sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize in HAM/TSP that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. Ann Neurol 2017;82:719-728. © 2017 American Neurological Association.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials.

PubMed

Verma, Nishant; Beretvas, S Natasha; Pascual, Belen; Masdeu, Joseph C; Markey, Mia K

2018-03-14

Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

PubMed Central

Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji

2014-01-01

The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

Adaptive optics imaging of geographic atrophy.

PubMed

Gocho, Kiyoko; Sarda, Valérie; Falah, Sabrina; Sahel, José-Alain; Sennlaub, Florian; Benchaboune, Mustapha; Ullern, Martine; Paques, Michel

2013-05-01

To report the findings of en face adaptive optics (AO) near infrared (NIR) reflectance fundus flood imaging in eyes with geographic atrophy (GA). Observational clinical study of AO NIR fundus imaging was performed in 12 eyes of nine patients with GA, and in seven controls using a flood illumination camera operating at 840 nm, in addition to routine clinical examination. To document short term and midterm changes, AO imaging sessions were repeated in four patients (mean interval between sessions 21 days; median follow up 6 months). As compared with scanning laser ophthalmoscope imaging, AO NIR imaging improved the resolution of the changes affecting the RPE. Multiple hyporeflective clumps were seen within and around GA areas. Time-lapse imaging revealed micrometric-scale details of the emergence and progression of areas of atrophy as well as the complex kinetics of some hyporeflective clumps. Such dynamic changes were observed within as well as outside atrophic areas. in eyes affected by GA, AO nir imaging allows high resolution documentation of the extent of RPE damage. this also revealed that a complex, dynamic process of redistribution of hyporeflective clumps throughout the posterior pole precedes and accompanies the emergence and progression of atrophy. therefore, these clumps are probably also a biomarker of rpe damage. AO NIR imaging may, therefore, be of interest to detect the earliest stages, to document the retinal pathology and to monitor the progression oF GA. (ClinicalTrials.gov number, NCT01546181.).

Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats.

PubMed

Reddy, S Sreenivasa; Shruthi, Karnam; Prabhakar, Y Konda; Sailaja, Gummadi; Reddy, G Bhanuprakash

2018-02-01

Skeletal muscle is adversely affected in type-1 diabetes, and excessively stimulated ubiquitin-proteasome system (UPS) was found to be a leading cause of muscle wasting or atrophy. The role of endoplasmic reticulum (ER) stress in muscle atrophy of type-1 diabetes is not known. Hence, we investigated the role of UPS and ER stress in the muscle atrophy of chronic diabetes rat model. Diabetes was induced with streptozotocin (STZ) in male Sprague-Dawley rats and were sacrificed 2- and 4-months thereafter to collect gastrocnemius muscle. In another experiment, 2-months post-STZ-injection diabetic rats were treated with MG132, a proteasome inhibitor, for the next 2-months and gastrocnemius muscle was collected. The muscle fiber cross-sectional area was diminished in diabetic rats. The expression of UPS components: E1, MURF1, TRIM72, UCHL1, UCHL5, ubiquitinated proteins, and proteasome activity were elevated in the diabetic rats indicating activated UPS. Altered expression of ER-associated degradation (ERAD) components and increased ER stress markers were detected in 4-months diabetic rats. Proteasome inhibition by MG132 alleviated alterations in the UPS and ER stress in diabetic rat muscle. Increased UPS activity and ER stress were implicated in the muscle atrophy of diabetic rats and proteasome inhibition exhibited beneficiary outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

White matter lesions and brain atrophy in systemic lupus erythematosus patients: correlation to cognitive dysfunction in a cohort of systemic lupus erythematosus patients using different definition models for neuropsychiatric systemic lupus erythematosus.

PubMed

Cannerfelt, B; Nystedt, J; Jönsen, A; Lätt, J; van Westen, D; Lilja, A; Bengtsson, A; Nilsson, P; Mårtensson, J; Sundgren, P C

2018-06-01

Aim The aim of this study was to evaluate the extent of white matter lesions, atrophy of the hippocampus and corpus callosum, and their correlation with cognitive dysfunction (CD), in patients diagnosed with systemic lupus erythematosus (SLE). Methods Seventy SLE patients and 25 healthy individuals (HIs) were included in the study. To evaluate the different SLE and neuropsychiatric SLE (NPSLE) definition schemes, patients were grouped both according to the American College of Rheumatology (ACR) definition, as well as the more stringent ACR-Systemic Lupus International Collaborating Clinics definition. Patients and HIs underwent a 3 Tesla brain MRI and a standardized neuropsychological test. MRI data were evaluated for number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum. Differences between groups and subgroups were evaluated for significance. Number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum were correlated to cognitive dysfunction. Results The total volume of white matter lesions was significantly larger in SLE patients compared to HIs ( p = 0.004). However, no significant differences were seen between the different SLE subgroups. Atrophy of the bilateral hippocampus was significantly more pronounced in patients with NPSLE compared to those with non-NPSLE (right: p = 0.010; left p = 0.023). Significant negative correlations between cognitive test scores on verbal memory and number and volume of white matter lesions were present. Conclusion SLE patients have a significantly larger volume of white matter lesions on MRI compared to HIs and the degree of white matter lesion volume correlates to cognitive dysfunction, specifically to verbal memory. No significant differences in the number or volume of white matter lesions were identified between subgroups of SLE patients regardless of the definition model used.

Gender effects on age-related changes in brain structure.

PubMed

Xu, J; Kobayashi, S; Yamaguchi, S; Iijima, K; Okada, K; Yamashita, K

2000-01-01

Previous reports have suggested that brain atrophy is associated with aging and that there are gender differences in brain atrophy with aging. These reports, however, neither exclude silent brain lesions in "healthy subjects" nor divide the brain into subregions. The aim of this study is to clarify the effect of gender on age-related changes in brain subregions by MR imaging. A computer-assisted system was used to calculate the brain matter area index (BMAI) of various regions of the brain from MR imaging of 331 subjects without brain lesions. There was significantly more brain atrophy with aging in the posterior parts of the right frontal lobe in male subjects than there was in female subjects. Age-related atrophy in the middle part of the right temporal lobe, the left basal ganglia, the parietal lobe, and the cerebellum also was found in male subjects, but not in female subjects. In the temporal lobe, thalamus, parieto-occipital lobe, and cerebellum, brain volume in the left hemisphere is significantly smaller than in the right hemisphere; sex and age did not affect the hemisphere differences of brain volume in these regions. The effect of gender on brain atrophy with aging varied in different subregions of the brain. There was more brain atrophy with aging in male subjects than in female subjects.

Relation between reflux of bile acids into the stomach and gastric mucosal atrophy, intestinal metaplasia in biopsy specimens.

PubMed

Matsuhisa, Takeshi; Tsukui, Taku

2012-05-01

During endoscopic examinations we collected fluid in the stomach that included reflux fluid from the duodenum, and assessed the effect of quantitatively determined bile acids on glandular atrophy and intestinal metaplasia using biopsy specimens. A total of 294 outpatients were enrolled in this study. Total bile acid concentration was measured by an enzyme immunoassay. Glandular atrophy and intestinal metaplasia scores were graded according to the Updated Sydney System. An effect of refluxed bile acids on atrophy and intestinal metaplasia was shown in the high-concentration reflux group in comparison with the control group. However, when the odds ratios (ORs) were calculated according to whether Helicobacter pylori (H. pylori) infection was present, no significant associations were shown between reflux bile acids and atrophy in either the H. pylori-positive cases or -negative cases. The same was true for intestinal metaplasia in the H. pylori-positive cases, whereas intestinal metaplasia was more pronounced in the high-concentration reflux group in the H. pylori-negative cases (OR 2.4, 95%CI 1.1-5.6). We could not clarify the effect of the reflux of bile acids into the stomach in the progression of atrophy. High-concentration bile acids had an effect on the progression of intestinal metaplasia in the H. pylori-negative cases.

Quantitative and semi-quantitative histopathological examination of renal biopsies in healthy individuals, and associations with kidney function.

PubMed

Bar, Yael; Barregard, Lars; Sallsten, Gerd; Wallin, Maria; Mölne, Johan

2016-05-01

This study assesed the prevalence of histopathological changes in renal biopsies from healthy individuals, and the association with age, sex and smoking. Donor biopsies from 109 subjects were obtained from living kidney donors, and blood and urine samples were collected together with medical history. All biopsies were scored according to the Banff '97 classification with some modifications. The parameters included in this study were tubular atrophy, interstitial fibrosis, glomerulosclerosis, arteriosclerosis, arteriolohyalinosis and a sclerosis score. An alternative scoring system for tubular atrophy was examined (using ≤5% rather than <1% as a cut-off for grade 0). Glomerular filtration rate was measured in most cases as chromium ethylenediaminetetra-acetic acid (Cr-EDTA) clearance. Age was a significant predictor for tubular atrophy, fibrosis and sclerosis. Pack-years of smoking increased the risk of tubular atrophy, fibrosis and arteriolohyalinosis. The alternative scoring of tubular atrophy showed a stronger association with smoking, but a weaker association with age, compared with the original one. Limited histopathological changes are common in healthy kidney donors around 50 years of age with normal kidney function. We propose that a cut-off of ≤5% yields a better definition of grade 0 tubular atrophy compared with the established cut-off of >0%. © 2016 APMIS. Published by John Wiley & Sons Ltd.

Skeletal muscle atrophy in bioengineered skeletal muscle: a new model system.

PubMed

Lee, Peter H U; Vandenburgh, Herman H

2013-10-01

Skeletal muscle atrophy has been well characterized in various animal models, and while certain pathways that lead to disuse atrophy and its associated functional deficits have been well studied, available drugs to counteract these deficiencies are limited. An ex vivo tissue-engineered skeletal muscle offers a unique opportunity to study skeletal muscle physiology in a controlled in vitro setting. Primary mouse myoblasts isolated from adult muscle were tissue engineered into bioartificial muscles (BAMs) containing hundreds of aligned postmitotic muscle fibers expressing sarcomeric proteins. When electrically stimulated, BAMs generated measureable active forces within 2-3 days of formation. The maximum isometric tetanic force (Po) increased for ∼3 weeks to 2587±502 μN/BAM and was maintained at this level for greater than 80 days. When BAMs were reduced in length by 25% to 50%, muscle atrophy occurred in as little as 6 days. Length reduction resulted in significant decreases in Po (50.4%), mean myofiber cross-sectional area (21.7%), total protein synthesis rate (22.0%), and noncollagenous protein content (6.9%). No significant changes occurred in either the total metabolic activity or protein degradation rates. This study is the first in vitro demonstration that length reduction alone can induce skeletal muscle atrophy, and establishes a novel in vitro model for the study of skeletal muscle atrophy.

Pulmonary inflammation-induced loss and subsequent recovery of skeletal muscle mass require functional poly-ubiquitin conjugation.

PubMed

Ceelen, Judith J M; Schols, Annemie M W J; Thielen, Nathalie G M; Haegens, Astrid; Gray, Douglas A; Kelders, Marco C J M; de Theije, Chiel C; Langen, Ramon C J

2018-05-02

Pulmonary inflammation in response to respiratory infections can evoke muscle wasting. Increased activity of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Since poly-Ub conjugation is required for UPS-mediated proteolysis and has been implicated in the ALP, we assessed the effect of impaired ubiquitin conjugation on muscle atrophy and recovery following pulmonary inflammation, and compared activation and suppression of these proteolytic systems to protein synthesis regulation. Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS. Proteolysis (UPS and ALP) and synthesis signaling were examined in gastrocnemius muscle homogenates. Ub-conjugation-dependency of muscle atrophy and recovery was addressed using Ub-K48R (K48R) mice with attenuated poly-ubiquitin conjugation, and compared to UBWT control mice. Pulmonary inflammation caused a decrease in skeletal muscle mass which was accompanied by a rapid increase in expression of UPS and ALP constituents and reduction in protein synthesis signaling acutely after LPS. Muscle atrophy was attenuated in K48R mice, while ALP and protein synthesis signaling were not affected. Muscle mass recovery starting 72 h post LPS, correlated with reduced expression of UPS and ALP constituents and restoration of protein synthesis signaling. K48R mice however displayed impaired recovery of muscle mass. Pulmonary inflammation-induced muscle atrophy is in part attributable to UPS-mediated proteolysis, as activation of ALP- and suppression of protein synthesis signaling occur independently of poly-Ub conjugation during muscle atrophy. Recovery of muscle mass following pulmonary inflammation involves inverse regulation of proteolysis and protein synthesis signaling, and requires a functional poly-Ub conjugation.

Short-term, daily exposure to cold temperature may be an efficient way to prevent muscle atrophy and bone loss in a microgravity environment

NASA Astrophysics Data System (ADS)

Deng, Claudia; Wang, Ping; Zhang, Xiangming; Wang, Ya

2015-04-01

Microgravity induces less pressure on muscle/bone, which is a major reason for muscle atrophy as well as bone loss. Currently, physical exercise is the only countermeasure used consistently in the U.S. human space program to counteract the microgravity-induced skeletal muscle atrophy and bone loss. However, the routinely almost daily time commitment is significant and represents a potential risk to the accomplishment of other mission operational tasks. Therefore, development of more efficient exercise programs (with less time) to prevent astronauts from muscle atrophy and bone loss are needed. Consider the two types of muscle contraction: exercising forces muscle contraction and prevents microgravity-induced muscle atrophy/bone loss, which is a voluntary response through the motor nervous system; and cold temperature exposure-induced muscle contraction is an involuntary response through the vegetative nervous system, we formed a new hypothesis. The main purpose of this pilot study was to test our hypothesis that exercise at 4 °C is more efficient than at room temperature to prevent microgravity-induced muscle atrophy/bone loss and, consequently reduces physical exercise time. Twenty mice were divided into two groups with or without daily short-term (10 min × 2, at 12 h interval) cold temperature (4 °C) exposure for 30 days. The whole bodyweight, muscle strength and bone density were measured after terminating the experiments. The results from the one-month pilot study support our hypothesis and suggest that it would be reasonable to use more mice, in a microgravity environment and observe for a longer period to obtain a conclusion. We believe that the results from such a study will help to develop efficient exercise, which will finally benefit astronauts' heath and NASA's missions.

mRNA-seq reveals skeletal muscle atrophy in response to handling stress in a marine teleost, the red cusk-eel (Genypterus chilensis).

PubMed

Aedo, Jorge E; Maldonado, Jonathan; Aballai, Víctor; Estrada, Juan M; Bastias-Molina, Macarena; Meneses, Claudio; Gallardo-Escarate, Cristian; Silva, Herman; Molina, Alfredo; Valdés, Juan A

2015-12-01

Fish reared under intensive conditions are repeatedly exposed to stress, which negatively impacts growth. Although most fish follow a conserved pattern of stress response, with increased concentrations of cortisol, each species presents specificities in the cell response and stress tolerance. Therefore, culturing new species requires a detailed knowledge of these specific responses. The red cusk-eel (Genypterus chilensis) is a new economically important marine species for the Chilean aquaculture industry. However, there is no information on the stress- and cortisol-induced mechanisms that decrease skeletal muscle growth in this teleost. Using Illumina RNA-seq technology, skeletal muscle sequence reads for G. chilensis were generated under control and handling stress conditions. Reads were mapped onto a reference transcriptome, resulting in the in silico identification of 785 up-regulated and 167 down-regulated transcripts. Gene ontology enrichment analysis revealed a significant up-regulation of catabolic genes associated with skeletal muscle atrophy. These results were validated by RT-qPCR analysis for ten candidates genes involved in ubiquitin-mediated proteolysis, autophagy and skeletal muscle growth. Additionally, using a primary culture of fish skeletal muscle cells, the effect of cortisol was evaluated in relation to red cusk-eel skeletal muscle atrophy. The present data demonstrated that handling stress promotes skeletal muscle atrophy in the marine teleost G. chilensis through the expression of components of the ubiquitin-proteasome and autophagy-lysosome systems. Furthermore, cortisol was a powerful inductor of skeletal muscle atrophy in fish myotubes. This study is an important step towards understanding the atrophy system in non-model teleost species and provides novel insights on the cellular and molecular mechanisms that control skeletal muscle growth in early vertebrates.

Short-term, daily exposure to cold temperature may be an efficient way to prevent muscle atrophy and bone loss in a microgravity environment

PubMed Central

Deng, Claudia; Wang, Ping; Zhang, Xiangming; Wang, Ya

2015-01-01

Microgravity induces less pressure on muscle/bone, which is a major reason for muscle atrophy as well as bone loss. Currently, physical exercise is the only countermeasure used consistently in the U.S. human space program to counteract the microgravity-induced skeletal muscle atrophy and bone loss. However, the routinely almost daily time commitment is significant and represents a potential risk to the accomplishment of other mission operational tasks. Therefore, development of more efficient exercise programs (with less time) to prevent astronauts from muscle atrophy and bone loss are needed. Consider the two types of muscle contraction: exercising forces muscle contraction and prevents microgravity-induced muscle atrophy/bone loss, which is a voluntary response through the motor nervous system; and cold temperature exposure-induced muscle contraction is an involuntary response through the vegetative nervous system, we formed a new hypothesis. The main purpose of this pilot study was to test our hypothesis that exercise at 4°C is more efficient than at room temperature to prevent microgravity-induced muscle atrophy/bone loss and, consequently reduces physical exercise time. Twenty mice were divided into two groups with or without daily short-term (10 min × 2, at 12 h interval) cold temperature (4°C) exposure for 30 days. The whole bodyweight, muscle strength and bone density were measured after terminating the experiments. The results from the one-month pilot study support our hypothesis and suggest that it would be reasonable to use more mice, in a microgravity environment and observe for a longer period to obtain a conclusion. We believe that the results from such a study will help to develop efficient exercise, which will finally benefit astronauts’ heath and NASA’s mission. PMID:25821722

The Long-term Natural History of Geographic Atrophy from Age-Related Macular Degeneration

PubMed Central

Sunness, Janet S.; Margalit, Eyal; Srikumaran, Divya; Applegate, Carol A.; Tian, Yan; Perry, Daniel; Hawkins, Barbara S.; Bressler, Neil M.

2008-01-01

Purpose To report the enlargement rate of geographic atrophy (GA) over time, its relationship to size of atrophy at baseline and to prior enlargement rate, and the implications for designing future treatment trials for GA. Design Prospective natural history study of GA resulting from age-related macular degeneration. Participants Two hundred twelve eyes of 131 patients were included in the analysis. Methods Annual follow-up included stereo color fundus photographs. The areas of GA were identified and measured, and the rate of enlargement of the atrophy was assessed. Sample sizes for clinical trials using systemic treatment and uniocular treatment were determined. Main Outcome Measure Rate of enlargement of the atrophy. Results The median overall enlargement rate was 2.1 mm2/year (mean, 2.6 mm2/year). Eyes with larger areas of atrophy at baseline tended to have larger enlargement rates, but knowledge of prior rates of enlargement was the most significant factor in predicting subsequent enlargement rates. There was high concordance between the enlargement rates in the 2 eyes of patients with bilateral GA (correlation coefficient, 0.76). To detect a 25% reduction in enlargement rate for a systemic treatment (α, 0.05; power, 0.80; losses to follow-up, 15%), 153 patients each in a control and treatment group would be required for a trial with a 2-year follow-up period for each patient. For a uniocular treatment, 38 patients with bilateral GA would be required, with the untreated eye serving as a control for the treated eye. Conclusions Treatment trials for GA with an outcome variable of change in enlargement rate are feasible. PMID:17270676

Global brain atrophy is associated with physical performance and the risk of falls in older adults with cognitive impairment.

PubMed

Yamada, Minoru; Takechi, Hajime; Mori, Shuhei; Aoyama, Tomoki; Arai, Hidenori

2013-04-01

Falls are common in patients with cognitive disorder. The purpose of this study was to determine whether global brain atrophy is associated with cognitive function, physical performance and fall incidents in older adults with mild cognitive disorder. A total of 31 older adults with mild cognitive disorders (mean age 78.9 ± 7.3 years) were studied, and 10 of them had experienced falls and the others had not in the past 1 year. Cognitive function and physical performance were measured in these patients. Global brain atrophy was determined by the Voxel-Based Specific Regional Analysis System for Alzheimer's Disease software. Fallers showed significantly worse scores than the non-fallers in the Global Brain Atrophy Index, Clock Drawing Test (CDT), Verbal Fluency Test (animal), maximum walking time and Timed Up & Go (TUG) Test. The Global Brain Atrophy Index was correlated with the Verbal Fluency Test (animal; r = -0.522), the Verbal Fluency Test with letter (ka; r = -0.337), CDT (r = -0.547), TUG (r = 0.276) and Five Chair Stands Test (r = 0.303) by age-adjusted correlation analyses. Stepwise regression analysis showed that the Global Brain Atrophy Index (β = 1.265, 95% CI 1.022-1.567) was a significant and independent determinant of falls (R(2) = 0.356, P = 0.003). Global brain atrophy might be indicated as one of the risk factors for falls in older adults with mild cognitive disorders. © 2012 Japan Geriatrics Society.

Cascaded discrimination of normal, abnormal, and confounder classes in histopathology: Gleason grading of prostate cancer

PubMed Central

2012-01-01

Background Automated classification of histopathology involves identification of multiple classes, including benign, cancerous, and confounder categories. The confounder tissue classes can often mimic and share attributes with both the diseased and normal tissue classes, and can be particularly difficult to identify, both manually and by automated classifiers. In the case of prostate cancer, they may be several confounding tissue types present in a biopsy sample, posing as major sources of diagnostic error for pathologists. Two common multi-class approaches are one-shot classification (OSC), where all classes are identified simultaneously, and one-versus-all (OVA), where a “target” class is distinguished from all “non-target” classes. OSC is typically unable to handle discrimination of classes of varying similarity (e.g. with images of prostate atrophy and high grade cancer), while OVA forces several heterogeneous classes into a single “non-target” class. In this work, we present a cascaded (CAS) approach to classifying prostate biopsy tissue samples, where images from different classes are grouped to maximize intra-group homogeneity while maximizing inter-group heterogeneity. Results We apply the CAS approach to categorize 2000 tissue samples taken from 214 patient studies into seven classes: epithelium, stroma, atrophy, prostatic intraepithelial neoplasia (PIN), and prostate cancer Gleason grades 3, 4, and 5. A series of increasingly granular binary classifiers are used to split the different tissue classes until the images have been categorized into a single unique class. Our automatically-extracted image feature set includes architectural features based on location of the nuclei within the tissue sample as well as texture features extracted on a per-pixel level. The CAS strategy yields a positive predictive value (PPV) of 0.86 in classifying the 2000 tissue images into one of 7 classes, compared with the OVA (0.77 PPV) and OSC approaches (0.76 PPV). Conclusions Use of the CAS strategy increases the PPV for a multi-category classification system over two common alternative strategies. In classification problems such as histopathology, where multiple class groups exist with varying degrees of heterogeneity, the CAS system can intelligently assign class labels to objects by performing multiple binary classifications according to domain knowledge. PMID:23110677

Mesenchymal stem cells can modulate longitudinal changes in cortical thickness and its related cognitive decline in patients with multiple system atrophy

PubMed Central

Sunwoo, Mun Kyung; Yun, Hyuk Jin; Song, Sook K.; Ham, Ji Hyun; Hong, Jin Yong; Lee, Ji E.; Lee, Hye S.; Sohn, Young H.; Lee, Jong-Min; Lee, Phil Hyu

2014-01-01

Multiple system atrophy (MSA) is an adult-onset, sporadic neurodegenerative disease. Because the prognosis of MSA is fatal, neuroprotective or regenerative strategies may be invaluable in MSA treatment. Previously, we obtained clinical and imaging evidence that mesenchymal stem cell (MSC) treatment could have a neuroprotective role in MSA patients. In the present study, we evaluated the effects of MSC therapy on longitudinal changes in subcortical deep gray matter volumes and cortical thickness and their association with cognitive performance. Clinical and imaging data were obtained from our previous randomized trial of autologous MSC in MSA patients. During 1-year follow-up, we assessed longitudinal differences in automatic segmentation-based subcortical deep gray matter volumes and vertex-wise cortical thickness between placebo (n = 15) and MSC groups (n = 11). Next, we performed correlation analysis between the changes in cortical thickness and changes in the Korean version of the Montreal Cognitive Assessment (MoCA) scores and cognitive performance of each cognitive subdomain using a multiple, comparison correction. There were no significant differences in age at baseline, age at disease onset, gender ratio, disease duration, clinical severity, MoCA score, or education level between the groups. The automated subcortical volumetric analysis revealed that the changes in subcortical deep gray matter volumes of the caudate, putamen, and thalamus did not differ significantly between the groups. The areas of cortical thinning over time in the placebo group were more extensive, including the frontal, temporal, and parietal areas, whereas these areas in the MSC group were less extensive. Correlation analysis indicated that declines in MoCA scores and phonemic fluency during the follow-up period were significantly correlated with cortical thinning of the frontal and posterior temporal areas and anterior temporal areas in MSA patients, respectively. In contrast, no significant correlations were observed in the MSC group. These results suggest that MSC treatment in patients with MSA may modulate cortical thinning over time and related cognitive performance, inferring a future therapeutic candidate for cognitive disorders. PMID:24982631

Hippocampal atrophy and memory dysfunction associated with physical inactivity in community-dwelling elderly subjects: The Sefuri study.

PubMed

Hashimoto, Manabu; Araki, Yuko; Takashima, Yuki; Nogami, Kohjiro; Uchino, Akira; Yuzuriha, Takefumi; Yao, Hiroshi

2017-02-01

Physical inactivity is one of the modifiable risk factors for hippocampal atrophy and Alzheimer's disease. We investigated the relationship between physical activity, hippocampal atrophy, and memory using structural equation modeling (SEM). We examined 213 community-dwelling elderly subjects (99 men and 114 women with a mean age of 68.9 years) without dementia or clinically apparent depression. All participants underwent Mini-Mental State Examination (MMSE) and Rivermead Behavioral Memory Test (RBMT). Physical activities were assessed with a structured questionnaire. We evaluated the degree of hippocampal atrophy (z-score-referred to as ZAdvance hereafter), using a free software program-the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) based on statistical parametric mapping 8 plus Diffeomorphic Anatomical Registration Through an Exponentiated Lie algebra. Routine magnetic resonance imaging findings were as follows: silent brain infarction, n  = 24 (11.3%); deep white matter lesions, n  = 72 (33.8%); periventricular hyperintensities, n  = 35 (16.4%); and cerebral microbleeds, n  = 14 (6.6%). Path analysis based on SEM indicated that the direct paths from leisure-time activity to hippocampal atrophy (β = -.18, p  < .01) and from hippocampal atrophy to memory dysfunction (RBMT) (β = -.20, p  < .01) were significant. Direct paths from "hippocampus" gray matter volume to RBMT and MMSE were highly significant, while direct paths from "whole brain" gray matter volume to RBMT and MMSE were not significant. The presented SEM model fit the data reasonably well. Based on the present SEM analysis, we found that hippocampal atrophy was associated with age and leisure-time physical inactivity, and hippocampal atrophy appeared to cause memory dysfunction, although we are unable to infer a causal or temporal association between hippocampal atrophy and memory dysfunction from the present observational study.

PSP as distinguished from CBD, MSA-P and PD by clinical and imaging differences at an early stage.

PubMed

Kurata, Tomoko; Kametaka, Satsuki; Ohta, Yasuyuki; Morimoto, Nobutoshi; Deguchi, Shoko; Deguchi, Kentaro; Ikeda, Yoshio; Takao, Yoshiki; Ohta, Taisei; Manabe, Yasuhiro; Sato, Shuhei; Abe, Koji

2011-01-01

Because it is often difficult to precisely diagnose and distinguish progressive supranuclear palsy (PSP) from corticobasal degeneration (CBD), multiple system atrophy-parkinsonism (MSA-P) and Parkinson's disease (PD) at the onset of the disease, we compared the patients and clarified the features of these diseases. We compared 77 PSP, 26 CBD, 26 MSA-P and 166 PD patients from clinical and imaging points of view including cerebral blood flow (CBF) in the frontal eye field. The clinical characteristics of PSP were supranuclear gaze disturbance, optokinetic nystagmus (OKN) impairment and falls at the first visit. On head MRI, midbrain tegmentum atrophy was much more frequently detected in PSP than in all of the other groups. Heart-to-mediastinum average count ratio (H/M) in iodine-123 meta-iodobenzyl guanidine ((123)I-MIBG) myocardial scintigraphy was not decreased in PSP, CBD, MSA-P and PD-Yahr 1 (-1), but patients of PD-2, 3, 4 and 5 showed a significant decrease compared with the PSP group. The CBF in the left frontal eye field of PD-3 group and that in right frontal eye field of PD-3 and PD-4 groups were lower than that of PSP group, although other groups showed a tendency without a significant decrease compared with PSP group. PSP is distinguishable from CBD, MSA-P and PD even at the early stage with extra-ocular movement (EOM) disturbance, falls, atrophy of the midbrain tegmentum, and H/M in (123)I-MIBG myocardial scintigraphy, and the reduction of CBF in area 8 could serve as a supplemental diagnostic method for distinguishing PSP from PD-3 or PD-4.

Multiple micronutrient supplementation transiently ameliorates environmental enteropathy in Malawian children aged 12-35 months in a randomized controlled clinical trial

USDA-ARS?s Scientific Manuscript database

Environmental enteropathy (EE) is subclinical, diffuse villous atrophy characterized by T cell infiltration of the small intestinal mucosa associated with nutrient malabsorption and stunting. EE is assessed by the lactulose:mannitol (L:M) test, whereby nonmetabolized sugars are ingested and quantifi...

Imaging outcome measures for progressive multiple sclerosis trials

PubMed Central

Moccia, Marcello; de Stefano, Nicola; Barkhof, Frederik

2017-01-01

Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Position emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation. PMID:29041865

Hamiltonian Systems and Optimal Control in Computational Anatomy: 100 Years Since D'Arcy Thompson.

PubMed

Miller, Michael I; Trouvé, Alain; Younes, Laurent

2015-01-01

The Computational Anatomy project is the morphome-scale study of shape and form, which we model as an orbit under diffeomorphic group action. Metric comparison calculates the geodesic length of the diffeomorphic flow connecting one form to another. Geodesic connection provides a positioning system for coordinatizing the forms and positioning their associated functional information. This article reviews progress since the Euler-Lagrange characterization of the geodesics a decade ago. Geodesic positioning is posed as a series of problems in Hamiltonian control, which emphasize the key reduction from the Eulerian momentum with dimension of the flow of the group, to the parametric coordinates appropriate to the dimension of the submanifolds being positioned. The Hamiltonian viewpoint provides important extensions of the core setting to new, object-informed positioning systems. Several submanifold mapping problems are discussed as they apply to metamorphosis, multiple shape spaces, and longitudinal time series studies of growth and atrophy via shape splines.

Intranasal Insulin Prevents Cognitive Decline, Cerebral Atrophy and White Matter Changes in Murine Type I Diabetic Encephalopathy

ERIC Educational Resources Information Center

Francis, George J.; Martinez, Jose A.; Liu, Wei Q.; Xu, Kevin; Ayer, Amit; Fine, Jared; Tuor, Ursula I.; Glazner, Gordon; Hanson, Leah R.; Frey, William H., II; Toth, Cory

2008-01-01

Insulin deficiency in type I diabetes may lead to cognitive impairment, cerebral atrophy and white matter abnormalities. We studied the impact of a novel delivery system using intranasal insulin (I-I) in a mouse model of type I diabetes (streptozotocin-induced) for direct targeting of pathological and cognitive deficits while avoiding potential…

Tumor-induced thymic atrophy: alteration in interferons and Jak/Stats signaling pathways.

PubMed

Carrio, Roberto; Torroella-Kouri, Marta; Iragavarapu-Charyulu, Vijaya; Lopez, Diana M

2011-02-01

The thymus is the major site of T cell differentiation and a key organ of the immune system. Thym atrophy has been observed in several model systems including aging, and tumor development. Previous results from our laboratory have reported that the thymic atrophy seen in mammary tumor bearers is associated with a severe depletion of CD4+CD8+ double positive immature cells and changes in the levels of cytokines expressed in the thymus microenvironment. Cytokines regulate numerous aspects of hematopoiesis via activation of the Jak/Stat pathways. In the present study we have used our mammary tumor model to investigate whether changes in the levels of cytokines in the thymus could affect the normal expression of the aforementioned pathways. RNA and protein analysis revealed an overexpression of the different members of interferons, a downregulation of most of the Jak/Stat pathways, and an increased expression of several suppressors of cytokine signaling (SOSC) in the thymuses of tumor bearers. Together, our data suggest that the impaired Jak/Stat signaling pathways observed in the whole thymus of tumor-bearing mice could be contributing to the abnormal T cell development and apoptosis observed during the tumor-induced thymic atrophy.

Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: A retrospective, pilot, observational longitudinal study.

PubMed

Zivadinov, Robert; Ramasamy, Deepa P; Vaneckova, Manuela; Gandhi, Sirin; Chandra, Avinash; Hagemeier, Jesper; Bergsland, Niels; Polak, Paul; Benedict, Ralph Hb; Hojnacki, David; Weinstock-Guttman, Bianca

2017-09-01

Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients as a potential in vivo marker of cortical pathology. To investigate the association of LM CE and development of cortical atrophy in 50 MS patients (27 relapsing-remitting (RR) and 23 secondary-progressive (SP)) followed for 5 years. The presence and number of LM CE foci were assessed only at the 5-year follow-up using three-dimensional (3D) fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequence obtained 10 minutes after single dose of gadolinium injection on 3T scanner. The percentage change in whole brain, cortical and deep gray matter (GM) volumes, and lesion volume (LV) was measured between baseline and the 5-year follow-up. In total, 25 (50%) of MS patients had LM CE at the 5-year follow-up. Significantly more SPMS patients (12, 85.7%) had multiple LM CE foci, compared to those with RRMS (2, 18.2%) ( p = 0.001). MS patients with LM CE showed significantly greater percentage decrease in total GM (-3.6% vs -2%, d = 0.80, p = 0.006) and cortical (-3.4% vs -1.8%, d = 0.84, p = 0.007) volumes and greater percentage increase in ventricular cerebrospinal fluid (vCSF) volume (22.8% vs 9.9%, d = 0.90, p = 0.003) over the follow-up, compared to those without. In this retrospective, pilot, observational longitudinal study, the presence of LM CE was associated with progression of cortical atrophy over 5 years.

Effect of IR Laser on Myoblasts: Prospects of Application for Counteracting Microgravity-Induced Muscle Atrophy

NASA Astrophysics Data System (ADS)

Monici, Monica; Cialdai, Francesca; Romano, Giovanni; Corsetto, Paola Antonia; Rizzo, Angela Maria; Caselli, Anna; Ranaldi, Francesco

2013-02-01

Microgravity-induced muscle atrophy is a problem of utmost importance for the impact it may have on the health and performance of astronauts. Therefore, appropriate countermeasures are needed to prevent disuse atrophy and favour muscle recovery. Muscle atrophy is characterized by loss of muscle mass and strength, and a shift in substrate utilization from fat to glucose, that leads to a reduced metabolic efficiency and enhanced fatigability. Laser therapy is already used in physical medicine and rehabilitation to accelerate muscle recovery and in sports medicine to prevent damages produced by metabolic disturbances and inflammatory reactions after heavy exercise. The aim of the research we present was to get insights on possible benefits deriving from the application of an advanced infrared laser system to counteract deficits of muscle energy metabolism and stimulate the recovery of the hypotrophic tissue. The source used was a Multiwave Locked System (MLS) laser, which combines continuous and pulsed emissions at 808 nm and 905 nm, respectively. We studied the effect of MLS treatment on morphology and energy metabolism of C2C12 cells, a widely accepted myoblast model, previously exposed to microgravity conditions modelled by a Random Positioning Machine. The MLS laser treatment was able to restore basal levels of serine/threonine protein phosphatase activity and to counteract cytoskeletal alterations and increase in glycolytic enzymes activity that occurred following the exposure to modelled microgravity. In conclusion, the results provide interesting insights for the application of infrared laser in the treatment of muscle atrophy.

Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis.

PubMed

Kappus, Natalie; Weinstock-Guttman, Bianca; Hagemeier, Jesper; Kennedy, Cheryl; Melia, Rebecca; Carl, Ellen; Ramasamy, Deepa P; Cherneva, Mariya; Durfee, Jacqueline; Bergsland, Niels; Dwyer, Michael G; Kolb, Channa; Hojnacki, David; Ramanathan, Murali; Zivadinov, Robert

2016-02-01

Cardiovascular (CV) risk factors have been associated with changes in clinical outcomes in patients with multiple sclerosis (MS). To investigate the frequency of CV risks in patients with MS and their association with MRI outcomes. In a prospective study, 326 patients with relapsing-remitting MS and 163 patients with progressive MS, 61 patients with clinically isolated syndrome (CIS) and 175 healthy controls (HCs) were screened for CV risks and scanned on a 3T MRI scanner. Examined CV risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. MRI measures assessed lesion volumes (LVs) and brain atrophy. Association between individual or multiple CV risks and MRI outcomes was examined adjusting for age, sex, race, disease duration and treatment status. Patients with MS showed increased frequency of smoking (51.7% vs 36.5%, p = 0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared with HCs. In total, 49.9% of patients with MS and 36% of HCs showed ≥ 2 CV risks (p = 0.003), while the frequency of ≥ 3 CV risks was 18.8% in the MS group and 8.6% in the HCs group (p = 0.002). In patients with MS, hypertension and heart disease were associated with decreased grey matter (GM) and cortical volumes (p < 0.05), while overweight/obesity was associated with increased T1-LV (p < 0.39) and smoking with decreased whole brain volume (p = 0.049). Increased lateral ventricle volume was associated with heart disease (p = 0.029) in CIS. Patients with MS with one or more CV risks showed increased lesion burden and more advanced brain atrophy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Undiagnosed neurological disease as a potential cause of male lower urinary tract symptoms.

PubMed

Wei, Diana Y; Drake, Marcus J

2016-01-01

In the central nervous system there are many regulatory processes controlling the lower urinary tract. This review considers the possibility that urinary dysfunction may precede diagnosis of neurological disease. Lower urinary tract symptoms (LUTS) occur early in multiple system atrophy, Parkinson's disease and normal pressure hydrocephalus, and may present before neurological diagnosis. Some people present with LUTS and subsequently are diagnosed with multiple sclerosis or a spinal condition. In male LUTS, the symptoms could reflect early stages of a neurological disease, which has not yet been diagnosed ('occult neurology'). Key symptoms include erectile dysfunction, retrograde ejaculation, enuresis, loss of filling sensation or unexplained stress urinary incontinence. Directed questioning should enquire about visual symptoms, back pain, anosmia, bowel dysfunction and incontinence, or memory loss. Examination features can include resting tremor, 'croaky' speech, abnormal gait, orthostatic hypotension, ataxia, or altered perineal sensation. Imaging, such as MRI scan, should only be requested after expert neurological examination, to ensure the correct parts of the central nervous system are scanned with appropriate radiological protocols. Urologists should consider an undiagnosed neurological condition can be present in a few cases. Any finding should be further evaluated by colleagues with relevant expertise.

Image-enhanced endoscopy with I-scan technology for the evaluation of duodenal villous patterns.

PubMed

Cammarota, Giovanni; Ianiro, Gianluca; Sparano, Lucia; La Mura, Rossella; Ricci, Riccardo; Larocca, Luigi M; Landolfi, Raffaele; Gasbarrini, Antonio

2013-05-01

I-scan technology is the newly developed endoscopic tool that works in real time and utilizes a digital contrast method to enhance endoscopic image. We performed a feasibility study aimed to determine the diagnostic accuracy of i-scan technology for the evaluation of duodenal villous patterns, having histology as the reference standard. In this prospective, single center, open study, patients undergoing upper endoscopy for an histological evaluation of duodenal mucosa were enrolled. All patients underwent upper endoscopy using high resolution view in association with i-scan technology. During endoscopy, duodenal villous patterns were evaluated and classified as normal, partial villous atrophy, or marked villous atrophy. Results were then compared with histology. One hundred fifteen subjects were recruited in this study. The endoscopist was able to find marked villous atrophy of the duodenum in 12 subjects, partial villous atrophy in 25, and normal villi in the remaining 78 individuals. The i-scan system was demonstrated to have great accuracy (100 %) in the detection of marked villous atrophy patterns. I-scan technology showed quite lower accuracy in determining partial villous atrophy or normal villous patterns (respectively, 90 % for both items). Image-enhancing endoscopic technology allows a clear visualization of villous patterns in the duodenum. By switching from the standard to the i-scan view, it is possible to optimize the accuracy of endoscopy in recognizing villous alteration in subjects undergoing endoscopic evaluation.

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

PubMed Central

El Mendili, Mohamed-Mounir; Lenglet, Timothée; Stojkovic, Tanya; Behin, Anthony; Guimarães-Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaelle; Le Forestier, Nadine; Laforêt, Pascal; Lehéricy, Stéphane; Benali, Habib; Pradat, Pierre-François

2016-01-01

Purpose The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness. Materials and Methods Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores. Results CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10−5). There were no correlations between atrophy measurements, strength and disability scores. Conclusions Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients. PMID:27089520

Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies.

PubMed

Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio; Palma, Jose-Alberto; Shibao, Cyndya A; Biaggioni, Italo; Peltier, Amanda C; Singer, Wolfgang; Low, Phillip A; Goldstein, David S; Gibbons, Christopher H; Freeman, Roy; Robertson, David

2018-03-01

Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 ± 25 vs -21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522-531. © 2018 American Neurological Association.

Plasma biomarkers of decreased vesicular storage distinguish Parkinson disease with orthostatic hypotension from the parkinsonian form of multiple system atrophy.

PubMed

Goldstein, David S; Kopin, Irwin J; Sharabi, Yehonatan; Holmes, Courtney

2015-02-01

Parkinson disease with orthostatic hypotension (PD + OH) and the parkinsonian form of multiple system atrophy (MSA-P) can be difficult to distinguish clinically. Recent studies indicate that PD entails a vesicular storage defect in catecholaminergic neurons. Although cardiac sympathetic neuroimaging by (18)F-dopamine positron emission tomography can identify decreased vesicular storage, this testing is not generally available. We assessed whether plasma biomarkers of a vesicular storage defect can separate PD + OH from MSA-P. We conceptualized that after F-dopamine injection, augmented production of F-dihydroxyphenylacetic acid (F-DOPAC) indicates decreased vesicular storage, and we therefore predicted that arterial plasma F-DOPAC would be elevated in PD + OH but not in MSA-P. We measured arterial plasma F-DOPAC after (18)F-dopamine administration (infused i.v. over 3 min) in patients with PD + OH (N = 12) or MSA-P (N = 21) and in healthy control subjects (N = 26). Peak F-DOPAC:dihydroxyphenylglycol (DHPG) was also calculated to adjust for effects of denervation on F-DOPAC production. Plasma F-DOPAC accumulated rapidly after initiation of (18)F-dopamine infusion. Peak F-DOPAC (5-10 min) in PD + OH averaged three times that in MSA-P (P < 0.0001). Among MSA-P patients, none had peak F-DOPAC > 300 nCi-kg/cc-mCi, in contrast with 7 of 12 PD + OH patients (χ(2) = 16.6, P < 0.0001). DHPG was lower in PD + OH (3.83 ± 0.36 nmol/L) than in MSA-P (5.20 ± 0.29 nmol/L, P = 0.007). All MSA-P patients had peak F-DOPAC:DHPG < 60, in contrast with 9 of 12 PD + OH patients (χ(2) = 17.5, P < 0.0001). Adjustment of peak F-DOPAC for DHPG increased test sensitivity from 58 to 81% at similar high specificity. After F-dopamine injection, plasma F-DOPAC and F-DOPAC:DHPG distinguish PD + OH from MSA-P.

L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure.

PubMed

Mathias, C J; Senard, J M; Braune, S; Watson, L; Aragishi, A; Keeling, J E; Taylor, M D

2001-08-01

This study was designed to determine the efficacy and tolerability of increasing doses of L-threo-dihydroxyphenylserine (L-threo-DOPS) in treating symptomatic orthostatic hypotension associated with multiple system atrophy (MSA) and pure autonomic failure (PAF). Following a one-week run-in, patients (26 MSA; 6 PAF) with symptomatic orthostatic hypotension received increasing doses of L-threo-DOPS (100, 200 and 300 mg, twice daily) in an open, dose-ranging study. Incremental dose adjustment (after weeks two and four of outpatient treatment) was based on clinical need until blood pressure (BP), and symptoms improved. Final dosage was maintained for six weeks. With L-threo-DOPS, systolic BP decrease was reduced during orthostatic challenge (-22+/-28 mm Hg reduction from a baseline decrease of 54.3+/-27.7 mm Hg, p = 0.0001, n = 32; supine systolic BP at final visit was 118.9+/-28.2 mm Hg). By the end of the study, 25 patients (78%) improved, and in 14 patients (44%) orthostatic hypotension was no longer observed. Decreased orthostatic systolic BP decrease occurred in 22% (7/32), 24% (6/25) and 61% (11/18) of patients treated with 100, 200, and 300 mg L-threo-DOPS twice daily, respectively. An improvement occurred in symptoms associated with orthostatic hypotension, such as light-headedness, dizziness (p = 0.0125), and blurred vision (p = 0.0290). L-threo-DOPS was well tolerated, with the 2 serious adverse events reported being a possible complication of the disease under study, and with no reports of supine hypertension. In conclusion, L-threo-DOPS (100, 200, and 300 mg, twice daily) was well tolerated. The dosage of 300 mg twice daily L-threo-DOPS seemed to offer the most effective control of symptomatic orthostatic hypotension in MSA and PAF.

Focal atrophy in Dementia with Lewy Bodies on MRI: a distinct pattern from Alzheimer's disease

PubMed Central

Whitwell, Jennifer L; Weigand, Stephen D; Shiung, Maria M; Boeve, Bradley F; Ferman, Tanis J; Smith, Glenn E; Knopman, David S; Petersen, Ronald C; Benarroch, Eduardo E; Josephs, Keith A; Jack, Clifford R

2009-01-01

SUMMARY Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). However, unlike in AD the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it to the pattern found in AD. Seventy-two patients that fulfilled clinical criteria for probable DLB were age and gender-matched to 72 patients with probable AD and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the DLB and AD groups, relative to controls, after correction for multiple comparisons (p<0.05). Study specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional grey matter loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the AD group showed a widespread pattern of grey matter loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in AD however they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the AD group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain grey matter in both the AD and DLB groups. The SI grey matter was reduced more in AD than DLB, yet the midbrain was reduced more in DLB than AD. The hippocampus and temporoparietal cortex showed significantly greater loss in the AD group compared to the DLB group. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex, is therefore suggestive of DLB and may aid in the differentiation of DLB from AD. These findings support recent pathological studies showing an ascending pattern of Lewy Body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB. PMID:17267521

Alteration of histological gastritis after cure of Helicobacter pylori infection.

PubMed

Hojo, M; Miwa, H; Ohkusa, T; Ohkura, R; Kurosawa, A; Sato, N

2002-11-01

It is still disputed whether gastric atrophy or intestinal metaplasia improves after the cure of Helicobacter pylori infection. To clarify the histological changes after the cure of H. pylori infection through a literature survey. Fifty-one selected reports from 1066 relevant articles were reviewed. The extracted data were pooled according to histological parameters of gastritis based on the (updated) Sydney system. Activity improved more rapidly than inflammation. Eleven of 25 reports described significant improvement of atrophy. Atrophy was not improved in one of four studies with a large sample size (> 100 samples) and in two of five studies with a long follow-up period (> 12 months), suggesting that disagreement between the studies was not totally due to sample size or follow-up period. Methodological flaws, such as patient selection, and statistical analysis based on the assumption that atrophy improves continuously and generally in all patients might be responsible for the inconsistent results. Four of 28 studies described significant improvement of intestinal metaplasia [corrected]. Activity and inflammation were improved after the cure of H. pylori infection. Atrophy did not improve generally among all patients, but improved in certain patients. Improvement of intestinal metaplasia was difficult to analyse due to methodological problems including statistical power.

Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy

NASA Technical Reports Server (NTRS)

Gomes, M. D.; Lecker, S. H.; Jagoe, R. T.; Navon, A.; Goldberg, A. L.

2001-01-01

Muscle wasting is a debilitating consequence of fasting, inactivity, cancer, and other systemic diseases that results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. To identify key factors in this process, we have used cDNA microarrays to compare normal and atrophying muscles and found a unique gene fragment that is induced more than ninefold in muscles of fasted mice. We cloned this gene, which is expressed specifically in striated muscles. Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain. On fasting, atrogin-1 mRNA levels increase specifically in skeletal muscle and before atrophy occurs. Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases.

Role of muscle spindle in weightlessness-induced amyotrophia and muscle pain.

PubMed

Ali, Umar; Fan, Xiao-Li; You, Hao-Jun

2009-10-01

To date, the medium and long-term space flight is urgent in need and has become a major task of our manned space flight program. There is no doubt that medium and long-term space flight has serious damaging impact upon human physiological systems. For instance, atrophy of the lower limb anti-gravity muscle can be induced during the space flight. Muscle atrophy significantly affects the flight of astronauts in space. Most importantly, it influences the precise manipulation of the astronauts and their response capacity to emergencies on returning to the atmosphere from space. Muscle atrophy caused by weightlessness may also seriously disrupt the normal life and work of the astronauts during the re-adaptation period. Here we summarize the corresponding research concentrating on weightlessness-induced changes of muscular structure and function. By combining research on muscle pain, which is a common clinical pain disease, we further provide a hypothesis concerning a dynamic feedback model of "weightlessness condition right triple arrow muscular atrophy <--> muscle pain". This may be useful to explore the neural mechanisms underlying the occurrence and development of muscular atrophy and muscle pain, through the key study of muscle spindle, and furthermore provide more effective therapy for clinical treatment.

Treatment of postmenopausal vaginal atrophy with 10-μg estradiol vaginal tablets.

PubMed

Panay, Nick; Maamari, Ricardo

2012-03-01

Postmenopausal estrogen deficiency can lead to symptoms of urogenital atrophy. Individuals with urogenital atrophy have symptoms that include vaginal dryness, vaginal and vulval irritation, vaginal soreness, pain and burning during urination (dysuria), increased vaginal discharge, vaginal odour, vaginal infections, recurrent urinary tract infections, pain associated with sexual activity (dyspareunia) and vaginal bleeding associated with sexual activity. Despite the frequency and effects of vaginal atrophy symptoms, they are often under-reported and, consequently, under-treated. Therefore, care of a menopausal woman should include a physical assessment of vaginal atrophy and a dialogue between the physician and the patient that explores existing symptoms and their effect on vulvovaginal health, sexuality and quality-of-life issues. The development of the ultra-low-dose 10-µg estradiol vaginal tablets is in line with the requirements of regulatory agencies and women's health societies regarding the use of the lowest effective hormonal dose. Because of its effectiveness and safety profiles, in addition to its minimal systemic absorption, the 10-µg estradiol vaginal tablet can offer greater reassurance to health-care providers and postmenopausal women with an annual estradiol administration of only 1.14 mg.

Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

PubMed Central

Baehr, Leslie M.; West, Daniel W. D.; Marshall, Andrea G.; Marcotte, George R.; Baar, Keith

2017-01-01

Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (−9 to −38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. NEW & NOTEWORTHY In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy. PMID:28336537

HISTOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION: A Multilayer Approach.

PubMed

Li, Miaoling; Huisingh, Carrie; Messinger, Jeffrey; Dolz-Marco, Rosa; Ferrara, Daniela; Freund, K Bailey; Curcio, Christine A

2018-05-03

To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch membrane-choriocapillaris complex and associated extracellular deposits. Geographic atrophy was delimited by the external limiting membrane (ELM) descent towards Bruch membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models. On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Müller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch membrane thinned, and choriocapillaris density decreased. The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Müller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick deposits impede therapeutic intervention.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Brain volume and fatigue in patients with postpoliomyelitis syndrome.

PubMed

Trojan, Daria A; Narayanan, Sridar; Francis, Simon J; Caramanos, Zografos; Robinson, Ann; Cardoso, Mauro; Arnold, Douglas L

2014-03-01

Acute paralytic poliomyelitis is associated with encephalitis. Early brain inflammation may produce permanent neuronal injury with brain atrophy, which may result in symptoms such as fatigue. Brain volume has not been assessed in postpoliomyelitis syndrome (PPS). To determine whether brain volume is decreased compared with that in normal controls, and whether brain volume is associated with fatigue in patients with PPS. A cross-sectional study. Tertiary university-affiliated hospital postpolio and multiple sclerosis (MS) clinics. Forty-nine ambulatory patients with PPS, 28 normal controls, and 53 ambulatory patients with MS. We studied the brains of all study subjects with magnetic resonance imaging by using a 1.5 T Siemens Sonata machine. The subjects completed the Fatigue Severity Scale. Multivariable linear regression models were computed to evaluate the contribution of PPS and MS compared with controls to explain brain volume. Normalized brain volume (NBV) was assessed with the automated program Structured Image Evaluation, using Normalization, of Atrophy method from the acquired magnetic resonance images. This method may miss brainstem atrophy. Technically adequate NBV measurements were available for 42 patients with PPS, 27 controls, and 49 patients with MS. The mean (standard deviation) age was 60.9 ± 7.6 years for patients with PPS, 47.0 ± 14.6 years for controls, and 46.2 ± 9.4 years for patients with MS. In a multivariable model adjusted for age and gender, NBV was not significantly different in patients with PPS compared with that in controls (P = .28). As expected, when using a similar model for patients with MS, NBV was significantly decreased compared with that in controls (P = .006). There was no significant association between NBV and fatigue in subjects with PPS (Spearman ρ = 0.23; P = .19). No significant whole-brain atrophy was found, and no association of brain volume with fatigue in PPS. Brain atrophy was confirmed in MS. It is possible that brainstem atrophy was not recognized by this study. Copyright © 2014 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis.

PubMed

Barro, Christian; Benkert, Pascal; Disanto, Giulio; Tsagkas, Charidimos; Amann, Michael; Naegelin, Yvonne; Leppert, David; Gobbi, Claudio; Granziera, Cristina; Yaldizli, Özgür; Michalak, Zuzanna; Wuerfel, Jens; Kappos, Ludwig; Parmar, Katrin; Kuhle, Jens

2018-05-30

Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8% and 4.9% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5% (P < 0.001) and spinal cord volume of 2.5% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.

Fiber typing in aging muscle.

PubMed

Purves-Smith, Fennigje M; Sgarioto, Nicolas; Hepple, Russell T

2014-04-01

It is accepted widely that fast-twitch muscle fibers are preferentially impacted in aging muscle, yet we hypothesize that this is not valid when aging muscle atrophy becomes severe. In this review, we summarize the evidence of fiber type-specific effect in aging muscle and the potential confounding roles of fibers coexpressing multiple myosin heavy-chain isoforms and their histochemical identification.

[Helicobacter pylori gastritis: assessment of OLGA and OLGIM staging systems].

PubMed

Ben Slama, Sana; Ben Ghachem, Dorra; Dhaoui, Amen; Jomni, Mohamed Taieb; Dougui, Mohamed Hédi; Bellil, Khadija

2016-01-01

Helicobacter pylori (H pylori) gastritis presents a risk of cancer related to atrophy and intestinal metaplasia. Two recent classifications OLGA (Operative Link on Gastritis Assessment) and OLGIM (Operative Link on Gastritic Intestinal Metaplasia assessment) have been proposed to identify high-risk forms (stages III and IV). The aim of this study is to evaluate the OLGA and OLGIM staging systems in H pylori gastritis. A descriptive study of 100 cases of chronic H pylori gastritis was performed. The revaluation of Sydney System parameters of atrophy and intestinal metaplasia, of gastric antrum and corpus, allowed identifying respectively the stages of OLGA and OLGIM systems. The progressive risk of our H pylori gastritis was 6% according to OLGA staging and 7% according to OLGIM staging. Significant correlation was revealed between age and OLGA staging. High-risk gastritis according to OLGIM staging was significantly associated with moderate to severe atrophy. High-risk forms according to OLGA staging were associated in 80% of the cases to intestinal metaplasia. OLGA and OLGIM systems showed a highly significant positive correlation between them with a mismatch at 5% for H pylori gastritis. The OLGA and OLGIM staging systems in addition to Sydney System, allow selection of high risk forms of chronic gastritis requiring accurate observation.

Muscle atrophy and metal-on-metal hip implants: a serial MRI study of 74 hips.

PubMed

Berber, Reshid; Khoo, Michael; Cook, Erica; Guppy, Andrew; Hua, Jia; Miles, Jonathan; Carrington, Richard; Skinner, John; Hart, Alister

2015-06-01

Muscle atrophy is seen in patients with metal-on-metal (MOM) hip implants, probably because of inflammatory destruction of the musculo-tendon junction. However, like pseudotumors, it is unclear when atrophy occurs and whether it progresses with time. Our objective was to determine whether muscle atrophy associated with MOM hip implants progresses with time. We retrospectively reviewed 74 hips in 56 patients (32 of them women) using serial MRI. Median age was 59 (23-83) years. The median time post-implantation was 83 (35-142) months, and the median interval between scans was 11 months. Hip muscles were scored using the Pfirrmann system. The mean scores for muscle atrophy were compared between the first and second MRI scans. Blood cobalt and chromium concentrations were determined. The median blood cobalt was 6.84 (0.24-90) ppb and median chromium level was 4.42 (0.20-45) ppb. The median Oxford hip score was 34 (5-48). The change in the gluteus minimus mean atrophy score between first and second MRI was 0.12 (p = 0.002). Mean change in the gluteus medius posterior portion (unaffected by surgical approach) was 0.08 (p = 0.01) and mean change in the inferior portion was 0.10 (p = 0.05). Mean pseudotumor grade increased by 0.18 (p = 0.02). Worsening muscle atrophy and worsening pseudotumor grade occur over a 1-year period in a substantial proportion of patients with MOM hip implants. Serial MRI helps to identify those patients who are at risk of developing worsening soft-tissue pathology. These patients should be considered for revision surgery before irreversible muscle destruction occurs.

Glucocorticoids Induce Bone and Muscle Atrophy by Tissue-Specific Mechanisms Upstream of E3 Ubiquitin Ligases

PubMed Central

Sato, Amy Y.; Richardson, Danielle; Cregor, Meloney; Davis, Hannah M.; Au, Ernie D.; McAndrews, Kevin; Zimmers, Teresa A.; Organ, Jason M.; Peacock, Munro; Plotkin, Lilian I.

2017-01-01

Glucocorticoid excess, either endogenous with diseases of the adrenal gland, stress, or aging or when administered for immunosuppression, induces bone and muscle loss, leading to osteopenia and sarcopenia. Muscle weakness increases the propensity for falling, which, combined with the lower bone mass, increases the fracture risk. The mechanisms underlying glucocorticoid-induced bone and muscle atrophy are not completely understood. We have demonstrated that the loss of bone and muscle mass, decreased bone formation, and reduced muscle strength, hallmarks of glucocorticoid excess, are accompanied by upregulation in both tissues in vivo of the atrophy-related genes atrogin1, MuRF1, and MUSA1. These are E3 ubiquitin ligases traditionally considered muscle-specific. Glucocorticoids also upregulated atrophy genes in cultured osteoblastic/osteocytic cells, in ex vivo bone organ cultures, and in muscle organ cultures and C2C12 myoblasts/myotubes. Furthermore, glucocorticoids markedly increased the expression of components of the Notch signaling pathway in muscle in vivo, ex vivo, and in vitro. In contrast, glucocorticoids did not increase Notch signaling in bone or bone cells. Moreover, the increased expression of atrophy-related genes in muscle, but not in bone, and the decreased myotube diameter induced by glucocorticoids were prevented by inhibiting Notch signaling. Thus, glucocorticoids activate different mechanisms in bone and muscle that upregulate atrophy-related genes. However, the role of these genes in the effects of glucocorticoids in bone is unknown. Nevertheless, these findings advance our knowledge of the mechanism of action of glucocorticoids in the musculoskeletal system and provide the basis for novel therapies to prevent glucocorticoid-induced atrophy of bone and muscle. PMID:28359087

Differential sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy.

PubMed

de Theije, C C; Langen, R C J; Lamers, W H; Gosker, H R; Schols, A M W J; Köhler, S E

2015-01-15

Hypoxia as a consequence of acute and chronic respiratory disease has been associated with muscle atrophy. This study investigated the sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy. Male mice were exposed to 8% normobaric oxygen for up to 21 days. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were isolated, weighed, and assayed for expression profiles of the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF1α) signaling. Fiber-type composition and the capillary network were investigated. Hypoxia-induced muscle atrophy was more prominent in the EDL than the soleus muscle. Although increased expression of HIF1α target genes showed that both muscle types sensed hypoxia, their adaptive responses differed. Atrophy consistently involved a hypoxia-specific effect (i.e., not attributable to a hypoxia-mediated reduction of food intake) in the EDL only. Hypoxia-specific activation of the UPS and ALP and increased expression of the glucocorticoid receptor (Gr) and its target genes were also mainly observed in the EDL. In the soleus, stimulation of gene expression of those pathways could be mimicked to a large extent by food restriction alone. Hypoxia increased the number of capillary contacts per fiber cross-sectional area in both muscles. In the EDL, this was due to type II fiber atrophy, whereas in the soleus the absolute number of capillary contacts increased. These responses represent two distinct modes to improve oxygen supply to muscle fibers, but may aggravate muscle atrophy in chronic obstructive pulmonary disease patients who have a predominance of type II fibers. Copyright © 2015 the American Physiological Society.

Alterations in intrinsic mitochondrial function with aging are fiber type-specific and do not explain differential atrophy between muscles.

PubMed

Picard, Martin; Ritchie, Darmyn; Thomas, Melissa M; Wright, Kathryn J; Hepple, Russell T

2011-12-01

To determine whether mitochondrial dysfunction is causally related to muscle atrophy with aging, we examined respiratory capacity, H(2) O(2) emission, and function of the mitochondrial permeability transition pore (mPTP) in permeabilized myofibers prepared from four rat muscles that span a range of fiber type and degree of age-related atrophy. Muscle atrophy with aging was greatest in fast-twitch gastrocnemius (Gas) muscle (-38%), intermediate in both the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (Sol) muscles (-21%), and non-existent in adductor longus (AL) muscle (+47%). In contrast, indices of mitochondrial dysfunction did not correspond to this differential degree of atrophy. Specifically, despite higher protein expression for oxidative phosphorylation (oxphos) system in fast Gas and EDL, state III respiratory capacity per myofiber wet weight was unchanged with aging, whereas the slow Sol showed proportional decreases in oxphos protein, citrate synthase activity, and state III respiration. Free radical leak (H(2) O(2) emission per O(2) flux) under state III respiration was higher with aging in the fast Gas, whereas state II free radical leak was higher in the slow AL. Only the fast muscles had impaired mPTP function with aging, with lower mitochondrial calcium retention capacity in EDL and shorter time to mPTP opening in Gas and EDL. Collectively, our results underscore that the age-related changes in muscle mitochondrial function depend largely upon fiber type and are unrelated to the severity of muscle atrophy, suggesting that intrinsic changes in mitochondrial function are unlikely to be causally involved in aging muscle atrophy. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Novel Musculoskeletal Loading System for Small Exercise Devices

NASA Technical Reports Server (NTRS)

Downs, Meghan; Newby, Nate; Trinh, Tinh; Hanson, Andrea

2016-01-01

Long duration spaceflight places astronauts at increased risk for muscle strain and bone fracture upon return to a 1-g or partial gravity environment. Functionally limiting decrements in musculoskeletal health are likely during Mars proving-ground and Earth-independent missions given extended transit times and the vehicle limitations for exercise devices (low-mass, small volume, little to no power). This is particularly alarming for exploration missions because astronauts will be required to perform novel and physically demanding tasks (i.e. vehicle egress, exploration, and habitat building activities) on unfamiliar terrain. Accordingly, NASA's exploration roadmap identifies the need for development of small exercise equipment that can prevent musculoskeletal atrophy and has the ability to assess musculoskeletal health at multiple time points during long-duration missions.

Space travel directly induces skeletal muscle atrophy

NASA Technical Reports Server (NTRS)

Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

1999-01-01

Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

Cisplatin triggers atrophy of skeletal C2C12 myotubes via impairment of Akt signalling pathway and subsequent increment activity of proteasome and autophagy systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fanzani, Alessandro, E-mail: fanzani@med.unibs.it; Zanola, Alessandra; Rovetta, Francesca

2011-02-01

Cisplatin (cisPt) is an antineoplastic drug which causes an array of adverse effects on different organs and tissues, including skeletal muscle. In this work we show that cisPt behaves as a potent trigger to activate protein hypercatabolism in skeletal C2C12 myotubes. Within 24 h of 50 {mu}M cisPt administration, C2C12 myotubes displayed unchanged cell viability but showed a subset of hallmark signs typically recognized during atrophy, including severe reduction in body size, repression of Akt phosphorylation, transcriptional up-regulation of atrophy-related genes, such as atrogin-1, gabarap, beclin-1 and bnip-3, and loss of myogenic markers. As a consequence, proteasomal activity and formationmore » of autophagosomes were remarkably increased in cisPt-treated myotubes, but forced stimulation of Akt pathway, as obtained through insulin administration or delivery of a constitutively activated Akt form, was sufficient to counter the cisPt-induced protein breakdown, leading to rescue of atrophic size. Overall, these results indicate that cisPt induces atrophy of C2C12 myotubes via activation of proteasome and autophagy systems, suggesting that the Akt pathway represents one sensitive target of cisPt molecular action in skeletal muscle.« less

Pharmacological Inhibitors of the Proteosome in Atrophying Muscles

NASA Technical Reports Server (NTRS)

Goldberg, Alfred

1999-01-01

It is now clear that the marked loss of muscle mass that occurs with disuse, denervation or in many systemic diseases (cancer cachexia, sepsis, acidosis, various endocrine disorders) is due primarily to accelerated degradation of muscle proteins, especially myofibrillar components. Recent work primarily in Dr. Goldberg's laboratory had suggested that in these diverse conditions, the enhancement of muscle proteolysis results mainly from activation of the Ub-proteasome degradative pathway. In various experimental models of atrophy, rat muscles show a common series of changes indicative of activation of this pathway, including increases in MRNA for Ub and proteasome subunits, content of ubiquitinated proteins, and sensitivity to inhibitors of the proteasome. In order to understand the muscle atrophy seen in weightlessness, Dr. Goldberg's laboratory is collaborating with Dr. Baldwin in studies to define the changes in these parameters upon hind-limb suspension. Related experiments will explore the effects on this degradative system of exercise regimens and also of glucocorticoids, which are known to rise in space personnel and to promote muscle, especially in inactive muscles. The main goals will be: (A) to define the enzymatic changes leading to enhanced activity of the Ub-proteasome pathway in inactive muscles upon hind-limb suspension, and the effects on this system of exposure to glucocorticoids or exercise; and (B) to learn whether inhibitors of the Ub-proteasome pathway may be useful in retarding the excessive proteolysis in atrophying muscles. Using muscle extracts, Dr. Goldberg's group hopes to define the rate-limiting, enzymatic changes that lead to the accelerated Ub-conjugation and protein degradation. They have recently developed cell-free preparations from atrophying rat muscles, in which Ub-conjugation to muscle proteins is increased above control levels. Because these new preparations seem to reproduce the changes occurring in vivo, they will analyze in depth extracts from normal and atrophying muscles to compare the activities of the Ub-activating enzyme (El), the various LTh-carrier proteins (E2s), and Ub-protein ligases (E3s). Recent studies of other types of muscle wasting -suggest a very important role in muscle proteolysis of certain ubiquitination enzymes, E214k and E3-alpha(i.e. components of the "N-end pathway"). Future studies will focus in understanding their role and test whether they are in fact critical for muscle atrophy in vivo. Since weightlessness leads to a specific loss of contractile proteins and to a switching of myosin isotypes, Dr. Goldberg's group will attempt to identify the ubiquitination enzymes specifically involved in myosin degradation both in normal muscle and after hind-limb suspension.

Autoimmune comorbidities in multiple sclerosis: what is the influence on brain volumes? A case-control MRI study.

PubMed

Lorefice, Lorena; Fenu, Giuseppe; Pitzalis, Roberta; Scalas, Giulia; Frau, Jessica; Coghe, Giancarlo; Musu, Luigina; Sechi, Vincenzo; Barracciu, Maria Antonietta; Marrosu, Maria Giovanna; Cocco, Eleonora

2018-05-01

Several studies indicated that multiple sclerosis (MS) is frequently associated with other autoimmune diseases. However, it is little known if the coexistence of these conditions may influence the radiologic features of MS, and in particular the brain volumes. To evaluate the effect of autoimmune comorbidities on brain atrophy in a large case-control MS population. A group of MS patients affected by a second autoimmune disorder, and a control MS group without any comorbidity, were recruited. Patients underwent a brain MRI and volumes of whole brain (WB), white matter (WM), and gray matter (GM) with cortical GM were estimated by SIENAX. The sample included 286 MS patients, of which 30 (10.5%) subjects with type 1 diabetes (T1D), 53 (18.5%) with autoimmune thyroiditis (AT) and 4 (0.1%) with celiac disease. Multiple regression analysis found an association between T1D and lower GM (p = 0.038) and cortical GM (p = 0.036) volumes, independent from MS clinical features and related to T1D duration (p < 0.01), while no association was observed with AT and celiac disease. Our data support the importance of considering T1D as possible factors influencing the brain atrophy in MS. Further studies are needed to confirm our data and to clarify the underlying mechanisms.

Six Month Report on Tissue Cultured Avian Skeletal Myofibers in the STL/A Module Aboard STS-77

NASA Technical Reports Server (NTRS)

Vandenburgh, Herman H.

1997-01-01

Space travel is know to effect skeletal muscle, causing rapid and pronounced atrophy in humans and animals, even when strenuous exercise is used as a countermeasure. The cellular and molecular bases of this atrophy are unknown. Space travel may cause muscle atrophy by a direct effect on the muscle fibers and/or indirectly by reducing circulating levels of growth factors such as growth hormone. The recent development of a tissue culture incubator system for Shuttle Middeck basic science experiments [Space Tissue Loss (STL) Module] by the Walter Reed Army Institute of Research (WRAIR) allows the study of the effects of space travel directly on isolated skeletal myofibers. Avian bioartificial skeletal muscle 'organoids' containing differentiated skeletal myofibers and connective tissue fibroblasts were flown aboard the Space Shuttle (Space Transportation System, STS) on Flight STS-77, a repeat of a similar experiment flown on STS-66. The results from these two flight experiments show for the first time that space travel has a direct effect on skeletal muscle cells separate from any systemic effects resulting from altered circulating growth factors.

Spinal cord normalization in multiple sclerosis.

PubMed

Oh, Jiwon; Seigo, Michaela; Saidha, Shiv; Sotirchos, Elias; Zackowski, Kathy; Chen, Min; Prince, Jerry; Diener-West, Marie; Calabresi, Peter A; Reich, Daniel S

2014-01-01

Spinal cord (SC) pathology is common in multiple sclerosis (MS), and measures of SC-atrophy are increasingly utilized. Normalization reduces biological variation of structural measurements unrelated to disease, but optimal parameters for SC volume (SCV)-normalization remain unclear. Using a variety of normalization factors and clinical measures, we assessed the effect of SCV normalization on detecting group differences and clarifying clinical-radiological correlations in MS. 3T cervical SC-MRI was performed in 133 MS cases and 11 healthy controls (HC). Clinical assessment included expanded disability status scale (EDSS), MS functional composite (MSFC), quantitative hip-flexion strength ("strength"), and vibration sensation threshold ("vibration"). SCV between C3 and C4 was measured and normalized individually by subject height, SC-length, and intracranial volume (ICV). There were group differences in raw-SCV and after normalization by height and length (MS vs. HC; progressive vs. relapsing MS-subtypes, P < .05). There were correlations between clinical measures and raw-SCV (EDSS:r = -.20; MSFC:r = .16; strength:r = .35; vibration:r = -.19). Correlations consistently strengthened with normalization by length (EDSS:r = -.43; MSFC:r = .33; strength:r = .38; vibration:r = -.40), and height (EDSS:r = -.26; MSFC:r = .28; strength:r = .22; vibration:r = -.29), but diminished with normalization by ICV (EDSS:r = -.23; MSFC:r = -.10; strength:r = .23; vibration:r = -.35). In relapsing MS, normalization by length allowed statistical detection of correlations that were not apparent with raw-SCV. SCV-normalization by length improves the ability to detect group differences, strengthens clinical-radiological correlations, and is particularly relevant in settings of subtle disease-related SC-atrophy in MS. SCV-normalization by length may enhance the clinical utility of measures of SC-atrophy. Copyright © 2014 by the American Society of Neuroimaging.

Brain MRI lesions and atrophy are associated with employment status in patients with multiple sclerosis.

PubMed

Tauhid, Shahamat; Chu, Renxin; Sasane, Rahul; Glanz, Bonnie I; Neema, Mohit; Miller, Jennifer R; Kim, Gloria; Signorovitch, James E; Healy, Brian C; Chitnis, Tanuja; Weiner, Howard L; Bakshi, Rohit

2015-11-01

Multiple sclerosis (MS) commonly affects occupational function. We investigated the link between brain MRI and employment status. Patients with MS (n = 100) completed a Work Productivity and Activity Impairment (WPAI) (general health version) survey measuring employment status, absenteeism, presenteeism, and overall work and daily activity impairment. Patients "working for pay" were considered employed; "temporarily not working but looking for work," "not working or looking for work due to age," and "not working or looking for work due to disability" were considered not employed. Brain MRI T1 hypointense (T1LV) and T2 hyperintense (T2LV) lesion volumes were quantified. To assess lesional destructive capability, we calculated each subject's ratio of T1LV to T2LV (T1/T2). Normalized brain parenchymal volume (BPV) assessed brain atrophy. The mean (SD) age was 45.5 (9.7) years; disease duration was 12.1 (8.1) years; 75 % were women, 76 % were relapsing-remitting, and 76 % were employed. T1LV, T1/T2, Expanded Disability Status Scale (EDSS) scores, and activity impairment were lower and BPV was higher in the employed vs. not employed group (Wilcoxon tests, p < 0.05). Age, disease duration, MS clinical subtype, and T2LV did not differ between groups (p > 0.05). In multivariable logistic regression modeling, adjusting for age, sex, and disease duration, higher T1LV predicted a lower chance of employment (p < 0.05). Pearson correlations showed that EDSS was associated with activity impairment (p < 0.05). Disease duration, age, and MRI measures were not correlated with activity impairment or other WPAI outcomes (p > 0.05). We report a link between brain atrophy and lesions, particularly lesions with destructive potential, to MS employment status.

Fingolimod's Impact on MRI Brain Volume Measures in Multiple Sclerosis: Results from MS-MRIUS.

PubMed

Zivadinov, Robert; Medin, Jennie; Khan, Nasreen; Korn, Jonathan R; Bergsland, Niels; Dwyer, Michael G; Chitnis, Tanuja; Naismith, Robert T; Alvarez, Enrique; Kinkel, Peter; Cohan, Stanley; Hunter, Samuel F; Silva, Diego; Weinstock-Guttman, Bianca

2018-05-11

Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD). MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups. Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P > 0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02). The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (>-.4%) or expansion of lateral ventricles (> 3.5%). Copyright © 2018 by the American Society of Neuroimaging.

Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

PubMed Central

Fowler, Benjamin J.; Gelfand, Bradley D.; Kim, Younghee; Kerur, Nagaraj; Tarallo, Valeria; Hirano, Yoshio; Amarnath, Shoba; Fowler, Daniel H.; Radwan, Marta; Young, Mark T.; Pittman, Keir; Kubes, Paul; Agarwal, Hitesh K.; Parang, Keykavous A.; Hinton, David R.; Bastos-Carvalho, Ana; Li, Shengjian; Yasuma, Tetsuhiro; Mizutani, Takeshi; Yasuma, Reo; Wright, Charles; Ambati, Jayakrishna

2014-01-01

Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium (RPE) in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease (GVHD), and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases. PMID:25414314

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.

PubMed

Finkel, Richard S; Mercuri, Eugenio; Meyer, Oscar H; Simonds, Anita K; Schroth, Mary K; Graham, Robert J; Kirschner, Janbernd; Iannaccone, Susan T; Crawford, Thomas O; Woods, Simon; Muntoni, Francesco; Wirth, Brunhilde; Montes, Jacqueline; Main, Marion; Mazzone, Elena S; Vitale, Michael; Snyder, Brian; Quijano-Roy, Susana; Bertini, Enrico; Davis, Rebecca Hurst; Qian, Ying; Sejersen, Thomas

2018-03-01

This is the second half of a two-part document updating the standard of care recommendations for spinal muscular atrophy published in 2007. This part includes updated recommendations on pulmonary management and acute care issues, and topics that have emerged in the last few years such as other organ involvement in the severe forms of spinal muscular atrophy and the role of medications. Ethical issues and the choice of palliative versus supportive care are also addressed. These recommendations are becoming increasingly relevant given recent clinical trials and the prospect that commercially available therapies will likely change the survival and natural history of this disease. Copyright © 2017. Published by Elsevier B.V.

Newly developed vaginal atrophy symptoms II and vaginal pH: a better correlation in vaginal atrophy?

PubMed

Tuntiviriyapun, P; Panyakhamlerd, K; Triratanachat, S; Chatsuwan, T; Chaikittisilpa, S; Jaisamrarn, U; Taechakraichana, N

2015-04-01

The primary objective of this study was to evaluate the correlation among symptoms, signs, and the number of lactobacilli in postmenopausal vaginal atrophy. The secondary objective was to develop a new parameter to improve the correlation. A cross-sectional descriptive study. Naturally postmenopausal women aged 45-70 years with at least one clinical symptom of vaginal atrophy of moderate to severe intensity were included in this study. All of the objective parameters (vaginal atrophy score, vaginal pH, the number of lactobacilli, vaginal maturation index, and vaginal maturation value) were evaluated and correlated with vaginal atrophy symptoms. A new parameter of vaginal atrophy, vaginal atrophy symptoms II, was developed and consists of the two most bothersome symptoms (vaginal dryness and dyspareunia). Vaginal atrophy symptoms II was analyzed for correlation with the objective parameters. A total of 132 naturally postmenopausal women were recruited for analysis. Vaginal pH was the only objective parameter found to have a weak correlation with vaginal atrophy symptoms (r = 0.273, p = 0.002). The newly developed vaginal atrophy symptoms II parameter showed moderate correlation with vaginal pH (r = 0.356, p < 0.001) and a weak correlation with the vaginal atrophy score (r = 0.230, p < 0.001). History of sexual intercourse within 3 months was associated with a better correlation between vaginal atrophy symptoms and the objective parameters. Vaginal pH was significantly correlated with vaginal atrophy symptoms. The newly developed vaginal atrophy symptoms II was associated with a better correlation. The vaginal atrophy symptoms II and vaginal pH may be better tools for clinical evaluation and future study of the vaginal ecosystem.

3D Mapping of Language Networks in Clinical and Pre-Clinical Alzheimer's Disease

ERIC Educational Resources Information Center

Apostolova, Liana G.; Lu, Po; Rogers, Steve; Dutton, Rebecca A.; Hayashi, Kiralee M.; Toga, Arthur W.; Cummings, Jeffrey L.; Thompson, Paul M.

2008-01-01

We investigated the associations between Boston naming and the animal fluency tests and cortical atrophy in 19 probable AD and 5 multiple domain amnestic mild cognitive impairment patients who later converted to AD. We applied a surface-based computational anatomy technique to MRI scans of the brain and then used linear regression models to detect…

Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.

PubMed

Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M Shawkat; Nabeshima, Yo-ichi

2014-08-01

Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.

Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes

PubMed Central

Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M. Shawkat; Nabeshima, Yo-ichi

2014-01-01

Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho-/- (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl-/- mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl-/- mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis. PMID:25080854

Genome Editing of Monogenic Neuromuscular Diseases: A Systematic Review.

PubMed

Long, Chengzu; Amoasii, Leonela; Bassel-Duby, Rhonda; Olson, Eric N

2016-11-01

Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing. PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9-mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed. Multiple proof-of-concept studies reveal the feasibility and efficacy of genome-editing-meditated correction of monogenic neuromuscular diseases in cultured cells and animal models. Genome editing is a rapidly evolving technology with enormous translational potential once efficacy, delivery, and safety issues are addressed. The clinical impact of this technology is that genome editing can permanently correct disease-causing mutations and circumvent the hurdles of traditional gene- and cell-based therapies.

Genome Editing of Monogenic Neuromuscular Diseases

PubMed Central

Long, Chengzu; Amoasii, Leonela; Bassel-Duby, Rhonda; Olson, Eric N.

2017-01-01

IMPORTANCE Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. OBJECTIVES To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing. EVIDENCE REVIEW PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, andmyotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9–mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed. FINDINGS Multiple proof-of-concept studies reveal the feasibility and efficacy of genome-editing–meditated correction of monogenic neuromuscular diseases in cultured cells and animal models. CONCLUSIONS AND RELEVANCE Genome editing is a rapidly evolving technology with enormous translational potential once efficacy, delivery, and safety issues are addressed. The clinical impact of this technology is that genome editing can permanently correct disease-causing mutations and circumvent the hurdles of traditional gene- and cell-based therapies. PMID:27668807

Schisandrae Fructus Supplementation Ameliorates Sciatic Neurectomy-Induced Muscle Atrophy in Mice

PubMed Central

Kim, Joo Wan; Ku, Sae-Kwang; Kim, Ki Young; Kim, Sung Goo; Han, Min Ho; Kim, Gi-Young; Hwang, Hye Jin; Kim, Byung Woo; Kim, Cheol Min

2015-01-01

The objective of this study was to assess the possible beneficial skeletal muscle preserving effects of ethanol extract of Schisandrae Fructus (EESF) on sciatic neurectomy- (NTX-) induced hindlimb muscle atrophy in mice. Here, calf muscle atrophy was induced by unilateral right sciatic NTX. In order to investigate whether administration of EESF prevents or improves sciatic NTX-induced muscle atrophy, EESF was administered orally. Our results indicated that EESF dose-dependently diminished the decreases in markers of muscle mass and activity levels, and the increases in markers of muscle damage and fibrosis, inflammatory cell infiltration, cytokines, and apoptotic events in the gastrocnemius muscle bundles are induced by NTX. Additionally, destruction of gastrocnemius antioxidant defense systems after NTX was dose-dependently protected by treatment with EESF. EESF also upregulated muscle-specific mRNAs involved in muscle protein synthesis but downregulated those involved in protein degradation. The overall effects of 500 mg/kg EESF were similar to those of 50 mg/kg oxymetholone, but it showed more favorable antioxidant effects. The present results suggested that EESF exerts a favorable ameliorating effect on muscle atrophy induced by NTX, through anti-inflammatory and antioxidant effects related to muscle fiber protective effects and via an increase in protein synthesis and a decrease in protein degradation. PMID:26064425

Degree of neutrophil, atrophy, and metaplasia intestinal were associate with malondialdehyde level in gastritis patients

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Sari, D. K.; Sungkar, T.

2018-03-01

The main pathogenesis of gastritis is inflammation that closely related to free radicals. Malondialdehyde (MDA) is a free radical biomarker and is found to increase in gastritis patients. However, these studies are generally performed on experimental animals as well as MDA examination in gastric mucosa. This study aim was to determine the association of degrees of gastritis (degree of lymphocyte infiltration, neutrophil activity, atrophy, and intestinal metaplasia) with plasma MDA level. A cross-sectional study of 80 consecutive gastritis patients who came to an endoscopic unit of Adam Malik General Hospital in Medan, Indonesia, from May–September 2017. Assessed for severity of chronic inflammatory, neutrophil activity, atrophy, and intestinal metaplasia refers to Updated Sydney System. Plasma MDA levels were examined using an HPLC MDA kit. Univariate analysis, bivariate (chi-square and Fisher exact test), and multivariate (binary logistic regression test) were programmed with SPSS version 22. There was no significant association between degree of lymphocyte infiltration with MDA level. There were significant associations between degree of neutrophil activity, atrophy, and intestinal metaplasia with MDA level (p=0.039, 0.003, 0.021; respectively). The moderate+severe degree of neutrophil activity, atrophy, and intestinal metaplasia were associated with high level of MDA.

Bilateral optic neuritis in pediatric systemic lupus erythematosus with antiphospholipid antibody syndrome.

PubMed

Patra, Soumya; Krishnamurthy, Sriram; Seth, Anju; Beri, Sarita; Aneja, Satinder

2011-02-01

Bilateral optic neuritis is an extremely uncommon complication of pediatric systemic lupus erythematosus and sporadic cases are reported in the literature. The authors describe an 11-yr-old girl who presented with fever and progressively increasing pallor for 4 months, headache for 7 days, severe anemia and hepatosplenomegaly. Soon after admission, she developed rapid deterioration of vision, worsening to no perception of light with afferent pupillary defect. Fundoscopy showed bilateral optic neuritis. Investigations revealed autoimmune hemolytic anemia and thrombocytopenia. Anti-dsDNA and anti-phospholipid antibodies were positive. Magnetic resonance venography showed multiple thrombi in the cerebral venous sinuses, for which anticoagulant therapy was initiated. She was managed with intravenous methylprednisolone followed by cyclophosphamide pulse therapy for 6 months along with oral prednisolone. Though she went into remission, visual outcome has been dismal, with development of bilateral optic atrophy, and absence of perception of light.

[Magnetic Resonance Imaging Conversion Predictors of Clinically Isolated Syndrome to Multiple Sclerosis].

PubMed

Peixoto, Sara; Abreu, Pedro

2016-11-01

Clinically isolated syndrome may be the first manifestation of multiple sclerosis, a chronic demyelinating disease of the central nervous system, and it is defined by a single clinical episode suggestive of demyelination. However, patients with this syndrome, even with long term follow up, may not develop new symptoms or demyelinating lesions that fulfils multiple sclerosis diagnostic criteria. We reviewed, in clinically isolated syndrome, what are the best magnetic resonance imaging findings that may predict its conversion to multiple sclerosis. A search was made in the PubMed database for papers published between January 2010 and June 2015 using the following terms: 'clinically isolated syndrome', 'cis', 'multiple sclerosis', 'magnetic resonance imaging', 'magnetic resonance' and 'mri'. In this review, the following conventional magnetic resonance imaging abnormalities found in literature were included: lesion load, lesion location, Barkhof's criteria and brain atrophy related features. The non conventional magnetic resonance imaging techniques studied were double inversion recovery, magnetization transfer imaging, spectroscopy and diffusion tensor imaging. The number and location of demyelinating lesions have a clear role in predicting clinically isolated syndrome conversion to multiple sclerosis. On the other hand, more data are needed to confirm the ability to predict this disease development of non conventional techniques and remaining neuroimaging abnormalities. In forthcoming years, in addition to the established predictive value of the above mentioned neuroimaging abnormalities, different clinically isolated syndrome neuroradiological findings may be considered in multiple sclerosis diagnostic criteria and/or change its treatment recommendations.

Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease

PubMed Central

Zhang, Liping; Rajan, Vik; Lin, Eugene; Hu, Zhaoyong; Han, H. Q.; Zhou, Xiaolan; Song, Yanping; Min, Hosung; Wang, Xiaonan; Du, Jie; Mitch, William E.

2011-01-01

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC50 ∼1.2 nM) reversed the loss of body weight (≈5–7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38±1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21±1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.—Zhang, L., Rajan, V., Lin, E., Hu, Z., Han, H.Q., Zhou, X., Song, Y., Min, H., Wang, X., Du, J., Mitch, W. E. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. PMID:21282204

The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain

PubMed Central

Haider, Lukas; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang

2016-01-01

Abstract Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. PMID:26912645

Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration.

PubMed

Kukreja, L; Shahidehpour, R; Kim, G; Keegan, J; Sadleir, K R; Russell, T; Csernansky, J; Mesulam, M; Vassar, R J; Wang, L; Dong, H; Geula, C

2018-05-28

Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) employing tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43 which is placed downstream of the tetracycline response element (TRE). The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in post-weaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3 and loss of neurons. The atrophy associated with tTA expression was rescuable by tetracycline analog, doxycycline in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration and behavioral deficits in FTLD. SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing genes. Here, we report on a mouse model that overexpresses human TDP-43 using tTA and attempt to recapitulate features of TDP-43 pathology present in human FTLD. The tTA expression system is problematic, resulting in dramatic degeneration of the hippocampus. Thus, our study adds a note of caution for the use of the tTA system. However, since FTLD is primarily characterized by cortical degeneration and our mouse model shows significant atrophy in most cortical areas due to human TDP-43 overexpression, our animal model remains useful for providing critical insight on this human disease. Copyright © 2018 the authors.

Autofluorescence Imaging With Near-Infrared Excitation:Normalization by Reflectance to Reduce Signal From Choroidal Fluorophores

PubMed Central

Cideciyan, Artur V.; Swider, Malgorzata; Jacobson, Samuel G.

2015-01-01

Purpose. We previously developed reduced-illuminance autofluorescence imaging (RAFI) methods involving near-infrared (NIR) excitation to image melanin-based fluorophores and short-wavelength (SW) excitation to image lipofuscin-based flurophores. Here, we propose to normalize NIR-RAFI in order to increase the relative contribution of retinal pigment epithelium (RPE) fluorophores. Methods. Retinal imaging was performed with a standard protocol holding system parameters invariant in healthy subjects and in patients. Normalized NIR-RAFI was derived by dividing NIR-RAFI signal by NIR reflectance point-by-point after image registration. Results. Regions of RPE atrophy in Stargardt disease, AMD, retinitis pigmentosa, choroideremia, and Leber congenital amaurosis as defined by low signal on SW-RAFI could correspond to a wide range of signal on NIR-RAFI depending on the contribution from the choroidal component. Retinal pigment epithelium atrophy tended to always correspond to high signal on NIR reflectance. Normalizing NIR-RAFI reduced the choroidal component of the signal in regions of atrophy. Quantitative evaluation of RPE atrophy area showed no significant differences between SW-RAFI and normalized NIR-RAFI. Conclusions. Imaging of RPE atrophy using lipofuscin-based AF imaging has become the gold standard. However, this technique involves bright SW lights that are uncomfortable and may accelerate the rate of disease progression in vulnerable retinas. The NIR-RAFI method developed here is a melanin-based alternative that is not absorbed by opsins and bisretinoid moieties, and is comfortable to view. Further development of this method may result in a nonmydriatic and comfortable imaging method to quantify RPE atrophy extent and its expansion rate. PMID:26024124

[Homeostasis and Disorder of Musculoskeletal System.Pathogenesis of musculoskeletal diseases and strategies for their treatment.

PubMed

Miyamoto, Takeshi

Decline of homeostasis in musculoskeletal locomotive organs such as bone and muscle with age leads to age-related diseases such as osteoporosis and muscle atrophy. To date, various findings underlying the pathogenesis of these tissues were accumulated. In this review, we discuss regarding the recent advances in the findings in the treatment for osteoporosis and the strategy for muscle atrophy, and our recent findings on the mechanisms underlying these diseases.

Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

PubMed Central

Tisdale, Sarah

2015-01-01

Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

Mild cognitive impairment: Profile of a cohort from a private sector memory clinic.

PubMed

Srinivasan, Srikanth

2014-07-01

Private hospital memory clinics might see a different clientele than university or academic institutes due to referral biases. To characterize the profile of patients with mild cognitive impairment (MCI) from a private sector memory clinic. MCI was diagnosed according to revised clinical criteria of Petersen et al. For a subset of patients with MCI medial temporal atrophy and cerebral small vessel disease (white matter lesions and lacunes) were rated on magnetic resonance imaging (MRI) scans and analyzed for their contribution towards cognitive impairment. Subjects with MCI formed one-third (113/371) of this memory clinic sample from a private hospital. MCI could be effectively diagnosed and subtyped using a brief cognitive scale (Concise Cognitive Test (CONCOG)). The amnestic MCI (single and multiple domains) subtype comprised the majority of cases with MCI. In a subsample of 33 patients, lacunar infarcts were more common than white matter lesions and hippocampal atrophy and were inversely associated with verbal fluency. MCI may be more commonly encountered in private hospital settings probably due to early referrals. It is possible to diagnose and subtype MCI using a brief cognitive instrument such as the CONCOG. In this sample, lacunar infarcts were more commonly encountered than medial temporal atrophy in such patients.

[Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

PubMed

Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

2016-07-01

We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases.

Intrajugular Vein Delivery of AAV9-RNAi Prevents Neuropathological Changes and Weight Loss in Huntington's Disease Mice

PubMed Central

Dufour, Brett D; Smith, Catherine A; Clark, Randall L; Walker, Timothy R; McBride, Jodi L

2014-01-01

Huntington's disease (HD) is a fatal neurological disorder caused by a CAG repeat expansion in the HTT gene, which encodes a mutant huntingtin protein (mHTT). The mutation confers a toxic gain of function on huntingtin, leading to widespread neurodegeneration and inclusion formation in many brain regions. Although the hallmark symptom of HD is hyperkinesia stemming from striatal degeneration, several other brain regions are affected which cause psychiatric, cognitive, and metabolic symptoms. Additionally, mHTT expression in peripheral tissue is associated with skeletal muscle atrophy, cardiac failure, weight loss, and diabetes. We, and others, have demonstrated a prevention of motor symptoms in HD mice following direct striatal injection of adeno-associated viral vector (AAV) serotype 1 encoding an RNA interference (RNAi) construct targeting mutant HTT mRNA (mHTT). Here, we expand these efforts and demonstrate that an intrajugular vein injection of AAV serotype 9 (AAV9) expressing a mutant HTT-specific RNAi construct significantly reduced mHTT expression in multiple brain regions and peripheral tissues affected in HD. Correspondingly, this approach prevented atrophy and inclusion formation in key brain regions as well as the severe weight loss germane to HD transgenic mice. These results demonstrate that systemic delivery of AAV9-RNAi may provide more widespread clinical benefit for patients suffering from HD. PMID:24390280

Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides-induced atrophy in skeletal muscle

PubMed Central

Mele, Antonietta; Calzolaro, Sara; Cannone, Gianluigi; Cetrone, Michela; Conte, Diana; Tricarico, Domenico

2014-01-01

The ATP-sensitive K+ (KATP) channel is an emerging pathway in the skeletal muscle atrophy which is a comorbidity condition in diabetes. The “in vitro” effects of the sulfonylureas and glinides were evaluated on the protein content/muscle weight, fibers viability, mitochondrial succinic dehydrogenases (SDH) activity, and channel currents in oxidative soleus (SOL), glycolitic/oxidative flexor digitorum brevis (FDB), and glycolitic extensor digitorum longus (EDL) muscle fibers of mice using biochemical and cell-counting Kit-8 assay, image analysis, and patch-clamp techniques. The sulfonylureas were: tolbutamide, glibenclamide, and glimepiride; the glinides were: repaglinide and nateglinide. Food and Drug Administration-Adverse Effects Reporting System (FDA-AERS) database searching of atrophy-related signals associated with the use of these drugs in humans has been performed. The drugs after 24 h of incubation time reduced the protein content/muscle weight and fibers viability more effectively in FDB and SOL than in the EDL. The order of efficacy of the drugs in reducing the protein content in FDB was: repaglinide (EC50 = 5.21 × 10−6) ≥ glibenclamide(EC50 = 8.84 × 10−6) > glimepiride(EC50 = 2.93 × 10−5) > tolbutamide(EC50 = 1.07 × 10−4) > nateglinide(EC50 = 1.61 × 10−4) and it was: repaglinide(7.15 × 10−5) ≥ glibenclamide(EC50 = 9.10 × 10−5) > nateglinide(EC50 = 1.80 × 10−4) ≥ tolbutamide(EC50 = 2.19 × 10−4) > glimepiride(EC50=–) in SOL. The drug-induced atrophy can be explained by the KATP channel block and by the enhancement of the mitochondrial SDH activity. In an 8-month period, muscle atrophy was found in 0.27% of the glibenclamide reports in humans and in 0.022% of the other not sulfonylureas and glinides drugs. No reports of atrophy were found for the other sulfonylureas and glinides in the FDA-AERS. Glibenclamide induces atrophy in animal experiments and in human patients. Glimepiride shows less potential for inducing atrophy. PMID:25505577

[Contribution of multimodal imaging in the various stages of Stargardt disease].

PubMed

El Matri, L; Falfoul, Y; Kortli, M; Hassairi, A; Charfi, H; Turki, A; Kort, F; Chebil, A

2017-10-01

To describe the contribution of multimodal imaging in the various stages of Stargardt disease (STGD). We retrospectively reviewed 46 eyes of 23 STGD patients with identified ABCA4 mutations. All patients underwent a complete ophthalmic examination, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), fluorescein angiography (FA) and Indocyanine green angiography (ICGA). The mean age of patients was 25.5 years (range 8-56). Fundus examination was normal in 2 patients (subclinical stage), where SD-OCT showed localized retrofoveolar retinal pigment epithelium (RPE) thickening. FAF was normal in 1 eye and showed mild heterogeneous hyper-FAF in 3 eyes. Twelve eyes had mild salt and pepper changes in the macula (early stage) with diffuse retinal atrophy on SD-OCT and mixed hyper and hypoautofluorescence on FAF. Nine patients showed central atrophy with white-yellow flecks distributed in the posterior pole and mid-periphery. This phenotype showed total foveal atrophy on SD-OCT and normal peripapillary area on FAF. Twelve eyes had a large demarcated area of RPE atrophy, pigment clumping and migration extending to the peripheral retina associated with peripapillary atrophy. These eyes showed diffuse retinochoroidal atrophy on OCT with diffuse alterations reaching the peripapillary area on FAF. On FA, it was difficult to analyze the choroidal silence sign in patients with advanced stages of the disease. A hyperfluorescent window defect pattern was also found in patients with white-yellow flecks and did not correspond exactly to them, or to the areas of peripheral autofluorescent lesions. ICGA showed hypocyanescent areas seen at intermediate and late phases with multiple cyanescent points adjacent to them. On ICGA, hypocyanescent areas were more extensive than lesions observed on FAF. Multimodal imaging is helpful for the diagnosis of early stages of STGD disease and to better understand its pathophysiology. FAF and mostly SD-OCT have supplanted FA in the early, especially subclinical, stages. Over all, ICGA shows more extensive damage, making this tool useful for better understanding STGD and suggesting possible direct damage to the choriocapillaris associated with RPE lesions. In advanced stages, only DNA testing can confirm the diagnosis of STGD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Impact of tissue atrophy on high-pass filtered MRI signal phase-based assessment in large-scale group-comparison studies: A simulation study

NASA Astrophysics Data System (ADS)

Schweser, Ferdinand; Dwyer, Michael G.; Deistung, Andreas; Reichenbach, Jürgen R.; Zivadinov, Robert

2013-10-01

The assessment of abnormal accumulation of tissue iron in the basal ganglia nuclei and in white matter plaques using the gradient echo magnetic resonance signal phase has become a research focus in many neurodegenerative diseases such as multiple sclerosis or Parkinson’s disease. A common and natural approach is to calculate the mean high-pass-filtered phase of previously delineated brain structures. Unfortunately, the interpretation of such an analysis requires caution: in this paper we demonstrate that regional gray matter atrophy, which is concomitant with many neurodegenerative diseases, may itself directly result in a phase shift seemingly indicative of increased iron concentration even without any real change in the tissue iron concentration. Although this effect is relatively small results of large-scale group comparisons may be driven by anatomical changes rather than by changes of the iron concentration.

Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program.

PubMed

Hindi, Sajedah M; Mishra, Vivek; Bhatnagar, Shephali; Tajrishi, Marjan M; Ogura, Yuji; Yan, Zhen; Burkly, Linda C; Zheng, Timothy S; Kumar, Ashok

2014-03-01

Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and TNF-like weak inducer of apoptosis (TWEAK)-Fn14 system are key regulators of skeletal muscle mass in various catabolic states. While the activation of TWEAK-Fn14 signaling causes muscle wasting, PGC-1α preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1α and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1α and mitochondrial content (∼50%) in skeletal muscle. Levels of PGC-1α are significantly increased in skeletal muscle of TWEAK-knockout (KO) and Fn14-KO mice compared to wild-type mice on denervation. Transgenic (Tg) overexpression of PGC-1α inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1α inhibited the TWEAK-induced activation of NF-κB (∼50%) and dramatically reduced (∼90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1α also prevented the inducible expression of Fn14 in denervated skeletal muscle. Collectively, our study demonstrates that TWEAK induces muscle atrophy through repressing the levels of PGC-1α. Overexpression of PGC-1α not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.

Different Surgical Approaches for Multiple Fractured Atrophic Mandibles

PubMed Central

Pereira, Felipe Ladeira; Gealh, Walter Cristiano; Barbosa, Carlos Eduardo Braga; Filho, Liogi Iwaki

2011-01-01

Atrophic edentulous mandible fractures in geriatric patients have low incidence but present several biological and biomechanical peculiarities that produce a nonunion rate of around 20%. Surgical extraoral approaches for internal fixation of these fractures can be transcervical or by one or two submandibular incisions. Two patients sustaining multiple fractures in atrophic edentulous mandible are presented: the first patient was 72-years-old, treated by two submandibular incisions, and the second was 81-years-old, treated by transcervical approach. We discuss the advantages and drawbacks of each approach and their indications according to the Luhr et al (1996) atrophy index. PMID:22379503

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study.

PubMed

Kinnunen, Kirsi M; Cash, David M; Poole, Teresa; Frost, Chris; Benzinger, Tammie L S; Ahsan, R Laila; Leung, Kelvin K; Cardoso, M Jorge; Modat, Marc; Malone, Ian B; Morris, John C; Bateman, Randall J; Marcus, Daniel S; Goate, Alison; Salloway, Stephen P; Correia, Stephen; Sperling, Reisa A; Chhatwal, Jasmeer P; Mayeux, Richard P; Brickman, Adam M; Martins, Ralph N; Farlow, Martin R; Ghetti, Bernardino; Saykin, Andrew J; Jack, Clifford R; Schofield, Peter R; McDade, Eric; Weiner, Michael W; Ringman, John M; Thompson, Paul M; Masters, Colin L; Rowe, Christopher C; Rossor, Martin N; Ourselin, Sebastien; Fox, Nick C

2018-01-01

Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy

PubMed Central

Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

2015-01-01

Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy.

PubMed

Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

2015-01-01

Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy.

Structural and functional characterization of two alpha-synuclein strains

NASA Astrophysics Data System (ADS)

Bousset, Luc; Pieri, Laura; Ruiz-Arlandis, Gemma; Gath, Julia; Jensen, Poul Henning; Habenstein, Birgit; Madiona, Karine; Olieric, Vincent; Böckmann, Anja; Meier, Beat H.; Melki, Ronald

2013-10-01

α-synuclein aggregation is implicated in a variety of diseases including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies.

Renin-angiotensin system: an old player with novel functions in skeletal muscle.

PubMed

Cabello-Verrugio, Claudio; Morales, María Gabriela; Rivera, Juan Carlos; Cabrera, Daniel; Simon, Felipe

2015-05-01

Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. © 2015 Wiley Periodicals, Inc.

Dysfunctional visual word form processing in progressive alexia

PubMed Central

Rising, Kindle; Stib, Matthew T.; Rapcsak, Steven Z.; Beeson, Pélagie M.

2013-01-01

Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent fusiform gyrus shows maximal selectivity for words and has been dubbed the ‘visual word form area’. We studied two patients with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects. All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases before the development of extensive atrophy. PMID:23471694

Dysfunctional visual word form processing in progressive alexia.

PubMed

Wilson, Stephen M; Rising, Kindle; Stib, Matthew T; Rapcsak, Steven Z; Beeson, Pélagie M

2013-04-01

Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent fusiform gyrus shows maximal selectivity for words and has been dubbed the 'visual word form area'. We studied two patients with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects. All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases before the development of extensive atrophy.

Vaginal Atrophy

MedlinePlus

... an Endocrinologist Search Featured Resource Menopause Map™ View Vaginal Atrophy October 2017 Download PDFs English Editors Christine ... during this time, including vaginal dryness. What is vaginal atrophy? Vaginal atrophy (also referred to as vulvovaginal ...

Automated analysis of whole skeletal muscle for muscular atrophy detection of ALS in whole-body CT images: preliminary study

NASA Astrophysics Data System (ADS)

Kamiya, Naoki; Ieda, Kosuke; Zhou, Xiangrong; Yamada, Megumi; Kato, Hiroki; Muramatsu, Chisako; Hara, Takeshi; Miyoshi, Toshiharu; Inuzuka, Takashi; Matsuo, Masayuki; Fujita, Hiroshi

2017-03-01

Amyotrophic lateral sclerosis (ALS) causes functional disorders such as difficulty in breathing and swallowing through the atrophy of voluntary muscles. ALS in its early stages is difficult to diagnose because of the difficulty in differentiating it from other muscular diseases. In addition, image inspection methods for aggressive diagnosis for ALS have not yet been established. The purpose of this study is to develop an automatic analysis system of the whole skeletal muscle to support the early differential diagnosis of ALS using whole-body CT images. In this study, the muscular atrophy parts including ALS patients are automatically identified by recognizing and segmenting whole skeletal muscle in the preliminary steps. First, the skeleton is identified by its gray value information. Second, the initial area of the body cavity is recognized by the deformation of the thoracic cavity based on the anatomical segmented skeleton. Third, the abdominal cavity boundary is recognized using ABM for precisely recognizing the body cavity. The body cavity is precisely recognized by non-rigid registration method based on the reference points of the abdominal cavity boundary. Fourth, the whole skeletal muscle is recognized by excluding the skeleton, the body cavity, and the subcutaneous fat. Additionally, the areas of muscular atrophy including ALS patients are automatically identified by comparison of the muscle mass. The experiments were carried out for ten cases with abnormality in the skeletal muscle. Global recognition and segmentation of the whole skeletal muscle were well realized in eight cases. Moreover, the areas of muscular atrophy including ALS patients were well identified in the lower limbs. As a result, this study indicated the basic technology to detect the muscle atrophy including ALS. In the future, it will be necessary to consider methods to differentiate other kinds of muscular atrophy as well as the clinical application of this detection method for early ALS detection and examine a large number of cases with stage and disease type.

Muscle atrophy in chronic inflammatory demyelinating polyneuropathy: a computed tomography assessment.

PubMed

Ohyama, K; Koike, H; Katsuno, M; Takahashi, M; Hashimoto, R; Kawagashira, Y; Iijima, M; Adachi, H; Watanabe, H; Sobue, G

2014-07-01

Muscle atrophy is generally mild in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) compared with the severity and duration of the muscle weakness. Muscle atrophy was evaluated using computed tomography (CT) in patients with CIDP. Thirty-one patients with typical CIDP who satisfied the diagnostic criteria for the definite CIDP classification proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society were assessed. The clinicopathological findings in patients with muscle atrophy were also compared with those in patients without atrophy. Computed tomography evidence was found of marked muscle atrophy with findings suggestive of fatty degeneration in 11 of the 31 patients with CIDP. CT-assessed muscle atrophy was in the lower extremities, particularly in the ankle plantarflexor muscles. Muscle weakness, which reflects the presence of muscle atrophy, tended to be more pronounced in the lower extremities than in the upper extremities in patients with muscle atrophy, whereas the upper and lower limbs tended to be equally affected in patients without muscle atrophy. Nerve conduction examinations revealed significantly greater reductions in compound muscle action potential amplitudes in the tibial nerves of patients with muscle atrophy. Sural nerve biopsy findings were similar in both groups. The functional prognoses after immunomodulatory therapies were significantly poorer amongst patients with muscle atrophy. Muscle atrophy was present in a subgroup of patients with CIDP, including patients with a typical form of the disease. These patients tended to demonstrate predominant motor impairments of the lower extremities and poorer functional prognoses. © 2014 The Author(s) European Journal of Neurology © 2014 EFNS.

Spinal Muscular Atrophy FAQ

MedlinePlus

... in SMA. What is Spinal Muscular Atrophy with Respiratory Distress (SMARD)? SMARD and SMA are separate diseases ... muscle weakness and atrophy. Spinal Muscular Atrophy with Respiratory Distress (SMARD) is a rare neuromuscular disease that ...

Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients.

PubMed

Braverman, Eric R; Blum, Kenneth; Hussman, Karl L; Han, David; Dushaj, Kristina; Li, Mona; Marin, Gabriela; Badgaiyan, Rajendra D; Smayda, Richard; Gold, Mark S

2015-01-01

To our knowledge, this is the largest study evaluating relationships between 3T Magnetic Resonance Imaging (MRI) and P300 and memory/cognitive tests in the literature. The 3T MRI using NeuroQuant has an increased resolution 15 times that of 1.5T MRI. Utilizing NeuroQuant 3T MRI as a diagnostic tool in primary care, subjects (N=169; 19-90 years) displayed increased areas of anatomical atrophy: 34.62% hippocampal atrophy (N=54), 57.14% central atrophy (N=88), and 44.52% temporal atrophy (N=69). A majority of these patients exhibited overlap in measured areas of atrophy and were cognitively impaired. These results positively correlated with decreased P300 values and WMS-III (WMS-III) scores differentially across various brain loci. Delayed latency (p=0.0740) was marginally associated with temporal atrophy; reduced fractional anisotropy (FA) in frontal lobes correlated with aging, delayed P300 latency, and decreased visual and working memory (p=0.0115). Aging and delayed P300 latency correlated with lower FA. The correlation between working memory and reduced FA in frontal lobes is marginally significant (p=0.0787). In the centrum semiovale (CS), reduced FA correlated with visual memory (p=0.0622). Lower demyelination correlated with higher P300 amplitude (p=0.0002). Compared to males, females have higher demyelination (p=0.0064). Along these lines, the higher the P300 amplitude, the lower the bilateral atrophy (p=0.0165). Hippocampal atrophy correlated with increased auditory memory and gender, especially in males (p=0.0087). In considering temporal lobe atrophy correlations: delayed P300 latency and high temporal atrophy (p=0.0740); high auditory memory and low temporal atrophy (p=0.0417); and high working memory and low temporal atrophy (p=0.0166). Central atrophy correlated with aging and immediate memory (p=0.0294): the higher the immediate memory, the lower the central atrophy. Generally, the validation of brain atrophy by P300 and WMS-III could lead to cost-effective methods utilizable in primary care medicine following further confirmation.

Evoked Potentials and Memory/Cognition Tests Validate Brain Atrophy as Measured by 3T MRI (NeuroQuant) in Cognitively Impaired Patients

PubMed Central

Braverman, Eric R.; Blum, Kenneth; Hussman, Karl L.; Han, David; Dushaj, Kristina; Li, Mona; Marin, Gabriela; Badgaiyan, Rajendra D.; Smayda, Richard; Gold, Mark S.

2015-01-01

To our knowledge, this is the largest study evaluating relationships between 3T Magnetic Resonance Imaging (MRI) and P300 and memory/cognitive tests in the literature. The 3T MRI using NeuroQuant has an increased resolution 15 times that of 1.5T MRI. Utilizing NeuroQuant 3T MRI as a diagnostic tool in primary care, subjects (N=169; 19–90 years) displayed increased areas of anatomical atrophy: 34.62% hippocampal atrophy (N=54), 57.14% central atrophy (N=88), and 44.52% temporal atrophy (N=69). A majority of these patients exhibited overlap in measured areas of atrophy and were cognitively impaired. These results positively correlated with decreased P300 values and WMS-III (WMS-III) scores differentially across various brain loci. Delayed latency (p=0.0740) was marginally associated with temporal atrophy; reduced fractional anisotropy (FA) in frontal lobes correlated with aging, delayed P300 latency, and decreased visual and working memory (p=0.0115). Aging and delayed P300 latency correlated with lower FA. The correlation between working memory and reduced FA in frontal lobes is marginally significant (p=0.0787). In the centrum semiovale (CS), reduced FA correlated with visual memory (p=0.0622). Lower demyelination correlated with higher P300 amplitude (p=0.0002). Compared to males, females have higher demyelination (p=0.0064). Along these lines, the higher the P300 amplitude, the lower the bilateral atrophy (p=0.0165). Hippocampal atrophy correlated with increased auditory memory and gender, especially in males (p=0.0087). In considering temporal lobe atrophy correlations: delayed P300 latency and high temporal atrophy (p=0.0740); high auditory memory and low temporal atrophy (p=0.0417); and high working memory and low temporal atrophy (p=0.0166). Central atrophy correlated with aging and immediate memory (p=0.0294): the higher the immediate memory, the lower the central atrophy. Generally, the validation of brain atrophy by P300 and WMS-III could lead to cost-effective methods utilizable in primary care medicine following further confirmation. PMID:26244349

Neuroimaging findings in children with retinopathy-confirmed cerebral malaria.

PubMed

Potchen, Michael J; Birbeck, Gretchen L; Demarco, J Kevin; Kampondeni, Sam D; Beare, Nicholas; Molyneux, Malcolm E; Taylor, Terrie E

2010-04-01

To describe brain CT findings in retinopathy-confirmed, paediatric cerebral malaria. In this outcomes study of paediatric cerebral malaria, a subset of children with protracted coma during initial presentation was scanned acutely. Survivors experiencing adverse neurological outcomes also underwent a head CT. All children had ophthalmological examination to confirm the presence of the retinopathy specific for cerebral malaria. Independent interpretation of CT images was provided by two neuroradiologists. Acute brain CT findings in three children included diffuse oedema with obstructive hydrocephalus (2), acute cerebral infarctions in multiple large vessel distributions with secondary oedema and herniation (1), and oedema of thalamic grey matter (1). One child who was reportedly normal prior to admission had parenchymal atrophy suggestive of pre-existing CNS injury. Among 56 survivors (9-84 months old), 15 had adverse neurologic outcomes-11/15 had a follow-up head CT, 3/15 died and 1/15 refused CT. Follow-up head CTs obtained 7-18 months after the acute infection revealed focal and multifocal lobar atrophy correlating to regions affected by focal seizures during the acute infection (5/11). Other findings were communicating hydrocephalus (2/11), vermian atrophy (1/11) and normal studies (3/11). The identification of pre-existing imaging abnormalities in acute cerebral malaria suggests that population-based studies are required to establish the rate and nature of incidental imaging abnormalities in Malawi. Children with focal seizures during acute cerebral malaria developed focal cortical atrophy in these regions at follow-up. Longitudinal studies are needed to further elucidate mechanisms of CNS injury and death in this common fatal disease. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy.

PubMed

Tucci, Arianna; Liu, Yo-Tsen; Preza, Elisabeth; Pitceathly, Robert D S; Chalasani, Annapurna; Plagnol, Vincent; Land, John M; Trabzuni, Daniah; Ryten, Mina; Jaunmuktane, Zane; Reilly, Mary M; Brandner, Sebastian; Hargreaves, Iain; Hardy, John; Singleton, Andrew B; Abramov, Andrey Y; Houlden, Henry

2014-05-01

Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified. We here describe a family with three affected individuals who inherited in an autosomal recessive fashion a childhood onset neuropathy and optic atrophy. Using homozygosity mapping in the family and exome sequencing in two affected individuals we identified a novel protein-truncating mutation in the C12orf65 gene, which encodes for a protein involved in mitochondrial translation. Using a variety of methods we investigated the possibility of mitochondrial impairment in the patients cell lines. We described a large consanguineous family with neuropathy and optic atrophy carrying a loss of function mutation in the C12orf65 gene. We report mitochondrial impairment in the patients cell lines, followed by multiple lines of evidence which include decrease of complex V activity and stability (blue native gel assay), decrease in mitochondrial respiration rate and reduction of mitochondrial membrane potential. This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.

Calpain 3 and CaMKIIβ signaling are required to induce HSP70 necessary for adaptive muscle growth after atrophy

PubMed Central

Kramerova, Irina; Torres, Jorge A; Eskin, Ascia; Nelson, Stanley F; Spencer, Melissa J

2018-01-01

Abstract Mutations in CAPN3 cause autosomal recessive limb girdle muscular dystrophy 2A. Calpain 3 (CAPN3) is a calcium dependent protease residing in the myofibrillar, cytosolic and triad fractions of skeletal muscle. At the triad, it colocalizes with calcium calmodulin kinase IIβ (CaMKIIβ). CAPN3 knock out mice (C3KO) show reduced triad integrity and blunted CaMKIIβ signaling, which correlates with impaired transcriptional activation of myofibrillar and oxidative metabolism genes in response to running exercise. These data suggest a role for CAPN3 and CaMKIIβ in gene regulation that takes place during adaptation to endurance exercise. To assess whether CAPN3- CaMKIIβ signaling influences skeletal muscle remodeling in other contexts, we subjected C3KO and wild type mice to hindlimb unloading and reloading and assessed CaMKIIβ signaling and gene expression by RNA-sequencing. After induced atrophy followed by 4 days of reloading, both CaMKIIβ activation and expression of inflammatory and cellular stress genes were increased. C3KO muscles failed to activate CaMKIIβ signaling, did not activate the same pattern of gene expression and demonstrated impaired growth at 4 days of reloading. Moreover, C3KO muscles failed to activate inducible HSP70, which was previously shown to be indispensible for the inflammatory response needed to promote muscle recovery. Likewise, C3KO showed diminished immune cell infiltration and decreased expression of pro-myogenic genes. These data support a role for CaMKIIβ signaling in induction of HSP70 and promotion of the inflammatory response during muscle growth and remodeling that occurs after atrophy, suggesting that CaMKIIβ regulates remodeling in multiple contexts: endurance exercise and growth after atrophy. PMID:29528394

A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations.

PubMed

Fujinami, Kaoru; Lois, Noemi; Mukherjee, Rajarshi; McBain, Vikki A; Tsunoda, Kazushige; Tsubota, Kazuo; Stone, Edwin M; Fitzke, Fred W; Bunce, Catey; Moore, Anthony T; Webster, Andrew R; Michaelides, Michel

2013-12-17

We characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease. Full clinical examination and AF imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken. The mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype. The AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.

Influence of cerebral white matter hyperintensities on cognitive impairment in elderly medical patients.

PubMed

Shibata, Koichi; Nishimura, Yoshiko; Otsuka, Kuniaki; Sakura, Hiroshi

2017-10-01

We investigated the characteristics of elderly medical patients with white matter hyperintensities on magnetic resonance imaging. A total of 213 patients (123 men and 90 women; mean age 74.8 years) reported their history of hypertension, diabetes, dyslipidemia, previous stroke, coronary heart disease and chronic kidney disease (CKD). All patients completed the Mini-Mental State Examination and Geriatric Depression Scale. White matter hyperintensities were evaluated for the periventricular region, basal ganglia (BGH), deep white matter and infratentorial region, and brain atrophy was calculated as bicaudate ratios. Patients with cognitive impairment (Mini-Mental State Examination score < 24) were significantly older (P = 0.001), had periventricular region hyperintensities (P = 0.029) and BGH (P = 0.0015), and showed atrophy (P < 0.0001). Logistic regression showed that cognitive impairment was predicted by stroke (OR 2.5, 95% CI 0.033-0.894, P = 0.036) and atrophy (OR 8.43, 95% CI 5.71-37.0, P = 0.0109). Multiple regressions showed that BGH was associated with CKD (β = 0.213; P = 0.003), and infratentorial region was associated with stroke (β = 0.157; P =0.035) and CKD (β = 0.172; P = 0.016). Periventricular region was associated with age (β = 0.2; P = 0.011) and Geriatric Depression Scale (β = 0.151; P = 0.037), and deep white matter hyperintensities with age (β = 0.189; P = 0.016). Although cognitive impairment in elderly medical patients is associated with stroke and brain atrophy, white matter hyperintensities, especially BGH and infratentorial region, are associated with cognitive decline in relation to CKD. Geriatr Gerontol Int 2017; 17: 1488-1493. © 2016 Japan Geriatrics Society.

Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size.

PubMed

Lee, David E; Brown, Jacob L; Rosa-Caldwell, Megan E; Blackwell, Thomas A; Perry, Richard A; Brown, Lemuel A; Khatri, Bhuwan; Seo, Dongwon; Bottje, Walter G; Washington, Tyrone A; Wiggs, Michael P; Kong, Byung-Whi; Greene, Nicholas P

2017-05-01

Muscle atrophy is a hallmark of cancer cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate-buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia. Copyright © 2017 the American Physiological Society.

Impaired renal function is associated with brain atrophy and poststroke cognitive decline.

PubMed

Auriel, Eitan; Kliper, Efrat; Shenhar-Tsarfaty, Shani; Molad, Jeremy; Berliner, Shlomo; Shapira, Itzhak; Ben-Bashat, Dafna; Shopin, Ludmila; Tene, Oren; Rosenberg, Gary A; Bornstein, Natan M; Ben Assayag, Einor

2016-05-24

To evaluate the interrelationship among impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. The Tel Aviv Brain Acute Stroke Cohort study is a prospective cohort of mild-moderate ischemic stroke/TIA survivors without dementia who underwent a 3T MRI and were cognitively assessed at admission and for 24 months following stroke. Renal function was evaluated at admission by creatinine clearance (CCl) estimation. The volumes of ischemic lesions and preexisting white matter hyperintensities (WMH), brain atrophy, and microstructural changes of the normal-appearing white matter tissue were measured using previously validated methods. Baseline data were available for 431 participants. Participants with a CCl <60 mL/min at baseline performed significantly worse in all cognitive tests over time (p = 0.001) than those with a CCl ≥60 mL/min and had larger WMH volume and cortical atrophy and smaller hippocampal volume (all p < 0.001). After 2 years, 15.5% of the participants were diagnosed with cognitive impairment. Multiple logistic regression analysis, controlling for traditional risk factors, suggested CCl <60 mL/min at baseline as a significant predictor for the development of cognitive impairment 2 years after the index stroke (odds ratio 2.01 [95% confidence interval 1.03-3.92], p = 0.041). Impaired renal function is associated with increased WMH volume and cortical atrophy, known biomarkers of the aging brain, and is a predictor for cognitive decline 2 years after stroke/TIA. Decreased renal function may be associated with cerebral small vessel disease underlying poststroke cognitive decline, suggesting a new target for early intervention. © 2016 American Academy of Neurology.

Progression of Myopic Maculopathy during 18-Year Follow-up.

PubMed

Fang, Yuxin; Yokoi, Tae; Nagaoka, Natsuko; Shinohara, Kosei; Onishi, Yuka; Ishida, Tomoka; Yoshida, Takeshi; Xu, Xian; Jonas, Jost B; Ohno-Matsui, Kyoko

2018-06-01

To examine the progression pattern of myopic maculopathy. Retrospective, observational case series. Highly myopic patients who had been followed up for 10 years or more. Using fundus photographs, myopic features were differentiated according to Meta-analysis of Pathologic Myopia (META-PM) Study Group recommendations. Progression pattern of maculopathy. The study included 810 eyes of 432 patients (mean age, 42.3±16.8 years; mean axial length, 28.8±1.9 mm; mean follow-up, 18.7±7.1 years). The progression rate of myopic maculopathy was 47.0 per 1000 eye-years. Within the pathologic myopia (PM) group (n = 521 eyes), progression of myopic maculopathy was associated with female gender (odds ratio [OR], 2.21; P = 0.001), older age (OR, 1.03; P = 0.002), longer axial length (OR, 1.20; P = 0.007), greater axial elongation (OR, 1.45; P = 0.005), and development of parapapillary atrophy (PPA; OR, 3.14; P < 0.001). Diffuse atrophy, found in 217 eyes without choroidal neovascularization (CNV) or lacquer cracks (LCs) at baseline, progressed in 111 (51%) eyes, leading to macular diffuse atrophy (n = 64; 64/111 or 58%), patchy atrophy (n = 59; 53%), myopic CNV (n = 18; 16%), LCs (n = 9; 5%), and patchy-related macular atrophy (n = 3; 3%). Patchy atrophy, detected in 63 eyes without CNV or LCs at baseline, showed progression in 60 eyes (95%), leading to enlargement of original patchy atrophy (n = 59; 59/60 or 98%), new patchy atrophy (n = 29; 48%), CNV-related macular atrophy (n = 13; 22%), and patchy-related macular atrophy (n = 5; 8%). Of 66 eyes with LCs, 43 eyes (65%) showed progression with development of new patchy atrophy (n = 38; 38/43 or 88%) and new LCs (n = 7; 16%). Reduction in best-corrected visual acuity (BCVA) was associated mainly (all P < 0.001) with the development of CNV or CNV-related macular atrophy and enlargement of macular atrophy. The most frequent progression patterns were an extension of peripapillary diffuse atrophy to macular diffuse atrophy in diffuse atrophy, enlargement of the original atrophic lesion in patchy atrophy, and development of patchy atrophy in LCs. Main risk factors for progression were older age, longer axial length, and development of PPA. Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Discrimination of dementia with Lewy bodies from Alzheimer's disease using voxel-based morphometry of white matter by statistical parametric mapping 8 plus diffeomorphic anatomic registration through exponentiated Lie algebra.

PubMed

Nakatsuka, Tomoya; Imabayashi, Etsuko; Matsuda, Hiroshi; Sakakibara, Ryuji; Inaoka, Tsutomu; Terada, Hitoshi

2013-05-01

The purpose of this study was to identify brain atrophy specific for dementia with Lewy bodies (DLB) and to evaluate the discriminatory performance of this specific atrophy between DLB and Alzheimer's disease (AD). We retrospectively reviewed 60 DLB and 30 AD patients who had undergone 3D T1-weighted MRI. We randomly divided the DLB patients into two equal groups (A and B). First, we obtained a target volume of interest (VOI) for DLB-specific atrophy using correlation analysis of the percentage rate of significant whole white matter (WM) atrophy calculated using the Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) based on statistical parametric mapping 8 (SPM8) plus diffeomorphic anatomic registration through exponentiated Lie algebra, with segmented WM images in group A. We then evaluated the usefulness of this target VOI for discriminating the remaining 30 DLB patients in group B from the 30 AD patients. Z score values in this target VOI obtained from VSRAD were used as the determinant in receiver operating characteristic (ROC) analysis. Specific target VOIs for DLB were determined in the right-side dominant dorsal midbrain, right-side dominant dorsal pons, and bilateral cerebellum. ROC analysis revealed that the target VOI limited to the midbrain exhibited the highest area under the ROC curves of 0.75. DLB patients showed specific atrophy in the midbrain, pons, and cerebellum. Midbrain atrophy demonstrated the highest power for discriminating DLB and AD. This approach may be useful for determining the contributions of DLB and AD pathologies to the dementia syndrome.

Myofibril breakdown during atrophy is a delayed response requiring the transcription factor PAX4 and desmin depolymerization

PubMed Central

Volodin, Alexandra; Kosti, Idit; Goldberg, Alfred Lewis; Cohen, Shenhav

2017-01-01

A hallmark of muscle atrophy is the excessive degradation of myofibrillar proteins primarily by the ubiquitin proteasome system. In mice, during the rapid muscle atrophy induced by fasting, the desmin cytoskeleton and the attached Z-band–bound thin filaments are degraded after ubiquitination by the ubiquitin ligase tripartite motif-containing protein 32 (Trim32). To study the order of events leading to myofibril destruction, we investigated the slower atrophy induced by denervation (disuse). We show that myofibril breakdown is a two-phase process involving the initial disassembly of desmin filaments by Trim32, which leads to the later myofibril breakdown by enzymes, whose expression is increased by the paired box 4 (PAX4) transcription factor. After denervation of mouse tibialis anterior muscles, phosphorylation and Trim32-dependent ubiquitination of desmin filaments increased rapidly and stimulated their gradual depolymerization (unlike their rapid degradation during fasting). Trim32 down-regulation attenuated the loss of desmin and myofibrillar proteins and reduced atrophy. Although myofibrils and desmin filaments were intact at 7 d after denervation, inducing the dissociation of desmin filaments caused an accumulation of ubiquitinated proteins and rapid destruction of myofibrils. The myofibril breakdown normally observed at 14 d after denervation required not only dissociation of desmin filaments, but also gene induction by PAX4. Down-regulation of PAX4 or its target gene encoding the p97/VCP ATPase reduced myofibril disassembly and degradation on denervation or fasting. Thus, during atrophy, the initial loss of desmin is critical for the subsequent myofibril destruction, and over time, myofibrillar proteins become more susceptible to PAX4-induced enzymes that promote proteolysis. PMID:28096335

Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer´s disease

PubMed Central

Grothe, Michel; Heinsen, Helmut; Teipel, Stefan J.

2013-01-01

Background The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer´s disease (AD). However, there is a controversy on how the cholinergic lesion in AD relates to early and incipient stages of the disease. In-vivo imaging studies on the structural integrity of the BFCS in normal and pathological aging are still rare. Methods We applied automated morphometry techniques in combination with high-dimensional image warping and a cytoarchitectonic map of BF cholinergic nuclei to a large cross-sectional dataset of high-resolution MRI scans, covering the whole adult age-range (20–94 years; N=211) as well as patients with very mild AD (vmAD; CDR=0.5; N=69) and clinically manifest AD (AD; CDR=1; N=28). For comparison, we investigated hippocampus volume using automated volumetry. Results Volume of the BFCS declined from early adulthood on and atrophy aggravated in advanced age. Volume reductions in vmAD were most pronounced in posterior parts of the nucleus basalis Meynert, while in AD atrophy was more extensive and included the whole BFCS. In clinically manifest AD, the diagnostic accuracy of BFCS volume reached the diagnostic accuracy of hippocampus volume. Conclusions Our findings indicate that cholinergic degeneration in AD occurs against a background of age-related atrophy and that exacerbated atrophy in AD can be detected at earliest stages of cognitive impairment. Automated in-vivo morphometry of the BFCS may become a useful tool to assess BF cholinergic degeneration in normal and pathological aging. PMID:21816388

New multiplex real-time PCR approach to detect gene mutations for spinal muscular atrophy.

PubMed

Liu, Zhidai; Zhang, Penghui; He, Xiaoyan; Liu, Shan; Tang, Shi; Zhang, Rong; Wang, Xinbin; Tan, Junjie; Peng, Bin; Jiang, Li; Hong, Siqi; Zou, Lin

2016-08-17

Spinal muscular atrophy (SMA) is the most common autosomal recessive disease in children, and the diagnosis is complicated and difficult, especially at early stage. Early diagnosis of SMA is able to improve the outcome of SMA patients. In our study, Real-time PCR was developed to measure the gene mutation or deletion of key genes for SMA and to further analyse genotype-phenotype correlation. The multiple real-time PCR for detecting the mutations of survival of motor neuron (SMN), apoptosis inhibitory protein (NAIP) and general transcription factor IIH, polypeptide 2 gene (GTF2H2) was established and confirmed by DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). The diagnosis and prognosis of 141 hospitalized children, 100 normal children and further 2000 cases of dry blood spot (DBS) samples were analysed by this multiple real-time PCR. The multiple real-time PCR was established and the accuracy of it to detect the mutations of SMN, NAIP and GTF2H2 was at least 98.8 % comparing with DNA sequencing and MLPA. Among 141 limb movement disorders children, 75 cases were SMA. 71 cases of SMA (94.67 %) were with SMN c.840 mutation, 9 cases (12 %) with NAIP deletion and 3 cases (4 %) with GTF2H2 deletion. The multiple real-time PCR was able to diagnose and predict the prognosis of SMA patients. Simultaneously, the real-time PCR was applied to detect trace DNA from DBS and able to make an early diagnosis of SMA. The clinical and molecular characteristics of SMA in Southwest of China were presented. Our work provides a novel way for detecting SMA in children by using real-time PCR and the potential usage in newborn screening for early diagnosis of SMA.

Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

PubMed

Nash, L A; Burns, J K; Chardon, J Warman; Kothary, R; Parks, R J

2016-01-01

Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Knockdown of metallothionein 1 and 2 does not affect atrophy or oxidant activity in a novel in vitro model.

PubMed

Hyldahl, Robert D; O'Fallon, Kevin S; Schwartz, Lawrence M; Clarkson, Priscilla M

2010-11-01

Skeletal muscle atrophy is a significant health problem that results in decreased muscle size and function and has been associated with increases in oxidative stress. The molecular mechanisms that regulate muscle atrophy, however, are largely unknown. The metallothioneins (MT), a family of genes with antioxidant properties, have been found to be consistently upregulated during muscle atrophy, although their function during muscle atrophy is unknown. Therefore, we hypothesized that MT knockdown would result in greater oxidative stress and an enhanced atrophy response in C(2)C(12) myotubes subjected to serum reduction (SR), a novel atrophy-inducing stimulus. Forty-eight hours before SR, myotubes were transfected with small interfering RNA (siRNA) sequences designed to decrease MT expression. Muscle atrophy and oxidative stress were then measured at baseline and for 72 h following SR. Muscle atrophy was quantified by immunocytochemistry and myotube diameter measurements. Oxidative stress was measured using the fluorescent probe 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein. SR resulted in a significant increase in oxidative stress and a decrease in myotube size and protein content. However, there were no differences observed in the extent of muscle atrophy or oxidant activity following MT knockdown. We therefore conclude that the novel SR model results in a strong atrophy response and an increase in oxidant activity in cultured myotubes and that knockdown of MT does not affect that response.

Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets.

PubMed

De Stefano, Nicola; Giorgio, Antonio; Battaglini, Marco; De Leucio, Alessandro; Hicking, Christine; Dangond, Fernando; Giovannoni, Gavin; Sormani, Maria Pia

2018-02-01

Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years' treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa. Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.

Morphostructural MRI abnormalities related to neuropsychiatric disorders associated to multiple sclerosis.

PubMed

Bonavita, Simona; Tedeschi, Gioacchino; Gallo, Antonio

2013-01-01

Multiple Sclerosis associated neuropsychiatric disorders include major depression (MD), obsessive-compulsive disorder (OCD), bipolar affective disorder, euphoria, pseudobulbar affect, psychosis, and personality change. Magnetic Resonance Imaging (MRI) studies focused mainly on identifying morphostructural correlates of MD; only a few anecdotal cases on OCD associated to MS (OCD-MS), euphoria, pseudobulbar affect, psychosis, personality change, and one research article on MRI abnormalities in OCD-MS have been published. Therefore, in the present review we will report mainly on neuroimaging abnormalities found in MS patients with MD and OCD. All together, the studies on MD associated to MS suggest that, in this disease, depression is linked to a damage involving mainly frontotemporal regions either with discrete lesions (with those visible in T1 weighted images playing a more significant role) or subtle normal appearing white matter abnormalities. Hippocampal atrophy, as well, seems to be involved in MS related depression. It is conceivable that grey matter pathology (i.e., global and regional atrophy, cortical lesions), which occurs early in the course of disease, may involve several areas including the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex whose disruption is currently thought to explain late-life depression. Further MRI studies are necessary to better elucidate OCD pathogenesis in MS.

Morphostructural MRI Abnormalities Related to Neuropsychiatric Disorders Associated to Multiple Sclerosis

PubMed Central

Bonavita, Simona; Tedeschi, Gioacchino; Gallo, Antonio

2013-01-01

Multiple Sclerosis associated neuropsychiatric disorders include major depression (MD), obsessive-compulsive disorder (OCD), bipolar affective disorder, euphoria, pseudobulbar affect, psychosis, and personality change. Magnetic Resonance Imaging (MRI) studies focused mainly on identifying morphostructural correlates of MD; only a few anecdotal cases on OCD associated to MS (OCD-MS), euphoria, pseudobulbar affect, psychosis, personality change, and one research article on MRI abnormalities in OCD-MS have been published. Therefore, in the present review we will report mainly on neuroimaging abnormalities found in MS patients with MD and OCD. All together, the studies on MD associated to MS suggest that, in this disease, depression is linked to a damage involving mainly frontotemporal regions either with discrete lesions (with those visible in T1 weighted images playing a more significant role) or subtle normal appearing white matter abnormalities. Hippocampal atrophy, as well, seems to be involved in MS related depression. It is conceivable that grey matter pathology (i.e., global and regional atrophy, cortical lesions), which occurs early in the course of disease, may involve several areas including the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex whose disruption is currently thought to explain late-life depression. Further MRI studies are necessary to better elucidate OCD pathogenesis in MS. PMID:23691320

Progressive accumulation of ubiquitin and disappearance of alpha-synuclein epitope in multiple system atrophy-associated glial cytoplasmic inclusions: triple fluorescence study combined with Gallyas-Braak method.

PubMed

Sakamoto, Masaki; Uchihara, Toshiki; Nakamura, Ayako; Mizutani, Toshio; Mizusawa, Hidehiro

2005-10-01

Alpha-synuclein (alphaS) and ubiquitin (Ub) are shared constituents of glial cytoplasmic inclusions (GCIs) and Lewy bodies (LBs), both composed of fibrillary structures. Staining profiles of GCIs were investigated with triple immunofluorescence involving immunostaining for alphaS and Ub, both amplified with catalyzed reporter deposition, and a fluorochrome, thiazin red (TR) that has an affinity to fibrillary structures. After observation for the triple-fluorescent images, the sections were subsequently stained with the Gallyas-Braak method. Sections of putamen, cerebellar white matter and motor cortex from patients suffering from multiple system atrophy (MSA) with varying duration of the disease (4-15 years) were quantified for these staining profiles of Gallyas-positive GCIs. Although most of GCIs were positive for Ub and variably positive for alphaS, they were consistently negative for TR. The result was opposite in LBs in Lewy body disease with variable affinity to TR, suggesting that the construction of GCIs is different from that of LBs. These four staining features (alphaS, Ub, TR and Gallyas) alone failed to exhibit apparent correlation with disease duration, lesion site or severity of degeneration as reported previously. The fraction of alphaS-negative and Ub-positive GCIs, however, linearly increased along the disease progression, while that of alphaS-positive and Ub-negative GCIs decreased in contrast. This reciprocal change suggests that alphaS immunoreactivity in GCIs is being replaced by Ub immunoreactivity during the disease progression, which resulted in the ultimate predominance of alphaS-negative and Ub-positive GCIs in the most advanced case. Interestingly, this predominance of alphaS-negative and Ub-positive GCIs was a feature of motor cortex, where degeneration usually remains mild in spite of robust appearance of Gallyas-positive GCIs. Another fraction, alphaS-positive and Ub-positive GCIs were frequent in cerebellar white matter, suggesting that GCI evolution is heterogeneous and dependent also on area examined. Progressive accumulation of Ub with concomitant disappearance of alphaS epitope and their colocalization, partly shared with LBs, may represent a process of GCI formation, possibly linked to an aspect of degeneration in MSA.

Differences between Spinocerebellar Ataxias and Multiple System Atrophy-Cerebellar Type on Proton Magnetic Resonance Spectroscopy

PubMed Central

Chen, Hung-Chieh; Soong, Bing-Wen; Guo, Wan Yuo; Wu, Hsiu-Mei; Chang, Cheng-Yen

2012-01-01

Purpose A broad spectrum of diseases can manifest cerebellar ataxia. In this study, we investigated whether proton magnetic resonance spectroscopy (MRS) may help differentiate spinocerebellar ataxias (SCA) from multiple systemic atrophy- cerebellar type (MSA-C). Material and Methods This prospective study recruited 156 patients with ataxia, including spinocerebellar ataxia (SCA) types 1, 2, 3, 6 and 17 (N = 94) and MSA-C (N = 62), and 44 healthy controls. Single voxel proton MRS in the cerebellar hemispheres and vermis were measured. The differences were evaluated using nonparametric statistic tests. Results When compared with healthy controls, the cerebellar and vermis NAA/Cr and NAA/Cho were lower in all patients(p<0.002). The Cho/Cr was lower in SCA2 and MSA-C (p<0.0005). The NAA/Cr and Cho/Cr were lower in MSA-C or SCA2 comparing with SCA3 or SCA6. The MRS features of SCA1 were in between (p<0.018). The cerebellar NAA/Cho was lower in SCA2 than SCA1, SCA3 or SCA6 (p<0.04). The cerebellar NAA/Cho in MSA-C was lower than SCA3 (p<0.0005). In the early stages of diseases (SARA score<10), significant lower NAA/Cr and NAA/Cho in SCA2, SCA3, SCA6 or MSA-C were observed comparing with healthy controls (p<0.017). The Cho/Cr was lower in MSA-C or SCA2 (p<0.0005). Patients with MSA-C and SCA2 had lower NAA/Cr and Cho/Cr than SCA3 or SCA6 (p<0.016). Conclusion By using MRS, significantly lower NAA/Cr, Cho/Cr and NAA/Cho in the cerebellar hemispheres and vermis were found in patients with ataxia (SCAs and MSA-C). Rapid neuronal degeneration and impairment of membrane activities were observed more often in patients with MSA-C than those with SCA, even in early stages. MRS could also help distinguish between SCA2 and other subtypes of SCAs. MRS ratios may be of use as biomarkers in early stages of disease and should be further assessed in a longitudinal study. PMID:23118909

Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

PubMed Central

Payan, Christine A. M.; Viallet, François; Landwehrmeyer, Bernhard G.; Bonnet, Anne-Marie; Borg, Michel; Durif, Franck; Lacomblez, Lucette; Bloch, Frédéric; Verny, Marc; Fermanian, Jacques; Agid, Yves; Ludolph, Albert C.

2011-01-01

Background The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Methods and Findings Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α≥0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80–0.93), and moderate (Intra-class coefficient = 0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho≥0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. Conclusions The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. Trial Registration ClinicalTrials.gov NCT00211224 PMID:21829612

A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability

PubMed Central

Rolland, Yan; Vérin, Marc; Payan, Christine A; Duchesne, Simon; Kraft, Eduard; Hauser, Till K; Jarosz, Josef; Deasy, Neil; Defevbre, Luc; Delmaire, Christine; Dormont, Didier; Ludolph, Albert C; Bensimon, Gilbert

2011-01-01

Aim To evaluate a standardised MRI acquisition protocol and a new image rating scale for disease severity in patients with progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) in a large multicentre study. Methods The MRI protocol consisted of two-dimensional sagittal and axial T1, axial PD, and axial and coronal T2 weighted acquisitions. The 32 item ordinal scale evaluated abnormalities within the basal ganglia and posterior fossa, blind to diagnosis. Among 760 patients in the study population (PSP=362, MSA=398), 627 had per protocol images (PSP=297, MSA=330). Intra-rater (n=60) and inter-rater (n=555) reliability were assessed through Cohen's statistic, and scale structure through principal component analysis (PCA) (n=441). Internal consistency and reliability were checked. Discriminant and predictive validity of extracted factors and total scores were tested for disease severity as per clinical diagnosis. Results Intra-rater and inter-rater reliability were acceptable for 25 (78%) of the items scored (≥0.41). PCA revealed four meaningful clusters of covarying parameters (factor (F) F1: brainstem and cerebellum; F2: midbrain; F3: putamen; F4: other basal ganglia) with good to excellent internal consistency (Cronbach α 0.75–0.93) and moderate to excellent reliability (intraclass coefficient: F1: 0.92; F2: 0.79; F3: 0.71; F4: 0.49). The total score significantly discriminated for disease severity or diagnosis; factorial scores differentially discriminated for disease severity according to diagnosis (PSP: F1–F2; MSA: F2–F3). The total score was significantly related to survival in PSP (p<0.0007) or MSA (p<0.0005), indicating good predictive validity. Conclusions The scale is suitable for use in the context of multicentre studies and can reliably and consistently measure MRI abnormalities in PSP and MSA. Clinical Trial Registration Number The study protocol was filed in the open clinical trial registry (http://www.clinicaltrials.gov) with ID No NCT00211224. PMID:21386111

A new model of skeletal muscle atrophy induced by immobilization using a hook-and-loop fastener in mice

PubMed Central

Aihara, Masahiro; Hirose, Noboru; Katsuta, Wakana; Saito, Fumiaki; Maruyama, Hitoshi; Hagiwara, Hiroki

2017-01-01

[Purpose] To study muscle atrophy, the muscle atrophy model mice have been used frequently. In particular, cast immobilization is the most common method to induce muscle atrophy. However, it is time consuming and often causes adverse events including skin injury, edema, and necrosis. The present study, we developed a hook-and-loop fastener (Velcro) immobilization method as a new, simple, and less invasive approach to induce muscle atrophy. [Subjects and Methods] Mice were bandaged in the knee joint extension and ankle plantar extension position. Muscle atrophy was induced by either winding a cast or Velcro around the limb. [Results] According to weight and fiber size, Velcro immobilization induced equivalent muscle atrophy to cast immobilization. Velcro immobilization reduced significantly the time for the procedure and the frequency of adverse events. [Conclusion] Velcro immobilization can induce muscle atrophy comparable to cast immobilization, but in a shorter time and with less complications. Velcro immobilization may contribute to the study of disuse muscle atrophy in clinical practice of physical therapy using a mouse model. PMID:29184288

Relationship between Social Cognition and traditional cognitive impairment in Progressive Multiple Sclerosis and possible implicated neuroanatomical regions.

PubMed

Ciampi, E; Uribe-San-Martin, R; Vásquez, M; Ruiz-Tagle, A; Labbe, T; Cruz, J P; Lillo, P; Slachevsky, A; Reyes, D; Reyes, A; Cárcamo-Rodríguez, C

2018-02-01

Cognitive impairment is a relevant contributor of the medical and social burden in Progressive MS. Social Cognition, the neurocognitive processes underlying social interaction, has been explored mainly in European and North American cohorts, influencing social aspects of quality of life (QOL) of early MS patients and families. Few studies have studied Social Cognition in Progressive MS and the literature on its neuroanatomical bases or brain atrophy measurements is still scarce. To explore the relationship between Social Cognition performance and its correlations with traditional cognitive domains, brain atrophy and QOL in primary and secondary Progressive MS patients. Cross-sectional analysis including: mini-Social-Cognition-and-Emotional-Assessment (mini-SEA), neuropsychological battery, disability, depression, fatigue, QOL, and brain volume. Forty-three MS patients, 23 primary and 20 secondary Progressive, 65% women, mean age and disease duration of 57.2 and 15.7 years, respectively, with high levels of disability (median EDSS 6.0) and a widespread impairment in traditional domains (mostly episodic verbal/visual and working memories) were assessed. The Mini-SEA score was correlated with executive functions (cognitive shifts Rho:0.55; p = 0.001) analyzing the whole group, and with visual episodic memory (Rho:0.58, p = 0.009) in the primary Progressive MS group. Mini-SEA score was also correlated with total normalized grey matter volume (Rho:0.48; p = 0.004). Particularly, atrophy within bilateral cortical regions of orbitofrontal, insula and cerebellum, and right regions of fusiform gyrus and precuneus were significantly associated with higher Social Cognition impairment. In this cohort, QOL was not correlated with Social Cognition, but with EDSS, fatigue and depression. In Progressive MS, Social Cognition is directly correlated with traditional cognitive domains such as executive function and episodic memory. It is also associated with global grey matter atrophy and regional atrophy within associative visual and executive cortical areas, but no correlations with QOL were found in this cohort. These findings may contribute to the understanding of the pathological bases behind Social Cognition in Progressive MS. Copyright © 2018 Elsevier B.V. All rights reserved.

Cortical and subcortical atrophy in Alzheimer disease: parallel atrophy of thalamus and hippocampus.

PubMed

Štěpán-Buksakowska, Irena; Szabó, Nikoletta; Hořínek, Daniel; Tóth, Eszter; Hort, Jakub; Warner, Joshua; Charvát, František; Vécsei, László; Roček, Miloslav; Kincses, Zsigmond T

2014-01-01

Brain atrophy is a key imaging hallmark of Alzheimer disease (AD). In this study, we carried out an integrative evaluation of AD-related atrophy. Twelve patients with AD and 13 healthy controls were enrolled. We conducted a cross-sectional analysis of total brain tissue volumes with SIENAX. Localized gray matter atrophy was identified with optimized voxel-wise morphometry (FSL-VBM), and subcortical atrophy was evaluated by active shape model implemented in FMRIB's Integrated Registration Segmentation Toolkit. SIENAX analysis demonstrated total brain atrophy in AD patients; voxel-based morphometry analysis showed atrophy in the bilateral mediotemporal regions and in the posterior brain regions. In addition, regarding the diminished volumes of thalami and hippocampi in AD patients, subsequent vertex analysis of the segmented structures indicated shrinkage of the bilateral anterior thalami and the left medial hippocampus. Interestingly, the volume of the thalami and hippocampi were highly correlated with the volume of the thalami and amygdalae on both sides in AD patients, but not in healthy controls. This complex structural information proved useful in the detailed interpretation of AD-related neurodegenerative process, as the multilevel approach showed both global and local atrophy on cortical and subcortical levels. Most importantly, our results raise the possibility that subcortical structure atrophy is not independent in AD patients.

Role of ATF4 in skeletal muscle atrophy.

PubMed

Adams, Christopher M; Ebert, Scott M; Dyle, Michael C

2017-05-01

Here, we discuss recent work focused on the role of activating transcription factor 4 (ATF4) in skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression; however, the transcriptional regulatory proteins responsible for those changes are not yet well defined. Recent work indicates that some forms of muscle atrophy require ATF4, a stress-inducible bZIP transcription factor subunit that helps to mediate a broad range of stress responses in mammalian cells. ATF4 expression in skeletal muscle fibers is sufficient to induce muscle fiber atrophy and required for muscle atrophy during several stress conditions, including aging, fasting, and limb immobilization. By helping to activate specific genes in muscle fibers, ATF4 contributes to the expression of numerous mRNAs, including at least two mRNAs (Gadd45a and p21) that encode mediators of muscle fiber atrophy. Gadd45a promotes muscle fiber atrophy by activating the protein kinase MEKK4. p21 promotes atrophy by reducing expression of spermine oxidase, a metabolic enzyme that helps to maintain muscle fiber size under nonstressed conditions. In skeletal muscle fibers, ATF4 is critical component of a complex and incompletely understood molecular signaling network that causes muscle atrophy during aging, fasting, and immobilization.

[Principles of bone tissue structures interaction with full removable dentures fixed on intraosseous implantates modelling].

PubMed

Shashmurina, V R; Chumachenko, E N; Olesova, V N; Volozhin, A I

2008-01-01

Math modelling "removable dentures-implantate-bone" with size and density of bone tissue as variables was created. It allowed to study biomechanical bases of mandibular bone tissue structures interaction with full removable dentures of different constructions and fixed on intraosseous implantates. Analysis of the received data showed that in the majority of cases it was expedient to recommend 3 bearing (abutments) system of denture making. Rest on 4 and more implantates was appropriate for patients with reduced density of spongy bone and significant mandibular bone atrophy. 2 abutment system can be used in patients with high density of spongy bone and absence of mandibular bone atrophy.

Tissue Engineering Organs for Space Biology Research

NASA Technical Reports Server (NTRS)

Vandenburgh, H. H.; Shansky, J.; DelTatto, M.; Lee, P.; Meir, J.

1999-01-01

Long-term manned space flight requires a better understanding of skeletal muscle atrophy resulting from microgravity. Atrophy most likely results from changes at both the systemic level (e.g. decreased circulating growth hormone, increased circulating glucocorticoids) and locally (e.g. decreased myofiber resting tension). Differentiated skeletal myofibers in tissue culture have provided a model system over the last decade for gaining a better understanding of the interactions of exogenous growth factors, endogenous growth factors, and muscle fiber tension in regulating protein turnover rates and muscle cell growth. Tissue engineering these cells into three dimensional bioartificial muscle (BAM) constructs has allowed us to extend their use to Space flight studies for the potential future development of countermeasures.

[Disease concept, etiology and mechanisms of multiple sclerosis].

PubMed

Kira, Jun-Ichi

2014-11-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system(CNS). MS is assumed to be caused by a complex interplay between genes and environments. Autoimmune mechanisms targeting CNS myelin has long been proposed, yet it has not been proved. Th17 cells producing interleukin-17 and Th1 cells producing interferon-gamma are postulated to play major roles in initiating inflammation while regulatory T cell functions are dampened. The forth nationwide survey of MS in Japan revealed that MS prevalence showed four-folds increase over 30 years and the increase was especially prominent in female. Thus, westernized life style and improved sanitation are suspected to increase MS susceptibility. Genome-wide association studies in Western MS patients disclosed more than 100 disease-susceptibility genes, most of which are immune-related genes. It therefore supports immune-mediated mechanisms to be operative. Detailed magnetic resonance imaging studies revealed an early atrophy of the cerebral gray matter where T cell infiltration is pathologically scarce. Therefore, neurodegenerative process also takes place in the early course beside neuroinflammation.

Association of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. The Wolfram or DIDMOAD syndrome.

PubMed Central

Najjar, S S; Saikaly, M G; Zaytoun, G M; Abdelnoor, A

1985-01-01

Seven patients with a rare syndrome of diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), neurosensory deafness (D), atony of the urinary tract, and other abnormalities (Wolfram or DIDMOAD syndrome) are reported. Of the seven patients, three siblings were followed up for 10-17 years. All seven patients had diabetes mellitus and optic atrophy; six had diabetes insipidus; and in the four patients investigated there was dilatation of the urinary tract. The severity of diabetes varied, and all required insulin for control of the hyperglycaemia. In one patient the course of the disease simulated maturity onset diabetes of the young; another presented with ketoacidosis; but none had haplotypes usually associated with insulin dependent diabetes mellitus. The diabetes insipidus responded to chlorpropamide, suggesting partial antidiuretic hormone deficiency. Onset of optic atrophy and loss of vision occurred relatively late and progressed slowly, although in one patient there was a rapid deterioration in visual acuity. Deafness was mild, of late onset, and of sensorineural origin. A degenerative process affecting the central and peripheral nervous system can explain all the manifestations of the syndrome except diabetes mellitus. The pathogenesis of the diabetes mellitus remains obscure. PMID:4051539

Comparative functional genomics of adaptation to muscular disuse in hibernating mammals

PubMed Central

Fedorov, Vadim B.; Goropashnaya, Anna V.; Stewart, Nathan C.; Tøien, Øivind; Chang, Celia; Wang, Haifang; Yan, Jun; Showe, Louise C.; Showe, Michael K.; Barnes, Brian M.

2014-01-01

Hibernation is an energy saving adaptation that involves a profound suppression of physical activity that can continue for 6-8 months in highly seasonal environments. While immobility and disuse generate muscle loss in most mammalian species, in contrast, hibernating bears and ground squirrels demonstrate limited muscle atrophy over the prolonged periods of physical inactivity during winter suggesting that hibernating mammals have adaptive mechanisms to prevent disuse muscle atrophy. To identify common transcriptional programs that underlie molecular mechanisms preventing muscle loss, we conducted a large-scale gene expression screen in hind limb muscles comparing hibernating and summer active black bears and arctic ground squirrels using custom 9,600 probe cDNA microarrays. A molecular pathway analysis showed an elevated proportion of over-expressed genes involved in all stages of protein biosynthesis and ribosome biogenesis in muscle of both species during torpor of hibernation that suggests induction of translation at different hibernation states. The induction of protein biosynthesis likely contributes to attenuation of disuse muscle atrophy through the prolonged periods of immobility of hibernation. The lack of directional changes in genes of protein catabolic pathways does not support the importance of metabolic suppression for preserving muscle mass during winter. Coordinated reduction of multiple genes involved in oxidation reduction and glucose metabolism detected in both species is consistent with metabolic suppression and lower energy demand in skeletal muscle during inactivity of hibernation. PMID:25314618

Subgroup of ADNI Normal Controls Characterized by Atrophy and Cognitive Decline Associated With Vascular Damage

PubMed Central

Nettiksimmons, Jasmine; Beckett, Laurel; Schwarz, Christopher; Carmichael, Owen; Fletcher, Evan; DeCarli, Charles

2013-01-01

Previous work examining Alzheimer’s Disease Neuroimaging Initiative (ADNI) normal controls using cluster analysis identified a subgroup characterized by substantial brain atrophy and white matter hyperintensities (WMH). We hypothesized that these effects could be related to vascular damage. Fifty-three individuals in the suspected vascular cluster (Normal 2) were compared with 31 individuals from the cluster characterized as healthy/typical (Normal 1) on a variety of outcomes, including magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers, vascular risk factors and outcomes, cognitive trajectory, and medications for vascular conditions. Normal 2 was significantly older but did not differ on ApoE4+ prevalence. Normal 2 differed significantly from Normal 1 on all MRI measures but not on Amyloid-Beta1-42 or total tau protein. Normal 2 had significantly higher body mass index (BMI), Hachinksi score, and creatinine levels, and took significantly more medications for vascular conditions. Normal 2 had marginally significantly higher triglycerides and blood glucose. Normal 2 had a worse cognitive trajectory on the Rey’s Auditory Verbal Learning Test (RAVLT) 30-min delay test and the Functional Activity Questionnaire (FAQ). Cerebral atrophy associated with multiple vascular risks is common among cognitively normal individuals, forming a distinct subgroup with significantly increased cognitive decline. Further studies are needed to determine the clinical impact of these findings. PMID:23527743

Muscle twitching

MedlinePlus

... Some are common and normal. Others are signs of a nervous system disorder. Causes Causes may include: Autoimmune disorders , such ... muscle Spinal muscular atrophy Weak muscles (myopathy) Symptoms of a nervous system disorder include: Loss of, or change in, sensation ...

ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

PubMed Central

Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

2014-01-01

Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice. PMID:25221469

Myositis, Ganglioneuritis, and Myocarditis with Distinct Perifascicular Muscle Atrophy in a 2-Year-Old Male Boxer

PubMed Central

Rossman, Paul M.; Thomovsky, Stephanie A.; Schafbuch, Ryan M.; Guo, Ling T.; Shelton, G. D.

2018-01-01

A 2-year-old male, intact Boxer was referred for chronic diarrhea, hyporexia, labored breathing, weakness and elevated creatine kinase, and alanine aminotransferase activities. Initial examination and diagnostics revealed a peripheral nervous system neurolocalization, atrial premature complexes, and generalized megaesophagus. Progressive worsening of the dog’s condition was noted after 36 h; the dog developed aspiration pneumonia, was febrile and oxygen dependent. The owners elected humane euthanasia. Immediately postmortem biopsies of the left cranial tibial and triceps muscles and the left peroneal nerve were obtained. Postmortem histology revealed concurrent myositis, myocarditis, endocarditis, and ganglioneuritis. Mixed mononuclear cell infiltrations and a distinct perifascicular pattern of muscle fiber atrophy was present in both muscles. This is a novel case of diffuse inflammatory myopathy with a distinct perifascicular pattern of atrophy in addition to endocarditis, myocarditis, and epicarditis. PMID:29516006

Boosted Regeneration and Reduced Denervated Muscle Atrophy by NeuroHeal in a Pre-clinical Model of Lumbar Root Avulsion with Delayed Reimplantation.

PubMed

Romeo-Guitart, David; Forés, Joaquim; Navarro, Xavier; Casas, Caty

2017-09-20

The "gold standard" treatment of patients with spinal root injuries consists of delayed surgical reconnection of nerves. The sooner, the better, but problems such as injury-induced motor neuronal death and muscle atrophy due to long-term denervation mean that normal movement is not restored. Herein we describe a preclinical model of root avulsion with delayed reimplantation of lumbar roots that was used to establish a new adjuvant pharmacological treatment. Chronic treatment (up to 6 months) with NeuroHeal, a new combination drug therapy identified using a systems biology approach, exerted long-lasting neuroprotection, reduced gliosis and matrix proteoglycan content, accelerated nerve regeneration by activating the AKT pathway, promoted the formation of functional neuromuscular junctions, and reduced denervation-induced muscular atrophy. Thus, NeuroHeal is a promising treatment for spinal nerve root injuries and axonal regeneration after trauma.

Mild Cognitive Impairment as a single sign of brain hemiatrophy in patient with Localized Scleroderma and Parry-Romberg Syndrome.

PubMed

Klimiec, Elzbieta; Klimkowicz-Mrowiec, Aleksandra

2016-01-01

Neurologic involvement is well recognized in Systemic Scleroderma and increasingly reported in Localized Scleroderma. MRI brain abnormalities are often associated with symptoms such as seizures or headaches. In some cases they may be clinically silent. We describe a 23 years old female with head, trunk and limbs scleroderma who developed Parry-Romberg Syndrome. Brain MRI showed ipsilateral temporal lobe atrophy without any prominent neurologic symptoms. Neuropsychological examination revealed Mild Cognitive Impairment. During the 7 years of follow up we have noticed progression of face atrophy but no progression of brain atrophy. Cognitive functions have been stable. This case highlight that major MRI brain abnormalities in LS may occur with only subtle clinical manifestation such as Mild Cognitive Impairment. Copyright © 2016 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Is there a cognitive signature for MS-related fatigue?

PubMed

Hanken, Katrin; Eling, Paul; Hildebrandt, Helmut

2015-04-01

The compensatory approach of fatigue argues that it is a state caused by task load. The neuropsychiatric approach argues that fatigue is a trait (like depression), unrelated to environmental challenges. We propose that fatigue is an internal state that can be measured behaviorally only by applying specific cognitive tasks. PubMed was searched for articles concerning the relation between fatigue and cognitive performance or brain atrophy or functional MRI, distinguishing between the following cognitive domains: learning/memory, cognitive speed/selective attention, language, visuospatial processing, working memory, alerting/vigilance. Only tasks assessing alerting/vigilance are strongly related to fatigue. Areas with brain atrophy in fatigue patients overlap with brain regions activated in healthy controls performing alerting/vigilance tasks. Fatigue is not a compensatory state, nor a psychogenic trait. It is a feeling with behavioral effects that seems to be caused by brain atrophy or a neurochemical dysfunction of the alerting/vigilance system. © The Author(s), 2014.

[Effectiveness of magnetotherapy in optic nerve atrophy. A preliminary study].

PubMed

Zobina, L V; Orlovskaia, L S; Sokov, S L; Sabaeva, G F; Kondé, L A; Iakovlev, A A

1990-01-01

Magnetotherapy effects on visual functions (vision acuity and field), on retinal bioelectric activity, on conductive vision system, and on intraocular circulation were studied in 88 patients (160 eyes) with optic nerve atrophy. A Soviet Polyus-1 low-frequency magnetotherapy apparatus was employed with magnetic induction of about 10 mT, exposure 7-10 min, 10-15 sessions per course. Vision acuity of patients with its low (below 0.04 diopters) values improved in 50 percent of cases. The number of patients with vision acuity of 0.2 diopters has increased from 46 before treatment to 75. Magnetotherapy improved ocular hemodynamics in patients with optic nerve atrophy, it reduced the time of stimulation conduction along the vision routes and stimulated the retinal ganglia cells. The maximal effect was achieved after 10 magnetotherapy sessions. A repeated course carried out in 6-8 months promoted a stabilization of the process.

The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain.

PubMed

Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang; Lassmann, Hans

2016-03-01

Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Hypoadrenocorticism in beagles exposed to aerosols of plutonium-238 dioxide by inhalation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weller, R.E.; Buschbom, R.L.; Dagle, G.E.

1996-12-01

Hypoadrenocorticism, known as Addison`s disease in humans, was diagnosed in six beagles after inhalation of at least 1.7 kBq/g lung of {sup 238}PuO{sub 2}. Histological examination of adrenal gland specimens obtained at necropsy revealed marked adrenal cortical atrophy in all cases. Autoadiographs showed only slight {alpha}-particle activity. Although the pathogenesis of adrenal cortical atrophy in these dogs is unclear, there is evidence to suggest an automimmune disorder linked to damage resulting from {alpha}-particle irradiation to the lymphatic system.

Hyperpigmentation and atrophy in folds as cutaneous manifestation in a case of mitochondrial myopathy.

PubMed

Campuzano-García, Andrés Eduardo; Rodríguez-Arámbula, Adriana; Torres-Alvarez, Bertha; Castanedo-Cázares, Juan Pablo

2015-05-18

Mitochondrial myopathies are inborn metabolism defect diseases manifested by symptoms reflecting failure of the final step in the mitochondrial respiratory chain. Clinical expression of these conditions can vary widely, but typically includes organ systems with a high energy demand, such as striated muscle, myocardium, and nervous and liver tissues. In contrast, cutaneous manifestations are rare and are non-specific, most commonly presenting as pigmentation disorders. In this case report, we present a case of Alpers syndrome accompanied by hyperpigmentation and atrophy in skin folds.

Structural and functional characterization of two alpha-synuclein strains

PubMed Central

Bousset, Luc; Pieri, Laura; Ruiz-Arlandis, Gemma; Gath, Julia; Jensen, Poul Henning; Habenstein, Birgit; Madiona, Karine; Olieric, Vincent; Böckmann, Anja; Meier, Beat H.; Melki, Ronald

2013-01-01

α-synuclein aggregation is implicated in a variety of diseases including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies. PMID:24108358

Droxidopa: a review of its use in symptomatic neurogenic orthostatic hypotension.

PubMed

Keating, Gillian M

2015-02-01

The norepinephrine prodrug droxidopa (NORTHERA™) is approved in the US for the treatment of orthostatic dizziness, lightheadedness, or the 'feeling that you are about to black out' in adults with symptomatic neurogenic orthostatic hypotension associated with primary autonomic failure (e.g. Parkinson's disease, multiple system atrophy or pure autonomic failure), dopamine β-hydroxylase deficiency or nondiabetic autonomic neuropathy. This article reviews the clinical efficacy and tolerability of droxidopa in symptomatic neurogenic orthostatic hypotension, as well as summarizing its pharmacological properties. Oral droxidopa was effective in the shorter-term treatment of patients with symptomatic neurogenic orthostatic hypotension, with improvements seen in symptoms, the impact of symptoms on daily activities and standing systolic blood pressure. More data are needed to confirm the longer-term efficacy of droxidopa. Droxidopa was generally well tolerated, although patients should be monitored for supine hypertension.

Utility and accuracy of perceptual voice and speech distinctions in the diagnosis of Parkinson's disease, PSP and MSA-P.

PubMed

Miller, Nick; Nath, Uma; Noble, Emma; Burn, David

2017-06-01

To determine if perceptual speech measures distinguish people with Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P) and progressive supranuclear palsy (PSP). Speech-language therapists blind to patient characteristics employed clinical rating scales to evaluate speech/voice in 24 people with clinically diagnosed PD, 17 with PSP and 9 with MSA-P, matched for disease duration (mean 4.9 years, standard deviation 2.2). No consistent intergroup differences appeared on specific speech/voice variables. People with PD were significantly less impaired on overall speech/voice severity. Analyses by severity suggested further investigation around laryngeal, resonance and fluency changes may characterize individual groups. MSA-P and PSP compared with PD were distinguished by severity of speech/voice deterioration, but individual speech/voice parameters failed to consistently differentiate groups.

Research opportunities in muscle atrophy

NASA Technical Reports Server (NTRS)

Herbison, G. J. (Editor); Talbot, J. M. (Editor)

1984-01-01

Muscle atrophy in a weightless environment is studied. Topics of investigation include physiological factors of muscle atrophy in space flight, biochemistry, countermeasures, modelling of atrophied muscle tissue, and various methods of measurement of muscle strength and endurance. A review of the current literature and suggestions for future research are included.

Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages.

PubMed

Laird, Angela S; Mackovski, Nikolce; Rinkwitz, Silke; Becker, Thomas S; Giacomotto, Jean

2016-05-01

Spinal muscular atrophy (SMA) is an autosomal recessive disease linked to survival motor neuron (SMN) protein deficiency. While SMN protein is expressed ubiquitously, its deficiency triggers tissue-specific hallmarks, including motor neuron death and muscle atrophy, leading to impaired motor functions and premature death. Here, using stable miR-mediated knockdown technology in zebrafish, we developed the first vertebrate system allowing transgenic spatio-temporal control of the smn1 gene. Using this new model it is now possible to investigate normal and pathogenic SMN function(s) in specific cell types, independently or in synergy with other cell populations. We took advantage of this new system to first test the effect of motor neuron or muscle-specific smn1 silencing. Anti-smn1 miRNA expression in motor neurons, but not in muscles, reproduced SMA hallmarks, including abnormal motor neuron development, poor motor function and premature death. Interestingly, smn1 knockdown in motor neurons also induced severe late-onset phenotypes including scoliosis-like body deformities, weight loss, muscle atrophy and, seen for the first time in zebrafish, reduction in the number of motor neurons, indicating motor neuron degeneration. Taken together, we have developed a new transgenic system allowing spatio-temporal control of smn1 expression in zebrafish, and using this model, we have demonstrated that smn1 silencing in motor neurons alone is sufficient to reproduce SMA hallmarks in zebrafish. It is noteworthy that this research is going beyond SMA as this versatile gene-silencing transgenic system can be used to knockdown any genes of interest, filling the gap in the zebrafish genetic toolbox and opening new avenues to study gene functions in this organism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Analysis of the fibroblast growth factor system reveals alterations in a mouse model of spinal muscular atrophy.

PubMed

Hensel, Niko; Ratzka, Andreas; Brinkmann, Hella; Klimaschewski, Lars; Grothe, Claudia; Claus, Peter

2012-01-01

The monogenetic disease Spinal Muscular Atrophy (SMA) is characterized by a progressive loss of motoneurons leading to muscle weakness and atrophy due to severe reduction of the Survival of Motoneuron (SMN) protein. Several models of SMA show deficits in neurite outgrowth and maintenance of neuromuscular junction (NMJ) structure. Survival of motoneurons, axonal outgrowth and formation of NMJ is controlled by neurotrophic factors such as the Fibroblast Growth Factor (FGF) system. Besides their classical role as extracellular ligands, some FGFs exert also intracellular functions controlling neuronal differentiation. We have previously shown that intracellular FGF-2 binds to SMN and regulates the number of a subtype of nuclear bodies which are reduced in SMA patients. In the light of these findings, we systematically analyzed the FGF-system comprising five canonical receptors and 22 ligands in a severe mouse model of SMA. In this study, we demonstrate widespread alterations of the FGF-system in both muscle and spinal cord. Importantly, FGF-receptor 1 is upregulated in spinal cord at a pre-symptomatic stage as well as in a mouse motoneuron-like cell-line NSC34 based model of SMA. Consistent with that, phosphorylations of FGFR-downstream targets Akt and ERK are increased. Moreover, ERK hyper-phosphorylation is functionally linked to FGFR-1 as revealed by receptor inhibition experiments. Our study shows that the FGF system is dysregulated at an early stage in SMA and may contribute to the SMA pathogenesis.

Celiac disease

PubMed Central

Rodrigo, Luis

2006-01-01

Celiac disease (CD) is a common autoimmune disorder, induced by the intake of gluten proteins present in wheat, barley and rye. Contrary to common belief, this disorder is a protean systemic disease, rather than merely a pure digestive alteration. CD is closely associated with genes that code HLA-II antigens, mainly of DQ2 and DQ8 classes. Previously, it was considered to be a rare childhood disorder, but is actually considered a frequent condition, present at any age, which may have multiple complications. Tissue transglutaminase-2 (tTG), appears to be an important component of this disease, both, in its pathogenesis and diagnosis. Active CD is characterized by intestinal and/or extra-intestinal symptoms, villous atrophy and crypt hyperplasia, and strongly positive tTG auto-antibodies. The duodenal biopsy is considered to be the “gold standard” for diagnosis, but its practice has significant limitations in its interpretation, especially in adults. Occasionally, it results in a false-negative because of patchy mucosal changes and the presence of mucosal villous atrophy is often more severe in the proximal jejunum, usually not reached by endoscopic biopsies. CD is associated with increased rates of several diseases, such as iron deficiency anemia, osteoporosis, dermatitis herpetiformis, several neurologic and endocrine diseases, persistent chronic hypertransami-nasemia of unknown origin, various types of cancer and other autoimmune disorders. Treatment of CD dictates a strict, life-long gluten-free diet, which results in remission for most individuals, although its effect on some associated extraintestinal manifestations remains to be established.

Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene.

PubMed

Dlamini, Nomazulu; Josifova, Dragana J; Paine, Simon M L; Wraige, Elizabeth; Pitt, Matthew; Murphy, Amanda J; King, Andrew; Buk, Stefan; Smith, Frances; Abbs, Stephen; Sewry, Caroline; Jacques, Thomas S; Jungbluth, Heinz

2013-05-01

Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A>T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development. Copyright © 2013 Elsevier B.V. All rights reserved.

The discovery of the pressor effect of DOPS and its blunting by decarboxylase inhibitors.

PubMed

Kaufmann, H

2006-01-01

In the 1950s it was found that an artificial aminoacid, 3,4-threo-dihydroxyphenylserine (DOPS), was converted to norepinephrine (NE) in a single step by the enzyme L-aromatic amino acid decarboxylase (AADC), bypassing the need for the rate limiting enzyme dopamine beta hydroxylase. Trying to replicate the success of dihydroxyphenylalanine (DOPA) in the treatment of Parkinson disease, treatment with DOPS was attempted in patients with autonomic failure who have impaired NE release. DOPS improved orthostatic hypotension in patients with familial amyloid polyneuropathy, congenital deficiency of dopamine beta hydroxylase, pure autonomic failure and multiple system atrophy. DOPS pressor effect is due to its conversion to NE outside the central nervous system because concomitant administration of carbidopa, an inhibitor of AADC that does not cross the blood-brain barrier, blunted both the increase in plasma NE and the pressor response. DOPS pressor response is not dependent on intact sympathetic terminals because its conversion to NE also occurs in non-neuronal tissues.

Dominant optic atrophy.

PubMed

Lenaers, Guy; Hamel, Christian; Delettre, Cécile; Amati-Bonneau, Patrizia; Procaccio, Vincent; Bonneau, Dominique; Reynier, Pascal; Milea, Dan

2012-07-09

DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients). Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time. To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation.

Dominant optic atrophy

PubMed Central

2012-01-01

Definition of the disease Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients). Prognosis Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time. Management To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation. PMID:22776096

Exercise training decreases NADPH oxidase activity and restores skeletal muscle mass in heart failure rats.

PubMed

Cunha, Telma F; Bechara, Luiz R G; Bacurau, Aline V N; Jannig, Paulo R; Voltarelli, Vanessa A; Dourado, Paulo M; Vasconcelos, Andrea R; Scavone, Cristóforo; Ferreira, Júlio C B; Brum, Patricia C

2017-04-01

We have recently demonstrated that NADPH oxidase hyperactivity, NF-κB activation, and increased p38 phosphorylation lead to atrophy of glycolytic muscle in heart failure (HF). Aerobic exercise training (AET) is an efficient strategy to counteract skeletal muscle atrophy in this syndrome. Therefore, we tested whether AET would regulate muscle redox balance and protein degradation by decreasing NADPH oxidase hyperactivity and reestablishing NF-κB signaling, p38 phosphorylation, and proteasome activity in plantaris muscle of myocardial infarcted-induced HF (MI) rats. Thirty-two male Wistar rats underwent MI or fictitious surgery (SHAM) and were randomly assigned into untrained (UNT) and trained (T; 8 wk of AET on treadmill) groups. AET prevented HF signals and skeletal muscle atrophy in MI-T, which showed an improved exercise tolerance, attenuated cardiac dysfunction and increased plantaris fiber cross-sectional area. To verify the role of inflammation and redox imbalance in triggering protein degradation, circulating TNF-α levels, NADPH oxidase profile, NF-κB signaling, p38 protein levels, and proteasome activity were assessed. MI-T showed a reduced TNF-α levels, NADPH oxidase activity, and Nox2 mRNA expression toward SHAM-UNT levels. The rescue of NADPH oxidase activity induced by AET in MI rats was paralleled by reducing nuclear binding activity of the NF-κB, p38 phosphorylation, atrogin-1, mRNA levels, and 26S chymotrypsin-like proteasome activity. Taken together our data provide evidence for AET improving plantaris redox homeostasis in HF associated with a decreased NADPH oxidase, redox-sensitive proteins activation, and proteasome hyperactivity further preventing atrophy. These data reinforce the role of AET as an efficient therapy for muscle wasting in HF. NEW & NOTEWORTHY This study demonstrates, for the first time, the contribution of aerobic exercise training (AET) in decreasing muscle NADPH oxidase activity associated with reduced reactive oxygen species production and systemic inflammation, which diminish NF-κB overactivation, p38 phosphorylation, and ubiquitin proteasome system hyperactivity. These molecular changes counteract plantaris atrophy in trained myocardial infarction-induced heart failure rats. Our data provide new evidence into how AET may regulate protein degradation and thus prevent skeletal muscle atrophy. Copyright © 2017 the American Physiological Society.

The combined influence of stretch, mobility and electrical stimulation in the prevention of muscle fiber atrophy caused hypokinesia and hypodynamia

NASA Technical Reports Server (NTRS)

Goldspink, G.; Goldspink, D.; Loughna, P.

1984-01-01

The morphological and biochemical changes which occur in the hind limb muscles of the rat in response to hypokinesia and hypodynamia were investigated. Hind limb cast fixation and suspension techniques were employed to study the musclar atrophy after five days of hypokinesia and hypodynamia induced by suspension, appreciable muscular atrophy was apparent, particularly in the anti-gravity muscles. The effect of passive stretching and electrical stimulation on muscle atrophy was studied. Changes in muscle protein mass were assessed with spectrophotometric and radioactive techniques. Passive stretch is shown to counteract muscle disuse atrophy. The change in the numbers of specific muscle fibers in atrophied muscles is discussed.

Voxel-based morphometry in autopsy proven PSP and CBD.

PubMed

Josephs, Keith A; Whitwell, Jennifer L; Dickson, Dennis W; Boeve, Bradley F; Knopman, David S; Petersen, Ronald C; Parisi, Joseph E; Jack, Clifford R

2008-02-01

The aim of this study was to compare the patterns of grey and white matter atrophy on MRI in autopsy confirmed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and to determine whether the patterns vary depending on the clinical syndrome. Voxel-based morphometry was used to compare patterns of atrophy in 13 PSP and 11 CBD subjects and 24 controls. PSP and CBD subjects were also subdivided into those with a dominant dementia or extrapyramidal syndrome. PSP subjects showed brainstem atrophy with involvement of the cortex and underlying white matter. Frontoparietal grey and subcortical grey matter atrophy occurred in CBD. When subdivided, PSP subjects with an extrapyramidal syndrome had more brainstem atrophy and less cortical atrophy than CBD subjects with an extrapyramidal syndrome. PSP subjects with a dementia syndrome had more subcortical white matter atrophy than CBD subjects with a dementia syndrome. These results show regional differences between PSP and CBD that are useful in predicting the underlying pathology, and help to shed light on the in vivo distribution of regional atrophy in PSP and CBD.

Spinal muscular atrophy: Selective motor neuron loss and global defect in the assembly of ribonucleoproteins.

PubMed

Beattie, Christine E; Kolb, Stephen J

2018-08-15

Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair. Thus, SMA is an exemplar, selective motor neuron disorder that is caused by defects in fundamental RNA processing events. A detailed molecular understanding of how motor neurons fail, and why other neurons do not, in SMA will yield important principals about motor neuron maintenance and neuronal specificity in neurodegenerative diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Revised upper limb module for spinal muscular atrophy: Development of a new module.

PubMed

Mazzone, Elena S; Mayhew, Anna; Montes, Jacqueline; Ramsey, Danielle; Fanelli, Lavinia; Young, Sally Dunaway; Salazar, Rachel; De Sanctis, Roberto; Pasternak, Amy; Glanzman, Allan; Coratti, Giorgia; Civitello, Matthew; Forcina, Nicola; Gee, Richard; Duong, Tina; Pane, Marika; Scoto, Mariacristina; Pera, Maria Carmela; Messina, Sonia; Tennekoon, Gihan; Day, John W; Darras, Basil T; De Vivo, Darryl C; Finkel, Richard; Muntoni, Francesco; Mercuri, Eugenio

2017-06-01

There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients. An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale. Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups. The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi-center clinical research. Muscle Nerve 55: 869-874, 2017. © 2016 Wiley Periodicals, Inc.

Frontal lobe atrophy is associated with small vessel disease in ischemic stroke patients.

PubMed

Chen, Yangkun; Chen, Xiangyan; Xiao, Weimin; Mok, Vincent C T; Wong, Ka Sing; Tang, Wai Kwong

2009-12-01

The pathogenesis of frontal lobe atrophy (FLA) in stroke patients is unclear. We aimed to ascertain whether subcortical ischemic changes were more associated with FLA than with parietal lobe atrophy (PLA) and temporal lobe atrophy (TLA). Brain magnetic resonance images (MRIs) from 471 Chinese ischemic stroke patients were analyzed. Lobar atrophy was defined by a widely used visual rating scale. All patients were divided into non-severe, mild-moderate, and severe atrophy of the frontal, parietal, and temporal lobe groups. The severity of white matter lesions (WMLs) was rated with the Fazekas' scale. Clinical and radiological features were compared among the groups. Subsequent logistic regressions were performed to determine the risk factors of atrophy and severe atrophy of the frontal, parietal and temporal lobes. The frequency of FLA in our cohort was 36.9% (174/471). Severe FLA occurred in 30 (6.4%) patients. Age, previous stroke, and periventricular hyperintensities (PVH) (odds ratio (OR)=1.640, p=0.039) were independent risk factors of FLA. Age and deep white matter hyperintensities (DWMH) (OR=3.634, p=0.002) were independent risk factors of severe FLA. PVH and DWMH were not independent risk factors of PLA and TLA. Frontal lobe atrophy in ischemic stroke patients may be associated with small vessel disease. The association between WMLs and FLA was predominant over atrophy of the parietal and temporal lobes, which suggests that the frontal lobe may be vulnerable to subcortical ischemic changes.

Development of Intelligent Suits for Disuse Atrophy of Musculoskeletal System Using Hybrid Exercise Method

NASA Astrophysics Data System (ADS)

Shiba, Naoto; Yoshimitsu, Kazuhiro; Matsugaki, Tohru; Narita, Arata; Maeda, Takashi; Inada, Tomohisa; Tagawa, Yoshihiko; Numada, Kiyoshi; Nishi, Tetsuya

We developed ‘Hybrid exercise’ method that was designed to maintain the musculoskeletal system by using electrically stimulated antagonist muscles to resist volitional contraction of agonist muscles. This approach also produces a minimum of inertial reaction forces and has the advantage that it may minimize the need for external stabilization that is currently necessary during exercise in a weightlessness environment. The purpose of this study was to develop the intelligent suits with virtual reality (VR) system that had function of preventing disuse atrophy of musculoskeletal system using hybrid exercise system. Installing of the hybrid exercise system to the subject became easy by the intelligent suits. VR system realized the sense of sight by computer graphics animation synchronized with subjects' motion, and sense of force induced by electrical stimulation. By using VR system, the management of the exercise accomplishment degree was enabled easily because the device could record the exercise history. Intelligent suits with VR hybrid exercise system might become one of the useful countermeasures for the disuse musculoskeletal system in the space.

Masticatory muscles of mouse do not undergo atrophy in space

PubMed Central

Philippou, Anastassios; Minozzo, Fabio C.; Spinazzola, Janelle M.; Smith, Lucas R.; Lei, Hanqin; Rassier, Dilson E.; Barton, Elisabeth R.

2015-01-01

Muscle loading is important for maintaining muscle mass; when load is removed, atrophy is inevitable. However, in clinical situations such as critical care myopathy, masticatory muscles do not lose mass. Thus, their properties may be harnessed to preserve mass. We compared masticatory and appendicular muscles responses to microgravity, using mice aboard the space shuttle Space Transportation System-135. Age- and sex-matched controls remained on the ground. After 13 days of space flight, 1 masseter (MA) and tibialis anterior (TA) were frozen rapidly for biochemical and functional measurements, and the contralateral MA was processed for morphologic measurements. Flight TA muscles exhibited 20 ± 3% decreased muscle mass, 2-fold decreased phosphorylated (P)-Akt, and 4- to 12-fold increased atrogene expression. In contrast, MAs had no significant change in mass but a 3-fold increase in P-focal adhesion kinase, 1.5-fold increase in P-Akt, and 50–90% lower atrogene expression compared with limb muscles, which were unaltered in microgravity. Myofibril force measurements revealed that microgravity caused a 3-fold decrease in specific force and maximal shortening velocity in TA muscles. It is surprising that myofibril-specific force from both control and flight MAs were similar to flight TA muscles, yet power was compromised by 40% following flight. Continued loading in microgravity prevents atrophy, but masticatory muscles have a different set point that mimics disuse atrophy in the appendicular muscle.—Philippou, A., Minozzo, F. C., Spinazzola, J. M., Smith, L. R., Lei, H., Rassier, D. E., Barton, E. R. Masticatory muscles of mouse do not undergo atrophy in space. PMID:25795455

Research on the adaptation of skeletal muscle to hypogravity: Past and future directions

NASA Astrophysics Data System (ADS)

Riley, D. A.; Ellis, S.

Our current understanding of hypogravity-induced atrophy of skeletal muscles is based primarily on studies comparing pre- and post-flight properties of muscles. Interpretations are necessarily qualified by the assumption that the stress of reentry and readjustment to terrestrial gravity do not alter the parameters being analyzed. The neuromuscular system is highly responsive to changes in functional demands and capable of rapid adaptation, making this assumption questionable. A reexamination of the changes in the connective tissue and synaptic terminals of soleus muscles from rats orbited in biosatellites and sampled postflight indicates that these structural alterations represent adaptative responses of the atrophic muscles to the increased workload of returning to 1 G, rather than hypogravity per se. The atrophy of weightlessness is postulated to result because muscles are both underloaded and used less often. Proper testing of this hypothesis requires quantitation of muscle function by monitoring electromyography, force output and length changes during the flight. Experiments conducted in space laboratories, like those being developed for the Space Shuttle, will avoid the complications of reentry before tissue sampling and allow time course studies of the rate of development of adaptive changes to zero gravity. Another area of great importance for future studies of muscle atrophy is inflight measurement of plasma levels of hormones and tissue receptor levels. Glucocorticoids, thyroid hormone and insulin exert dramatic regulatory influences on muscle structure. Prevention of neuromuscular atrophy becomes increasingly more important as spaceflights increase in duration. Definition of the atrophic mechanism is essential to developing means of preventing neuromuscular atrophy.

Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies.

PubMed

Rockenstein, Edward; Ostroff, Gary; Dikengil, Fusun; Rus, Florentina; Mante, Michael; Florio, Jazmin; Adame, Anthony; Trinh, Ivy; Kim, Changyoun; Overk, Cassia; Masliah, Eliezer; Rissman, Robert A

2018-01-24

Dementia with Lewy bodies, Parkinson's disease, and Multiple System Atrophy are age-related neurodegenerative disorders characterized by progressive accumulation of α-synuclein (α-syn) and jointly termed synucleinopathies. Currently, no disease-modifying treatments are available for these disorders. Previous preclinical studies demonstrate that active and passive immunizations targeting α-syn partially ameliorate behavioral deficits and α-syn accumulation; however, it is unknown whether combining humoral and cellular immunization might act synergistically to reduce inflammation and improve microglial-mediated α-syn clearance. Since combined delivery of antigen plus rapamycin (RAP) in nanoparticles is known to induce antigen-specific regulatory T cells (Tregs), we adapted this approach to α-syn using the antigen-presenting cell-targeting glucan microparticle (GP) vaccine delivery system. PDGF-α-syn transgenic (tg) male and female mice were immunized with GP-alone, GP-α-syn (active humoral immunization), GP+RAP, or GP+RAP/α-syn (combined active humoral and Treg) and analyzed using neuropathological and biochemical markers. Active immunization resulted in higher serological total IgG, IgG1, and IgG2a anti-α-syn levels. Compared with mice immunized with GP-alone or GP-α-syn, mice vaccinated with GP+RAP or GP+RAP/α-syn displayed increased numbers of CD25-, FoxP3-, and CD4-positive cells in the CNS. GP-α-syn or GP+RAP/α-syn immunizations resulted in a 30-45% reduction in α-syn accumulation, neuroinflammation, and neurodegeneration. Mice immunized with GP+RAP/α-syn further rescued neurons and reduced neuroinflammation. Levels of TGF-β1 were increased with GP+RAP/α-syn immunization, while levels of TNF-α and IL-6 were reduced. We conclude that the observed effects of GP+RAP/α-syn immunization support the hypothesis that cellular immunization may enhance the effects of active immunotherapy for the treatment of synucleinopathies. SIGNIFICANCE STATEMENT We show that a novel vaccination modality combining an antigen-presenting cell-targeting glucan particle (GP) vaccine delivery system with encapsulated antigen (α-synuclein) + rapamycin (RAP) induced both strong anti-α-synuclein antibody titers and regulatory T cells (Tregs). This vaccine, collectively termed GP+RAP/α-syn, is capable of triggering neuroprotective Treg responses in synucleinopathy models, and the combined vaccine is more effective than the humoral or cellular immunization alone. Together, these results support the further development of this multifunctional vaccine approach for the treatment of synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple systems atrophy. Copyright © 2018 the authors 0270-6474/18/381000-15$15.00/0.

The thalamus and multiple sclerosis

PubMed Central

Minagar, Alireza; Barnett, Michael H.; Benedict, Ralph H.B.; Pelletier, Daniel; Pirko, Istvan; Sahraian, Mohamad Ali; Frohman, Elliott

2013-01-01

The paired thalamic nuclei are gray matter (GM) structures on both sides of the third ventricle that play major roles in cortical activation, relaying sensory information to the higher cortical centers that influence cognition. Multiple sclerosis (MS) is an immune-mediated disease of the human CNS that affects both the white matter (WM) and GM. A number of clinical observations as well as recent neuropathologic and neuroimaging studies have clearly demonstrated extensive involvement of the thalamus, basal ganglia, and neocortex in patients with MS. Modern MRI techniques permit visualization of GM lesions and measurement of atrophy. These contemporary methods have fundamentally altered our understanding of the pathophysiologic nature of MS. Evidence confirms the contention that GM injury can be detected in the earliest phases of MS, and that iron deposition and atrophy of deep gray nuclei are closely related to the magnitude of inflammation. Extensive involvement of GM, and particularly of the thalamus, is associated with a wide range of clinical manifestations including cognitive decline, motor deficits, fatigue, painful syndromes, and ocular motility disturbances in patients with MS. In this review, we characterize the neuropathologic, neuroimaging, and clinical features of thalamic involvement in MS. Further, we underscore the contention that neuropathologic and neuroimaging correlative investigations of thalamic derangements in MS may elucidate not heretofore considered pathobiological underpinnings germane to understanding the ontogeny, magnitude, and progression of the disease process. PMID:23296131

The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects.

PubMed

Minagar, Alireza; Barnett, Michael H; Benedict, Ralph H B; Pelletier, Daniel; Pirko, Istvan; Sahraian, Mohamad Ali; Frohman, Elliott; Zivadinov, Robert

2013-01-08

The paired thalamic nuclei are gray matter (GM) structures on both sides of the third ventricle that play major roles in cortical activation, relaying sensory information to the higher cortical centers that influence cognition. Multiple sclerosis (MS) is an immune-mediated disease of the human CNS that affects both the white matter (WM) and GM. A number of clinical observations as well as recent neuropathologic and neuroimaging studies have clearly demonstrated extensive involvement of the thalamus, basal ganglia, and neocortex in patients with MS. Modern MRI techniques permit visualization of GM lesions and measurement of atrophy. These contemporary methods have fundamentally altered our understanding of the pathophysiologic nature of MS. Evidence confirms the contention that GM injury can be detected in the earliest phases of MS, and that iron deposition and atrophy of deep gray nuclei are closely related to the magnitude of inflammation. Extensive involvement of GM, and particularly of the thalamus, is associated with a wide range of clinical manifestations including cognitive decline, motor deficits, fatigue, painful syndromes, and ocular motility disturbances in patients with MS. In this review, we characterize the neuropathologic, neuroimaging, and clinical features of thalamic involvement in MS. Further, we underscore the contention that neuropathologic and neuroimaging correlative investigations of thalamic derangements in MS may elucidate not heretofore considered pathobiological underpinnings germane to understanding the ontogeny, magnitude, and progression of the disease process.

FIVE-YEAR OUTCOMES OF INTRAVITREAL RANIBIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN PATIENTS WITH PATHOLOGIC MYOPIA.

PubMed

Onishi, Yuka; Yokoi, Tae; Kasahara, Kaori; Yoshida, Takeshi; Nagaoka, Natsuko; Shinohara, Kosei; Kaneko, Yuichiro; Suga, Mitsuki; Uramoto, Kengo; Ohno-Tanaka, Akiko; Ohno-Matsui, Kyoko

2018-05-03

To determine the 5-year outcome of intravitreal ranibizumab (IVR) for myopic choroidal neovascularization (CNV). We retrospectively analyzed the medical records of 51 eyes of 51 consecutive patients with myopic CNV who had been treated with IVR with a minimum follow-up period of 5 years after the initial IVR injection. The factors that predicted the best-corrected visual acuity (BCVA) at 5 years after IVR were determined by multiple regression analysis. The mean age of the subjects was 63.6 years, and the mean axial length was 29.4 mm. The mean number of IVR was 1.6, and 34 eyes (66.7%) had only a single IVR. At the baseline and at the 1-year, 2-year, 4-year, and 5-year period, the mean BCVAs were 20/49, 20/37, 20/41, 20/45, and 20/42, respectively. Stepwise multiple regression analysis showed that the BCVA at 5-year period was significantly correlated with the baseline BCVA, the number of IVR injections, and the size of the CNV-related macular atrophy. Intravitreal ranibizumab provide a 5-year visual benefit in eyes with myopic CNV compared with the natural course. A lack of enlargement of the CNV-related macular atrophy, a better baseline BCVA, and a minimum number of IVR injections were associated with better visual outcomes.

Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients.

PubMed

Garcia-Martin, Elena; Pueyo, Victoria; Almarcegui, Carmen; Martin, Jesus; Ara, Jose R; Sancho, Eva; Pablo, Luis E; Dolz, Isabel; Fernandez, Javier

2011-11-01

To quantify structural and functional degeneration in the retinal nerve fibre layer (RNFL) of patients with multiple sclerosis (MS) over a 2-year time period, and to analyse the effect of prior optic neuritis (ON) as well as the duration and incidence of MS relapses. 166 MS patients and 120 healthy controls underwent assessment of visual acuity and colour vision, visual field examination, optical coherence tomography, scanning laser polarimetry and visual evoked potentials (VEPs). All subjects were re-evaluated after a period of 12 and 24 months. Changes in the optic nerve were detected by structural measurements but not by functional assessments. Changes registered in MS patients were greater than changes in healthy controls (p<0.05). Eyes with previous ON showed a greater reduction of parameters in the baseline evaluation, but RNFL atrophy was not significantly greater in the longitudinal study. Patients with MS relapses showed a greater reduction of RNFL thickness and VEP amplitude compared with non-relapsing cases. Patients with and without treatment showed similar measurement reduction, but the non-treated group had a significantly higher increase in Expanded Disability Status Scale (p=0.029). MS causes progressive axonal loss in the optic nerve, regardless of a history of ON. This ganglion cell atrophy occurs in all eyes but is more marked in MS eyes than in healthy eyes.

Postural muscle atrophy prevention and recovery and bone remodelling through high frequency proprioception for astronauts

NASA Astrophysics Data System (ADS)

Riva, Dario; Rossitto, Franco; Battocchio, Luciano

2009-09-01

The difficulty in applying active exercises during space flights increases the importance of passive countermeasures, but coupling load and instability remains indispensable for generating high frequency (HF) proprioceptive flows and preventing muscle atrophy and osteoporosis. The present study, in microgravity conditions during a parabolic flight, verified whether an electronic system, composed of a rocking board, a postural reader and a bungee-cord loading apparatus creates HF postural instability comparable to that reachable on the Earth. Tracking the subject, in single stance, to real-time visual signals is necessary to obtain HF instability situations. The bungee-cord loading apparatus allowed the subject to manage the 81.5% body weight load (100% could easily be exceeded). A preliminary training programme schedule on the Earth and in space is suggested. Comparison with a pathological muscle atrophy is presented. The possibility of generating HF proprioceptive flows could complement current countermeasures for the prevention and recovery of muscle atrophy and osteoporosis in terrestrial and space environments. These exercises combine massive activation of spindles and joint receptors, applying simultaneously HF variations of pressure to different areas of the sole of the foot. This class of exercises could improve the effectiveness of current countermeasures, reducing working time and fatigue.

Factors associated with voice therapy outcomes in the treatment of presbyphonia.

PubMed

Mau, Ted; Jacobson, Barbara H; Garrett, C Gaelyn

2010-06-01

Age, vocal fold atrophy, glottic closure pattern, and the burden of medical problems are associated with voice therapy outcomes for presbyphonia. Retrospective. Records of patients seen over a 3-year period at a voice center were screened. Inclusion criteria consisted of age over 55 years, primary complaint of hoarseness, presence of vocal fold atrophy on examination, and absence of laryngeal or neurological pathology. Videostroboscopic examinations on initial presentation were reviewed. Voice therapy outcomes were assessed with the American Speech-Language-Hearing Association National Outcomes Measurement System scale. Statistical analysis was performed with Spearman rank correlation and chi(2) tests. Sixty-seven patients were included in the study. Of the patients, 85% demonstrated improvement with voice therapy. The most common type of glottic closure consisted of a slit gap. Gender or age had no effect on voice therapy outcomes. Larger glottic gaps on initial stroboscopy examination and more pronounced vocal fold atrophy were weakly correlated with less improvement from voice therapy. A weak correlation was also found between the number of chronic medical conditions and poorer outcomes from voice therapy. The degree of clinician-determined improvement in vocal function from voice therapy is independent of patient age but is influenced by the degree of vocal fold atrophy, glottic closure pattern, and the patient's burden of medical problems.

38 CFR 4.46 - Accurate measurement.

Code of Federal Regulations, 2011 CFR

2011-07-01

... RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.46 Accurate measurement. Accurate... indispensable in examinations conducted within the Department of Veterans Affairs. Muscle atrophy must also be...

38 CFR 4.46 - Accurate measurement.

Code of Federal Regulations, 2014 CFR

2014-07-01

... RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.46 Accurate measurement. Accurate... indispensable in examinations conducted within the Department of Veterans Affairs. Muscle atrophy must also be...

38 CFR 4.46 - Accurate measurement.

Code of Federal Regulations, 2010 CFR

2010-07-01

... RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.46 Accurate measurement. Accurate... indispensable in examinations conducted within the Department of Veterans Affairs. Muscle atrophy must also be...

38 CFR 4.46 - Accurate measurement.

Code of Federal Regulations, 2013 CFR

2013-07-01

... RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.46 Accurate measurement. Accurate... indispensable in examinations conducted within the Department of Veterans Affairs. Muscle atrophy must also be...

38 CFR 4.46 - Accurate measurement.

Code of Federal Regulations, 2012 CFR

2012-07-01

... RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.46 Accurate measurement. Accurate... indispensable in examinations conducted within the Department of Veterans Affairs. Muscle atrophy must also be...

Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways.

PubMed

Rodriguez, J; Vernus, B; Chelh, I; Cassar-Malek, I; Gabillard, J C; Hadj Sassi, A; Seiliez, I; Picard, B; Bonnieu, A

2014-11-01

Myostatin, a member of the transforming growth factor-β superfamily, is a potent negative regulator of skeletal muscle growth and is conserved in many species, from rodents to humans. Myostatin inactivation can induce skeletal muscle hypertrophy, while its overexpression or systemic administration causes muscle atrophy. As it represents a potential target for stimulating muscle growth and/or preventing muscle wasting, myostatin regulation and functions in the control of muscle mass have been extensively studied. A wealth of data strongly suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression. Moreover, myostatin plays a central role in integrating/mediating anabolic and catabolic responses. Myostatin negatively regulates the activity of the Akt pathway, which promotes protein synthesis, and increases the activity of the ubiquitin-proteasome system to induce atrophy. Several new studies have brought new information on how myostatin may affect both ribosomal biogenesis and translation efficiency of specific mRNA subclasses. In addition, although myostatin has been identified as a modulator of the major catabolic pathways, including the ubiquitin-proteasome and the autophagy-lysosome systems, the underlying mechanisms are only partially understood. The goal of this review is to highlight outstanding questions about myostatin-mediated regulation of the anabolic and catabolic signaling pathways in skeletal muscle. Particular emphasis has been placed on (1) the cross-regulation between myostatin, the growth-promoting pathways and the proteolytic systems; (2) how myostatin inhibition leads to muscle hypertrophy; and (3) the regulation of translation by myostatin.

Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy

PubMed Central

Adams, Christopher M.; Ebert, Scott M.; Dyle, Michael C.

2017-01-01

Purpose of review Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. Recent findings Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. Summary Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function. PMID:25807353

Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy.

PubMed

Adams, Christopher M; Ebert, Scott M; Dyle, Michael C

2015-05-01

Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function.

Multidisciplinary Overview of Vaginal Atrophy and Associated Genitourinary Symptoms in Postmenopausal Women

PubMed Central

Goldstein, Irwin; Dicks, Brian; Kim, Noel N; Hartzell, Rose

2013-01-01

Introduction Vaginal atrophy, which may affect up to 45% of postmenopausal women, is often associated with one or more urinary symptoms, including urgency, increased frequency, nocturia, dysuria, incontinence, and recurrent urinary tract infection. Aims To provide an overview of the current literature regarding cellular and clinical aspects of vaginal atrophy and response to treatment with local vaginal estrogen therapy. Methods PubMed searches through February 2012 were conducted using the terms “vaginal atrophy,” “atrophic vaginitis,” and “vulvovaginal atrophy.” Expert opinion was based on review of the relevant scientific and medical literature. Main Outcome Measure Genitourinary symptoms and treatment of vaginal atrophy from peer-reviewed published literature. Results Typically, a diagnosis of vaginal atrophy is made based on patient-reported symptoms, including genitourinary symptoms, and an examination that reveals signs of the disorder; however, many women are hesitant to report vaginal-related symptoms, primarily because of embarrassment. Conclusions Physicians in various disciplines are encouraged to initiate open discussions about vulvovaginal health with postmenopausal women, including recommended treatment options. Goldstein I, Dicks B, Kim NN, and Hartzell R. Multidisciplinary overview of vaginal atrophy and associated genitourinary symptoms in postmenopausal women. Sex Med 2013;1:44–53. PMID:25356287

[Multiple retinal pigment epithelial detachments: a case report].

PubMed

González-Escobar, A B; González de Gor-Crooke, J L; López-Egea-Bueno, M A; García-Campos, J M

2014-05-01

A 47 year-old female who presented with a bilateral idiopathic multiple pigment epithelial detachment (PED) in a routine visit. This pathology is shown as a rare clinical manifestation, where the outcome is resolution of localized atrophy of the pigment epithelium, with a good functional prognosis. PED is a common clinical manifestation in several chorioretinal diseases, particularly in macular degeneration associated with age. Idiopathic PED can be considered as a kind of central type II serous chorioretinopathy. Fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) are complementary tests to study the number, extension, and nature of these PED. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

Protective personality traits: High openness and low neuroticism linked to better memory in multiple sclerosis.

PubMed

Leavitt, Victoria M; Buyukturkoglu, Korhan; Inglese, Matilde; Sumowski, James F

2017-11-01

Memory impairment in multiple sclerosis (MS) is common, although few risk/protective factors are known. To examine relationships of personality to memory/non-memory cognition in MS. 80 patients completed a cognitive battery and a personality scale measuring the "Big 5" traits: openness, neuroticism, agreeableness, extraversion, and conscientiousness. Memory was most related to openness, with higher openness linked to better memory and lower risk for memory impairment, controlling for age, atrophy, education, and intelligence quotient (IQ). Lower neuroticism was also related to better memory, and lower conscientiousness to memory impairment. Non-memory cognition was unrelated to personality. Personality may inform predictive models of memory impairment in MS.

Network structure of brain atrophy in de novo Parkinson's disease

PubMed Central

Zeighami, Yashar; Ulla, Miguel; Iturria-Medina, Yasser; Dadar, Mahsa; Zhang, Yu; Larcher, Kevin Michel-Herve; Fonov, Vladimir; Evans, Alan C; Collins, D Louis; Dagher, Alain

2015-01-01

We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation. DOI: http://dx.doi.org/10.7554/eLife.08440.001 PMID:26344547

mRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound that Increases Muscle Mass

PubMed Central

Kunkel, Steven D.; Suneja, Manish; Ebert, Scott M.; Bongers, Kale S.; Fox, Daniel K.; Malmberg, Sharon E.; Alipour, Fariborz; Shields, Richard K.; Adams, Christopher M.

2011-01-01

SUMMARY Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling, and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid’s effects on muscle were accompanied by reductions in adiposity, fasting blood glucose and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases. PMID:21641545

IMPROVING THE AGE-RELATED MACULAR DEGENERATION CONSTRUCT: A New Classification System.

PubMed

Spaide, Richard F

2018-05-01

Previous models of disease in age-related macular degeneration (AMD) were incomplete in that they did not encompass subretinal drusenoid deposits (pseudodrusen), subtypes of neovascularization, and polypoidal choroidal vasculopathy. In addition, Type 3 neovascularization starts in the retina and may not necessarily involve the choroid. As such, the term choroidal neovascularization is not appropriate for these eyes. The new aspects in the AMD construct are to include specific lipoprotein extracellular accumulations, namely drusen and subretinal drusenoid deposits, as early AMD. The deposition of specific types of deposit seems to be highly correlated with choroidal thickness and topographical location in the macula. Late AMD includes macular neovascularization or atrophy. The particular type of extracellular deposit is predictive of the future course of the patient. For example, eyes with subretinal drusenoid deposits have a propensity to develop outer retinal atrophy, complete outer retinal and retinal pigment epithelial atrophy, or Type 3 neovascularization as specific forms of late AMD. Given Type 3 neovascularization may never involve the choroid, the term macular neovascularization is suggested for the entire spectrum of neovascular disease in AMD. In contrast to older classification systems, the proposed system encompasses the relevant presentations of disease and more precisely predicts the future course of the patient. In doing so, the concept was developed that there may be genetic risk alleles, which are not necessarily the same alleles that influence disease expression.

Quantitative assessment of brain stem and cerebellar atrophy in spinocerebellar ataxia types 3 and 6: impact on clinical status.

PubMed

Eichler, L; Bellenberg, B; Hahn, H K; Köster, O; Schöls, L; Lukas, C

2011-05-01

Cerebellar and brain stem atrophy are important features in SCA3, whereas SCA6 has been regarded as a "pure" cerebellar disease. However, recent neuropathologic studies have described additional brain stem involvement in SCA6. We, therefore, aimed to investigate the occurrence and impact of regional infratentorial brain volume differences in patients with SCA3 and SCA6. Thirty-four patients with genetically proved SCA (SCA3, n = 17; SCA6, n = 17) and age-matched healthy control subjects (n = 51) were included. In all subjects, high-resolution T1-weighted images were acquired with a 1.5T MR imaging scanner. Individual brain stem and cerebellar volumes were calculated by using semiautomated volumetry approaches. For all patients with SCA, clinical dysfunction was scored according to the ICARS. Multiple regression analysis was used to identify the contribution of regional volumes to explain the variance in clinical dysfunction in each SCA genotype. Cerebellar volumes were lower in patients with SCA6 compared with controls and with those with SCA3. In contrast to controls, brain stem volume loss was observed in patients with SCA3 (P < .001) and, to a lesser extent, in those with SCA6 (P = .027). Significant linear dependencies were found between ICARS and cerebellum volume (SCA3: R(2) = 0.29, P = .02; SCA6: R(2) = 0.29, P = .03) and between ICARS and brain stem volume (SCA3: R(2) = 0.49, P = .002; SCA6: R(2) = 0.39, P < .01) in both subtypes. Both cerebellar and brain stem atrophy contributed independently to the variance in clinical dysfunction in SCA6, while in SCA3, only brain stem atrophy was of relevance. Our current findings in accordance with recent neuroradiologic and pathoanatomic studies suggest brain stem and cerebellar volume loss as attractive surrogate markers of disease severity in SCA3 and SCA6.

Contribution of four lifelong factors of cognitive reserve on late cognition in normal aging and Parkinson's disease.

PubMed

Rouillard, Maud; Audiffren, Michel; Albinet, Cédric; Ali Bahri, Mohamed; Garraux, Gaëtan; Collette, Fabienne

2017-03-01

Cognitive reserve (CR) was proposed to explain how individual differences in brain function help to cope with the effects of normal aging and neurodegenerative diseases. Education, professional solicitations, and engagement in leisure and physical activities across the lifetime are considered as major determinants of this reserve. Using multiple linear regression analyses, we tested separately in healthy elderly and Parkinson's disease (PD) populations to what extent cognitive performance in several domains was explained by (a) any of these four environmental lifespan variables; (b) demographic and clinical variables (age, gender, depression score, and, for the PD group, duration of disease and dopaminergic drugs). We also tested for an interaction, if any, between these lifespan variables and brain pathology indexed by global atrophy measured from high-resolution anatomical magnetic resonance imaging. Age was negatively associated with cognitive performance in the PD group. In healthy elderly participants, we observed significant positive associations between cognitive performance and (a) education, (b) leisure activities, and (c) professional solicitation (decisional latitude). Furthermore, participants with greater brain atrophy benefited more from CR. In PD patients, education and professional solicitations contributed to cognitive performance but to a lesser extent than in controls. CR factors modulated the relationship between cognition and brain atrophy only in patients with a slight or moderate brain atrophy. Education is the CR factor that contributed the most to late cognitive functioning in both groups, closely followed by leisure activity in normal aging and professional solicitations in PD. Our results also provide evidence suggesting that the effects of CR does not express similarly in normal aging and PD. From a broader perspective, these results seem to indicate that CR factors the most consistently practiced across lifespan (education and professional solicitation) are those that are the more strongly associated to late cognitive efficiency.

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease

PubMed Central

Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J.; Barrick, Thomas R.; Markus, Hugh S.

2016-01-01

Abstract Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson’s R = −0.69, P < 1 × 10 −7 ), and significant grey matter loss and whole brain atrophy occurs annually ( P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity progression is associated with increases in cortical grey matter atrophy rates, in the medial-frontal, orbito-frontal, parietal and occipital regions. Conversely, increased rates of global grey matter atrophy are significantly associated with faster white matter hyperintensity growth in the frontal and parietal regions. Together, these results link the progression of white matter hyperintensities with increasing rates of regional grey matter atrophy, and demonstrate that grey matter atrophy is the major contributor to whole brain atrophy in symptomatic cerebral small vessel disease. These measures provide novel insights into the longitudinal pathogenesis of small vessel disease, and imply that therapies aimed at reducing progression of white matter hyperintensities via end-arteriole damage may protect against secondary brain atrophy and consequent functional morbidity. PMID:26936939

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease.

PubMed

Lambert, Christian; Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J; Barrick, Thomas R; Markus, Hugh S

2016-04-01

Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson's R = -0.69, P < 1 × 10(-7)), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity progression is associated with increases in cortical grey matter atrophy rates, in the medial-frontal, orbito-frontal, parietal and occipital regions. Conversely, increased rates of global grey matter atrophy are significantly associated with faster white matter hyperintensity growth in the frontal and parietal regions. Together, these results link the progression of white matter hyperintensities with increasing rates of regional grey matter atrophy, and demonstrate that grey matter atrophy is the major contributor to whole brain atrophy in symptomatic cerebral small vessel disease. These measures provide novel insights into the longitudinal pathogenesis of small vessel disease, and imply that therapies aimed at reducing progression of white matter hyperintensities via end-arteriole damage may protect against secondary brain atrophy and consequent functional morbidity. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Frequent Seizures Are Associated with a Network of Gray Matter Atrophy in Temporal Lobe Epilepsy with or without Hippocampal Sclerosis

PubMed Central

Coan, Ana C.; Campos, Brunno M.; Yasuda, Clarissa L.; Kubota, Bruno Y.; Bergo, Felipe PG.; Guerreiro, Carlos AM.; Cendes, Fernando

2014-01-01

Objective Patients with temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) have diffuse subtle gray matter (GM) atrophy detectable by MRI quantification analyses. However, it is not clear whether the etiology and seizure frequency are associated with this atrophy. We aimed to evaluate the occurrence of GM atrophy and the influence of seizure frequency in patients with TLE and either normal MRI (TLE-NL) or MRI signs of HS (TLE-HS). Methods We evaluated a group of 172 consecutive patients with unilateral TLE-HS or TLE-NL as defined by hippocampal volumetry and signal quantification (122 TLE-HS and 50 TLE-NL) plus a group of 82 healthy individuals. Voxel-based morphometry was performed with VBM8/SPM8 in 3T MRIs. Patients with up to three complex partial seizures and no generalized tonic-clonic seizures in the previous year were considered to have infrequent seizures. Those who did not fulfill these criteria were considered to have frequent seizures. Results Patients with TLE-HS had more pronounced GM atrophy, including the ipsilateral mesial temporal structures, temporal lobe, bilateral thalami and pre/post-central gyri. Patients with TLE-NL had more subtle GM atrophy, including the ipsilateral orbitofrontal cortex, bilateral thalami and pre/post-central gyri. Both TLE-HS and TLE-NL showed increased GM volume in the contralateral pons. TLE-HS patients with frequent seizures had more pronounced GM atrophy in extra-temporal regions than TLE-HS with infrequent seizures. Patients with TLE-NL and infrequent seizures had no detectable GM atrophy. In both TLE-HS and TLE-NL, the duration of epilepsy correlated with GM atrophy in extra-hippocampal regions. Conclusion Although a diffuse network GM atrophy occurs in both TLE-HS and TLE-NL, this is strikingly more evident in TLE-HS and in patients with frequent seizures. These findings suggest that neocortical atrophy in TLE is related to the ongoing seizures and epilepsy duration, while thalamic atrophy is more probably related to the original epileptogenic process. PMID:24475055

Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension.

PubMed

Isaacson, Stuart; Vernino, Steven; Ziemann, Adam; Rowse, Gerald J; Kalu, Uwa; White, William B

2016-10-01

The long-term safety of droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Parkinson disease, pure autonomic failure, multiple system atrophy, or nondiabetic autonomic neuropathy was evaluated in a phase 3, multinational, open-label study in patients who previously participated in a double-blind, placebo-controlled clinical trial of droxidopa. A total of 350 patients received droxidopa 100 to 600 mg three times daily. Mean duration of droxidopa exposure was 363 days (range, 2-1133 days). Rates of serious adverse events (AEs), cardiac-related AEs, and supine hypertension were 24%, 5%, and 5%, respectively. Most AEs, including those of a cardiovascular nature, were not attributed by investigators to droxidopa. In this large cohort of patients with neurogenic orthostatic hypotension, droxidopa was well tolerated during long-term use. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Potential Modes of Intercellular α-Synuclein Transmission

PubMed Central

Valdinocci, Dario; Radford, Rowan A. W.; Siow, Sue Maye; Chung, Roger S.; Pountney, Dean L.

2017-01-01

Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson’s disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of α-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which α-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease. PMID:28241427

Potential Modes of Intercellular α-Synuclein Transmission.

PubMed

Valdinocci, Dario; Radford, Rowan A W; Siow, Sue Maye; Chung, Roger S; Pountney, Dean L

2017-02-22

Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson's disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of α-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which α-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease.

Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

ClinicalTrials.gov

2015-08-24

Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

Gluteal muscle fatty atrophy is not associated with elevated blood metal ions or pseudotumors in patients with a unilateral metal-on-metal hip replacement.

PubMed

Reito, Aleksi; Elo, Petra; Nieminen, Jyrki; Puolakka, Timo; Eskelinen, Antti

2016-02-01

There are no international guidelines to define adverse reaction to metal debris (ARMD). Muscle fatty atrophy has been reported to be common in patients with failing metal-on-metal (MoM) hip replacements. We assessed whether gluteal muscle fatty atrophy is associated with elevated blood metal ion levels and pseudotumors. 263 consecutive patients with unilateral ASR XL total hip replacement using a posterior approach and with an unoperated contralateral hip were included in the study. All patients had undergone a standard screening program at our institution, including MRI and blood metal ion measurement. Muscle fatty atrophy was graded as being absent, mild, moderate, or severe in each of the gluteal muscles. The prevalence of moderate-to-severe gluteal muscle atrophy was low (12% for gluteus minimus, 10% for gluteus medius, and 2% for gluteus maximus). Muscle atrophy was neither associated with elevated blood metal ion levels (> 5 ppb) nor with the presence of a clear (solid- or mixed-type) pseudotumor seen in MRI. A combination of moderate-to-severe atrophy in MRI, elevated blood metal ion levels, and MRI-confirmed mixed or solid pseudotumor was rare. Multivariable regression revealed that "preoperative diagnosis other than osteoarthrosis" was the strongest predictor of the presence of fatty atrophy. Gluteal muscle atrophy may be a clinically significant finding with influence on hip muscle strength in patients with MoM hip replacement. However, our results suggest that gluteal muscle atrophy seen in MRI is not associated with either the presence or severity of ARMD, at least not in patients who have been operated on using the posterior approach.

Intelligence and cognitive function in children and adolescents with spinal muscular atrophy.

PubMed

von Gontard, A; Zerres, K; Backes, M; Laufersweiler-Plass, C; Wendland, C; Melchers, P; Lehmkuhl, G; Rudnik-Schöneborn, S

2002-02-01

Spinal muscular atrophy is a chronic disease characterised by loss of motor function. The aim of the study was to analyse cognitive functions in a large group of patients with spinal muscular atrophy. It was hypothesised that their intelligence is comparable to controls, but not above average as previously postulated. Ninety-six children and adolescents with spinal muscular atrophy I-III, aged 6.0-18.11 years, 45 non-affected siblings and 59 healthy, matched controls were examined with one- (CPM/SPM), as well as multi-dimensional intelligence tests (Kaufman-ABC; Wechsler tests). The mean IQ measured with the CPM/SPM tests was 109.6 for the spinal muscular atrophy group, 107.3 for the sibs and 104.1 for the healthy controls (no significant difference). In the older children and adolescents (SPM only) the mean IQ was significantly higher for the spinal muscular atrophy patients (109.6) than for the controls (95.4). The standard score in the 'mental processing composite' scale of the Kaufman-ABC was identical in the spinal muscular atrophy group and controls (103.8). The cognitive profile was relatively homogeneous. However, the older children and adolescents did have a significantly higher verbal IQ (113.8) than controls (104.6) in the Wechsler tests. There were no significant differences in any of the tests among different grades of severity (spinal muscular atrophy types I-III). It can be concluded that children and adolescents with spinal muscular atrophy have a general intelligence in the normal range. By adolescence, environmentally mediated aspects of intelligence are higher in patients with spinal muscular atrophy. It could be speculated that the development of cognitive skills and knowledge is a creative way to compensate the many restrictions due to their physical handicap.

Distinct patterns of brain atrophy in Genetic Frontotemporal Dementia Initiative (GENFI) cohort revealed by visual rating scales.

PubMed

Fumagalli, Giorgio G; Basilico, Paola; Arighi, Andrea; Bocchetta, Martina; Dick, Katrina M; Cash, David M; Harding, Sophie; Mercurio, Matteo; Fenoglio, Chiara; Pietroboni, Anna M; Ghezzi, Laura; van Swieten, John; Borroni, Barbara; de Mendonça, Alexandre; Masellis, Mario; Tartaglia, Maria C; Rowe, James B; Graff, Caroline; Tagliavini, Fabrizio; Frisoni, Giovanni B; Laforce, Robert; Finger, Elizabeth; Sorbi, Sandro; Scarpini, Elio; Rohrer, Jonathan D; Galimberti, Daniela

2018-05-24

In patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms. Magnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas). Intra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers. These simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.

Willingness to Pay for a Newborn Screening Test for Spinal Muscular Atrophy.

PubMed

Lin, Pei-Jung; Yeh, Wei-Shi; Neumann, Peter J

2017-01-01

The current US mandatory newborn screening panel does not include spinal muscular atrophy, the most common fatal genetic disease among children. We assessed population preferences for newborn screening for spinal muscular atrophy, and how test preferences varied depending on immediate treatment implications. We conducted an online willingness-to-pay survey of US adults (n = 982). Respondents were asked to imagine being parents of a newborn. Each respondent was presented with two hypothetical scenarios following the spinal muscular atrophy screening test: current standard of care (no treatment available) and one of three randomly assigned scenarios (new treatment available to improve functioning, survival, or both). We used a bidding game to elicit willingness to pay for the spinal muscular atrophy test, and performed a two-part model to estimate median and mean willingness-to-pay values. Most respondents (79% to 87%) would prefer screening their newborns for spinal muscular atrophy. People expressed a willingness to pay for spinal muscular atrophy screening even without an available therapy (median: $142; mean: $253). Willingness to pay increased with treatment availability (median: $161 to $182; mean: $270 to $297) and respondent income. Most respondents considered test accuracy, treatment availability, and treatment effectiveness very important or important factors in deciding willingness to pay. Most people would prefer and would be willing to pay for testing their newborn for spinal muscular atrophy, even in the absence of direct treatment. People perceive the spinal muscular atrophy test more valuable if treatment were available to improve the newborn's functioning and survival. Despite preferences for the test information, adding spinal muscular atrophy to newborn screening programs remains controversial. Future studies are needed to determine how early detection may impact long-term patient outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

The efficacy and safety of estriol to treat vulvovaginal atrophy in postmenopausal women: a systematic literature review.

PubMed

Rueda, C; Osorio, A M; Avellaneda, A C; Pinzón, C E; Restrepo, O I

2017-08-01

To evaluate the efficacy and safety of estriol for the treatment of vulvovaginal atrophy in postmenopausal women. A systematic literature review was performed. We searched the following electronic databases: Medline, Cochrane, Embase, Lilacs, CINHAL and Google Scholar. The studies selected included controlled clinical trials and quasi-experimental studies. Selections were made in pairs and independently, first by title and abstract and then complete texts. We identified 188 studies, 22 of which met the inclusion criteria; 13 were controlled clinical trials and nine were quasi-experimental, and 1217 women were included. These studies confirmed the efficacy of local estrogens to treat symptoms of vulvovaginal atrophy with few adverse effects reported. Following treatment, serum estriol levels rose, peaking at 1 h. At the 6-month follow-up, there was no increase in serum estriol in treated women. The available evidence (of low and moderate quality) shows that, when administered vaginally, estriol preparations appear to be safe for women who have risk factors related to systemic estrogen therapy.

Bone and muscle atrophy with suspension of the rat

NASA Technical Reports Server (NTRS)

Leblanc, A.; Marsh, C.; Evans, H.; Johnson, P.; Schneider, V.; Jhingran, S.

1985-01-01

In order to identify a suitable model for the study of muscle atrophy due to suspension in space, a modified version of the Morey tail suspension model was used to measure the atrophic responses of rat bone and muscle to 14-30 days of unloading of the hindlimbs. The progress of atrophy was measured by increases in methylene diphosphonate (MDP) uptake. It is found that bone uptake of methylene diphosphonate followed a phasic pattern similar to changes in the bone formation rate of immobilized dogs and cats. Increased MDP uptake after a period of 60 days indicated an accelerated bone metabolism. Maximum muscle atrophy in the suspended rats was distinctly different from immobilization atrophy. On the basis of the experimental results, it is concluded that the tail suspension model is an adequate simulation of bone atrophy due to suspension.

Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy.

PubMed

Iyer, Chitra C; McGovern, Vicki L; Wise, Dawnne O; Glass, David J; Burghes, Arthur H M

2014-05-01

Spinal muscular atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx(-/-)-SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study.

PubMed

Miller, David H; Fox, Robert J; Phillips, J Theodore; Hutchinson, Michael; Havrdova, Eva; Kita, Mariko; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; MacManus, David G; Yousry, Tarek A; Goodsell, Mary; Yang, Minhua; Zhang, Ray; Viglietta, Vissia; Dawson, Katherine T

2015-03-17

To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment. © 2015 American Academy of Neurology.

Exploring the relationship between white matter and gray matter damage in early primary progressive multiple sclerosis: an in vivo study with TBSS and VBM.

PubMed

Bodini, Benedetta; Khaleeli, Zhaleh; Cercignani, Mara; Miller, David H; Thompson, Alan J; Ciccarelli, Olga

2009-09-01

We investigated the relationship between the damage occurring in the brain normal-appearing white matter (NAWM) and in the gray matter (GM) in patients with early Primary Progressive multiple sclerosis (PPMS), using Tract-Based Spatial Statistics (TBSS) and an optimized voxel-based morphometry (VBM) approach. Thirty-five patients with early PPMS underwent diffusion tensor and conventional imaging and were clinically assessed. TBSS and VBM were employed to localize regions of lower fractional anisotropy (FA) and lower GM volume in patients compared with controls. Areas of anatomical and quantitative correlation between NAWM and GM damage were detected. Multiple regression analyses were performed to investigate whether NAWM FA or GM volume of regions correlated with clinical scores independently from the other and from age and gender. In patients, we found 11 brain regions that showed an anatomical correspondence between reduced NAWM FA and GM atrophy; of these, four showed a quantitative correlation (i.e., the right sensory motor region with the adjacent corticospinal tract, the left and right thalamus with the corresponding thalamic radiations and the left insula with the adjacent WM). Either the NAWM FA or the GM volume in each of these regions correlated with disability. These results demonstrate a link between the pathological processes occurring in the NAWM and in the GM in PPMS in specific, clinically relevant brain areas. Longitudinal studies will determine whether the GM atrophy precedes or follows the NAWM damage. The methodology that we described may be useful to investigate other neurological disorders affecting both the WM and the GM. 2009 Wiley-Liss, Inc.

Identification of multiple sclerosis patients at highest risk of cognitive impairment using an integrated brain magnetic resonance imaging assessment approach.

PubMed

Uher, T; Vaneckova, M; Sormani, M P; Krasensky, J; Sobisek, L; Dusankova, J Blahova; Seidl, Z; Havrdova, E; Kalincik, T; Benedict, R H B; Horakova, D

2017-02-01

While impaired cognitive performance is common in multiple sclerosis (MS), it has been largely underdiagnosed. Here a magnetic resonance imaging (MRI) screening algorithm is proposed to identify patients at highest risk of cognitive impairment. The objective was to examine whether assessment of lesion burden together with whole brain atrophy on MRI improves our ability to identify cognitively impaired MS patients. Of the 1253 patients enrolled in the study, 1052 patients with all cognitive, volumetric MRI and clinical data available were included in the analysis. Brain MRI and neuropsychological assessment with the Brief International Cognitive Assessment for Multiple Sclerosis were performed. Multivariable logistic regression and individual prediction analysis were used to investigate the associations between MRI markers and cognitive impairment. The results of the primary analysis were validated at two subsequent time points (months 12 and 24). The prevalence of cognitive impairment was greater in patients with low brain parenchymal fraction (BPF) (<0.85) and high T2 lesion volume (T2-LV) (>3.5 ml) than in patients with high BPF (>0.85) and low T2-LV (<3.5 ml), with an odds ratio (OR) of 6.5 (95% CI 4.4-9.5). Low BPF together with high T2-LV identified in 270 (25.7%) patients predicted cognitive impairment with 83% specificity, 82% negative predictive value, 51% sensitivity and 75% overall accuracy. The risk of confirmed cognitive decline over the follow-up was greater in patients with high T2-LV (OR 2.1; 95% CI 1.1-3.8) and low BPF (OR 2.6; 95% CI 1.4-4.7). The integrated MRI assessment of lesion burden and brain atrophy may improve the stratification of MS patients who may benefit from cognitive assessment. © 2016 EAN.

Time-Course of Muscle Mass Loss, Damage, and Proteolysis in Gastrocnemius following Unloading and Reloading: Implications in Chronic Diseases

PubMed Central

Chacon-Cabrera, Alba; Lund-Palau, Helena; Gea, Joaquim; Barreiro, Esther

2016-01-01

Background Disuse muscle atrophy is a major comorbidity in patients with chronic diseases including cancer. We sought to explore the kinetics of molecular mechanisms shown to be involved in muscle mass loss throughout time in a mouse model of disuse muscle atrophy and recovery following immobilization. Methods Body and muscle weights, grip strength, muscle phenotype (fiber type composition and morphometry and muscle structural alterations), proteolysis, contractile proteins, systemic troponin I, and mitochondrial content were assessed in gastrocnemius of mice exposed to periods (1, 2, 3, 7, 15 and 30 days) of non-invasive hindlimb immobilization (plastic splint, I cohorts) and in those exposed to reloading for different time-points (1, 3, 7, 15, and 30 days, R cohorts) following a seven-day period of immobilization. Groups of control animals were also used. Results Compared to non-exposed controls, muscle weight, limb strength, slow- and fast-twitch cross-sectional areas, mtDNA/nDNA, and myosin content were decreased in mice of I cohorts, whereas tyrosine release, ubiquitin-proteasome activity, muscle injury and systemic troponin I levels were increased. Gastrocnemius reloading following splint removal improved muscle mass loss, strength, fiber atrophy, injury, myosin content, and mtDNA/nDNA, while reducing ubiquitin-proteasome activity and proteolysis. Conclusions A consistent program of molecular and cellular events leading to reduced gastrocnemius muscle mass and mitochondrial content and reduced strength, enhanced proteolysis, and injury, was seen in this non-invasive mouse model of disuse muscle atrophy. Unloading of the muscle following removal of the splint significantly improved the alterations seen during unloading, characterized by a specific kinetic profile of molecular events involved in muscle regeneration. These findings have implications in patients with chronic diseases including cancer in whom physical activity may be severely compromised. PMID:27792730

Head circumference, atrophy, and cognition: implications for brain reserve in Alzheimer disease.

PubMed

Perneczky, R; Wagenpfeil, S; Lunetta, K L; Cupples, L A; Green, R C; Decarli, C; Farrer, L A; Kurz, A

2010-07-13

Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference. A total of 270 patients with AD participating in the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study underwent cognitive testing, APOE genotyping, and MRI of the brain in a cross-sectional study. Linear regression analysis was used to examine the association between cerebral atrophy, as a proxy for AD pathology, and level of cognitive function, adjusting for age, duration of AD symptoms, gender, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity. An interaction term between atrophy and head circumference was introduced to explore if head circumference modified the association between cerebral atrophy and cognition. There was a significant inverse association between atrophy and cognitive function, and a significant interaction between atrophy and head circumference. With greater levels of atrophy, cognition was higher for individuals with greater head circumference. This study suggests that larger head circumference is associated with less cognitive impairment in the face of cerebral atrophy. This finding supports the notion that head circumference (and presumably brain size) offers protection against AD symptoms through enhanced brain reserve.

iss028e035566

NASA Image and Video Library

2011-08-31

ISS028-E-035566 (31 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, works with Muscle Atrophy Research & Exercise System (MARES) hardware in the Columbus laboratory of the International Space Station.

iss028e035603

NASA Image and Video Library

2011-08-31

ISS028-E-035603 (31 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, works with Muscle Atrophy Research & Exercise System (MARES) hardware in the Columbus laboratory of the International Space Station.

iss028e035301

NASA Image and Video Library

2011-08-31

ISS028-E-035301 (31 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, works with Muscle Atrophy Research & Exercise System (MARES) hardware in the Columbus laboratory of the International Space Station.

Testicular atrophy secondary to a large long standing incarcerated inguinal hernia.

PubMed

Salemis, Nikolaos S; Nisotakis, Konstantinos

2011-07-01

Testicular atrophy is a rare but distressing complication of inguinal hernia repair. Apart from the postsurgical etiology, ischemic orchitis and subsequent testicular atrophy may occur secondary to compression of the testicular vessels by chronically incarcerated hernias. We present a rare case of testicular atrophy secondary to a large long standing incarcerated inguinal hernia of 2-decade duration in a 79-year-old man. Testicular atrophy should be always considered in long standing incarcerated inguinal hernias and patients should be adequately informed of this possibility during the preoperative work-up. Preoperative scrotal ultrasonography can be used to determine testicular status in this specific group of patients.

Testicular atrophy secondary to a large long standing incarcerated inguinal hernia

PubMed Central

Salemis, Nikolaos S.; Nisotakis, Konstantinos

2011-01-01

Testicular atrophy is a rare but distressing complication of inguinal hernia repair. Apart from the postsurgical etiology, ischemic orchitis and subsequent testicular atrophy may occur secondary to compression of the testicular vessels by chronically incarcerated hernias. We present a rare case of testicular atrophy secondary to a large long standing incarcerated inguinal hernia of 2-decade duration in a 79-year-old man. Testicular atrophy should be always considered in long standing incarcerated inguinal hernias and patients should be adequately informed of this possibility during the preoperative work-up. Preoperative scrotal ultrasonography can be used to determine testicular status in this specific group of patients. PMID:24765329

The protective effect of dexpanthenol on testicular atrophy at 60th day following experimental testicular torsion.

PubMed

Etensel, Barlas; Ozkisacik, Sezen; Ozkara, Esra; Serbest, Yeşim Aksu; Oztan, Onur; Yazici, Mesut; Gürsoy, Harun

2007-03-01

Despite the prompt diagnosis and treatment of testicular torsion (TT), there are problems with fertility and atrophy after testicular salvage. Dexpanthenol (Dxp) is the biologically active alcohol of pantothenic acid (PA). Dxp is converted to PA in tissues. PA increases the content of reduced glutathione (GSH), Coenzyme A and ATP synthesis in cells. GSH and glutathione-dependent peroxidases (GPX) are the major defense systems against oxidative stress. GPX-4 is the major antioxidant in testicular tissue. However, the activity of GPX-4 appeared and increased only after puberty. We investigated the effect of Dxp on testicular atrophy after TT at the 60th day. Rats were separated randomly into four groups. Group C: control group, group Td: torsion + detorsion, group Sal: torsion + saline + detorsion, group Dxp: torsion + Dxp + detorsion. The left testis was rotated 720 degrees for 2 h. In group Sal, normal saline and in group Dxp, Dexpanthenol were injected intraperitonally, 30 min before detorsion. After 60 days, the testicular weights and volumes were measured. Histopathology of the left testis was evaluated with mean seminiferous tubular diameter (MSTD) and mean testicular biopsy score (MTBS). The left (torsed) testicular weight and volume of groups Td and Sal were significantly lower compared to group Dxp. The MSTD and MTBS of group Td and Sal were significantly lower than group Dxp. Contralateral testicular weight and volume of groups Td, Sal and Dxp had no significant difference compared to the control group. Dxp significantly prevented testicular atrophy after 60 days of TT. Dxp has FDA approval, is safe, cost effective and readily available. Its relevance for clinical trials may especially be for the problem of testicular atrophy catastrophe, seen very frequently following testicular salvage.

Time Trends in Helicobacter pylori Infection and Atrophic Gastritis Over 40 Years in Japan.

PubMed

Kamada, Tomoari; Haruma, Ken; Ito, Masanori; Inoue, Kazuhiko; Manabe, Noriaki; Matsumoto, Hiroshi; Kusunoki, Hiroaki; Hata, Jiro; Yoshihara, Masaharu; Sumii, Koji; Akiyama, Takashi; Tanaka, Shinji; Shiotani, Akiko; Graham, David Y

2015-06-01

Helicobacter pylori infection produces progressive mucosal damage that may eventually result in gastric cancer. We studied the changes that occurred in the presence and severity of atrophic gastritis and the prevalence of H. pylori infection that occurred coincident with improvements in economic and hygienic conditions in Japan since World War II. The prevalence of H. pylori infection and histologic grades of gastric damage were retrospectively evaluated using gastric biopsy specimens obtained over a 40-year period. Gastric atrophy and intestinal metaplasia were scored using the updated Sydney classification system. The prevalence of H. pylori and severity of atrophy were examined in 1381 patients including 289 patients examined in the 1970s (158 men; mean age, 44.9 years), 787 in the 1990s (430 men; 44.2 years), and 305 in the 2010s (163 men; 53.2 years). Overall, the prevalence of H. pylori infection decreased significantly from 74.7% (1970s) to 53% (1990s) and 35.1% (2010s) (p < .01). The prevalence of atrophy in the antrum and corpus was significantly lower in the 2010s (33, 19%, respectively) compared to those evaluated in either the 1970s (98, 82%) (p < .001) or 1990s (80, 67%) (p < .001). The severity of atrophy and intestinal metaplasia also declined remarkably among those with H. pylori infection. There has been a progressive and rapid decline in the prevalence of H. pylori infection as well a fall in the rate of progression of gastric atrophy among H. pylori-infected Japanese coincident with the westernization and improvements in economic and hygienic conditions in Japan since World War II. © 2015 John Wiley & Sons Ltd.

Voluntary saccade inhibition deficits correlate with extended white-matter cortico-basal atrophy in Huntington's disease.

PubMed

Vaca-Palomares, Israel; Coe, Brian C; Brien, Donald C; Munoz, Douglas P; Fernandez-Ruiz, Juan

2017-01-01

The ability to inhibit automatic versus voluntary saccade commands in demanding situations can be impaired in neurodegenerative diseases such as Huntington's disease (HD). These deficits could result from disruptions in the interaction between basal ganglia and the saccade control system. To investigate voluntary oculomotor control deficits related to the cortico-basal circuitry, we evaluated early HD patients using an interleaved pro- and anti-saccade task that requires flexible executive control to generate either an automatic response (look at a peripheral visual stimulus) or a voluntary response (look away from the stimulus in the opposite direction). The impairments of HD patients in this task are mainly attributed to degeneration in the striatal medium spiny neurons leading to an over-activation of the indirect-pathway thorough the basal ganglia. However, some studies have proposed that damage outside the indirect-pathway also contribute to executive and saccade deficits. We used the interleaved pro- and anti-saccade task to study voluntary saccade inhibition deficits, Voxel-based morphometry and Tract-based spatial statistic to map cortico-basal ganglia circuitry atrophy in HD. HD patients had voluntary saccade inhibition control deficits, including increased regular-latency anti-saccade errors and increased anticipatory saccades. These deficits correlated with white-matter atrophy in the inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior corona radiata and superior longitudinal fasciculus. These findings suggest that cortico-basal ganglia white-matter atrophy in HD, disrupts the normal connectivity in a network controlling voluntary saccade inhibitory behavior beyond the indirect-pathway. This suggests that in vivo measures of white-matter atrophy can be a reliable marker of the progression of cognitive deficits in HD.

Diagnostic criteria for selenium toxicosis in aquatic birds: histologic lesions

USGS Publications Warehouse

Green, D.E.; Albers, P.H.

1997-01-01

Chronic selenium toxicosis was induced in 1-year-old male mallard ducks (Anas platyrhynchos) by feeding selenium, as seleno-DL-methionine, in amounts of 0, 10, 20, 40, and 80 parts per million (ppm) to five groups of 21 ducks each for 16 wk during March to July 1988. All mallards in the 80 ppm group, three in the 40 ppm group, and one in the 20 ppm group died. Histologic lesions in mallards that died of selenosis were hepatocellular vacuolar degeneration progressing to centrolobular and panlobular necrosis, nephrosis, apoptosis of pancreatic exocrine cells, hypermaturity and avascularity of contour feathers of the head with atrophy of feather follicles, lymphocytic necrosis and atrophy of lymphoid organs (spleen, gut-associated lymphoid tissue, and lumbar lymph nodes), and severe atrophy and degeneration of fat. Histologic lesions in surviving mallards in the 40 ppm group, which had tissue residues of selenium comparable to mallards that died, were fewer and much milder than mallards that died; lesions consisted of atrophy of lymphoid tissue, hyalinogranular swelling of hepatocytes, atrophy of seminiferous tubules, and senescence of feathers. No significant histologic lesions were detected in euthanized mallards in the 0, 10 and 20 ppm groups. Based on tissue residues and histologic findings, primarily in the liver, there was a threshold of selenium accumulation above which pathophysiologic changes were rapid and fatal. Pathognomonic histologic lesions of fatal and nonfatal selenosis were not detected. Criteria for diagnosis of fatal selenosis in aquatic birds include consistent histologic lesions in the liver, kidneys, and organs of the immune system. Although histologic changes were present in cases of chronic non-fatal selenosis, these were inconsistent. Consistent features of fatal and non-fatal chronic selenosis were marked weight loss and elevated concentrations of selenium in organs.

Cell Science and Cell Biology Research at MSFC: Summary

NASA Technical Reports Server (NTRS)

2003-01-01

The common theme of these research programs is that they investigate regulation of gene expression in cells, and ultimately gene expression is controlled by the macromolecular interactions between regulatory proteins and DNA. The NASA Critical Path Roadmap identifies Muscle Alterations and Atrophy and Radiation Effects as Very Serious Risks and Severe Risks, respectively, in long term space flights. The specific problem addressed by Dr. Young's research ("Skeletal Muscle Atrophy and Muscle Cell Signaling") is that skeletal muscle loss in space cannot be prevented by vigorous exercise. Aerobic skeletal muscles (i.e., red muscles) undergo the most extensive atrophy during long-term space flight. Of the many different potential avenues for preventing muscle atrophy, Dr. Young has chosen to study the beta-adrenergic receptor (betaAR) pathway. The reason for this choice is that a family of compounds called betaAR agonists will preferentially cause an increase in muscle mass of aerobic muscles (i.e., red muscle) in animals, potentially providing a specific pharmacological solution to muscle loss in microgravity. In addition, muscle atrophy is a widespread medical problem in neuromuscular diseases, spinal cord injury, lack of exercise, aging, and any disease requiring prolonged bedridden status. Skeletal muscle cells in cell culture are utilized as a model system to study this problem. Dr. Richmond's research ("Radiation & Cancer Biology of Mammary Cells in Culture") is directed toward developing a laboratory model for use in risk assessment of cancer caused by space radiation. This research is unique because a human model will be developed utilizing human mammary cells that are highly susceptible to tumor development. This approach is preferential over using animal cells because of problems in comparing radiation-induced cancers between humans and animals.

Histopathological features of coeliac disease in a sample of Sudanese patients.

PubMed

Mokhtar, M A N; Mekki, S O; Mudawi, H M Y; Sulaiman, S H; Tahir, M A; Tigani, M A; Omer, I A; Yousif, B M; Fragalla, I A; Mohammed, Z; Dafaalla, M

2016-12-01

Coeliac disease can occur at any age but is more common in children. Its diagnosis requires correlation between clinical presentations, serological results, endoscopic findings and histopathological classification using the modified Marsh grading system. This study of coeliac disease with biopsies received in the department of histopathology at Soba University Hospital, and Fedail Hospital aimed to gain insight into the demographic profile, clinical presentations and histopathological classification of patients with coeliac disease. This was a descriptive study carried out at Soba University Hospital and Fedail Hospital during the period from January 2010-December 2013. Haematoxylin & Eosin and CD3-stained slides of small intestinal biopsies of coeliac disease patients were reviewed for various histological features (1) intraepithelial lymphocytes (IEL) count per 100 enterocytes, (2) crypt hyperplasia and (3) degree of villous atrophy. Based on the histopathological findings, the cases were categorized according to the modified Marsh classification. Demographic and clinical data were obtained from the patient request forms. The data were analyzed using Statistical Package for Social Sciences Software (SPSS). The study included 60 patients. Their age ranged from 2 to 70 years with a mean of 19.5 years (±15.7 SD). The most common age group was below 10 years old (41.6%). Male and female are equally affected. The most common clinical presentation was chronic diarrhoea (55.0%), followed by iron deficiency anemia (41.7%). The degree of villous atrophy ranged from complete atrophy (45.0%), marked atrophy (38.3%) to mild atrophy (16.6%). Marsh grade IIIC was the most common grade. The younger age-groups had a higher prevalence of iron deficiency anaemia and higher Marsh grade.

MARES

NASA Image and Video Library

2012-12-30

View of the Muscle Atrophy Research and Exercise System (MARES),in the Columbus Module (COL1F3). MARES will carry out research on musculoskeletal,bio-mechanical,and neuromuscular human physiology. Photo was taken during Expedition 34.

Verbal and non-verbal semantic impairment: From fluent primary progressive aphasia to semantic dementia

PubMed Central

Senaha, Mirna Lie Hosogi; Caramelli, Paulo; Porto, Claudia Sellitto; Nitrini, Ricardo

2007-01-01

Selective disturbances of semantic memory have attracted the interest of many investigators and the question of the existence of single or multiple semantic systems remains a very controversial theme in the literature. Objectives To discuss the question of multiple semantic systems based on a longitudinal study of a patient who presented semantic dementia from fluent primary progressive aphasia. Methods A 66 year-old woman with selective impairment of semantic memory was examined on two occasions, undergoing neuropsychological and language evaluations, the results of which were compared to those of three paired control individuals. Results In the first evaluation, physical examination was normal and the score on the Mini-Mental State Examination was 26. Language evaluation revealed fluent speech, anomia, disturbance in word comprehension, preservation of the syntactic and phonological aspects of the language, besides surface dyslexia and dysgraphia. Autobiographical and episodic memories were relatively preserved. In semantic memory tests, the following dissociation was found: disturbance of verbal semantic memory with preservation of non-verbal semantic memory. Magnetic resonance of the brain revealed marked atrophy of the left anterior temporal lobe. After 14 months, the difficulties in verbal semantic memory had become more severe and the semantic disturbance, limited initially to the linguistic sphere, had worsened to involve non-verbal domains. Conclusions Given the dissociation found in the first examination, we believe there is sufficient clinical evidence to refute the existence of a unitary semantic system. PMID:29213389

[The Autocad system for planimetric study of the optic disc in glaucoma: technique and reproducibility study].

PubMed

Sánchez Pérez, A; Honrubia López, F M; Larrosa Poves, J M; Polo Llorens, V; Melcon Sánchez-Frieras, B

2001-09-01

To develop a lens planimetry technique for the optic disc using AutoCAD. To determine variability magnitude of the optic disc morphological measurements. We employed AutoCAD R.14.0 Autodesk: image acquisition, contour delimitation by multiple lines fitting or ellipse adjustment, image sectorialization and measurements quantification (optic disc and excavation, vertical diameters, optic disc area, excavation area, neuroretinal sector area and Beta atrophy area). Intraimage or operator and interimage o total reproducibility was studied by coefficient of variability (CV) (n=10) in normal and myopic optic discs. This technique allows to obtain optic disc measurement in 5 to 10 minutes time. Total or interimage variability of measurements introduced by one observer presents CV range from 1.18-4.42. Operator or intraimage measurement presents CV range from 0.30-4.21. Optic disc contour delimitation by ellipse adjustment achieved better reproducibility results than multiple lines adjustment in all measurements. Computer assisted AutoCAD planimetry is an interactive method to analyse the optic disc, feasible to incorporate to clinical practice. Reproducibility results are comparable to other analyzers in quantification optic disc morphology. Ellipse adjustment improves results in optic disc contours delimitation.

Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

MedlinePlus

... myoclonic epilepsy Spinal muscular atrophy with progressive myoclonic epilepsy Printable PDF Open All Close All Enable Javascript ... boxes. Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

Protein turnover in atrophying muscle: from nutritional intervention to microarray expression analysis

NASA Technical Reports Server (NTRS)

Stein, T. Peter; Wade, Charles E.

2003-01-01

PURPOSE OF REVIEW: In response to decreased usage, skeletal muscle undergoes adaptive reductive remodeling due to the decrease in tension on the weight bearing components of the musculo-skeletal system. This response occurs with uncomplicated disuse (e.g. bed rest, space flight), as a secondary consequence of several widely prevalent chronic diseases for which activity is reduced (e.g. chronic obstructive pulmonary disease and chronic heart failure) and is part of the aging process. The problem is therefore one of considerable clinical importance. RECENT FINDINGS: The impaired function and exercise intolerance is related more to the associated muscle wasting rather than to the specific organ system primarily impacted by the disease. Progress has continued in describing the use of anabolic drugs and dietary manipulation. The major advance in the field has been: (i) the discovery of the atrogin-1 gene and (ii) the application of microarray expression analysis and proteomics with the objectives of obtaining comprehensive understanding of the pathways changed with disuse atrophy. SUMMARY: Disuse atrophy is a common clinical problem. There is a need for therapeutic interventions that do not involve exercise. A better understanding of the changes, particularly at the molecular level, could indicate hitherto unsuspected sites for nutritional and pharmacological intervention.

"Scleroderma linearis: hemiatrophia faciei progressiva (Parry-Romberg syndrom) without any changes in CNS and linear scleroderma "en coup de sabre" with CNS tumor

PubMed Central

Bergler-Czop, Beata; Lis-Święty, Anna; Brzezińska-Wcisło, Ligia

2009-01-01

Background Hemifacial atrophy (Parry-Romberg syndrome) is a relatively rare disease. The etiology of the disease is not clear. Some authors postulate its relation with limited scleroderma linearis. Linear scleroderma "en coup de sabre" is characterized by clinical presence of most commonly one-sided linear syndrome. In a number of patients, neurological affection is the medium of the disease. The treatment of both scleroderma varieties is similar to the treatment of limited systemic sclerosis. Case presentation We present two cases of a disease: a case of a 49-year-old woman with a typical image of hemifacial atrophy, without any changes of the nervous system and a case of a 33-year-old patient with an "en coup de sabre" scleroderma and with CNS tumor. Conclusion We described typical cases of a rare diseases, hemifacial atrophy and "en coup de sabre" scleroderma. In the patient diagnosed with Parry-Romberg syndrome, with Borrelia burgdoferi infection and with minor neurological symptoms, despite a four-year case history, there was a lack of proper diagnosis and treatment. In the second patient only skin changes without any neurological symptoms could be observed and only a precise neurological diagnosis revealed the presence of CNS tumor. PMID:19635150

Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

PubMed Central

Jordanova, Albena

2014-01-01

Hereditary spinal muscular atrophy is a motor neuron disorder characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by loss-of-function SMN1 mutations on 5q13. Recent developments in next generation sequencing technologies, however, have unveiled a growing number of clinical conditions designated as non-5q forms of spinal muscular atrophy. At present, 16 different genes and one unresolved locus are associated with proximal non-5q forms, having high phenotypic variability and diverse inheritance patterns. This review provides an overview of the current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies. We describe the molecular and cellular functions enriched among causative genes, and discuss the challenges in the post-genomics era of spinal muscular atrophy research. PMID:24970098

Carrier testing for spinal muscular atrophy

PubMed Central

Gitlin, Jonathan M.; Fischbeck, Kenneth; Crawford, Thomas O.; Cwik, Valerie; Fleischman, Alan; Gonye, Karla; Heine, Deborah; Hobby, Kenneth; Kaufmann, Petra; Keiles, Steven; MacKenzie, Alex; Musci, Thomas; Prior, Thomas; Lloyd-Puryear, Michele; Sugarman, Elaine A.; Terry, Sharon F.; Urv, Tiina; Wang, Ching; Watson, Michael; Yaron, Yuval; Frosst, Phyllis; Howell, R. Rodney

2014-01-01

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general. PMID:20808230

iss047e038968

NASA Image and Video Library

2016-04-05

ISS047e038968 (04/05/2016) --- ESA (European Space Agency) astronaut Tim Peake operates the Muscle Atrophy Research and Exercise System (MARES) equipment inside the Columbus module. MARES is an ESA system that will be used for research on musculoskeletal, biomechanical, and neuromuscular human physiology to better understand the effects of microgravity on the muscular system.

Combined striatal binding and cerebral influx analysis of dynamic 11C-raclopride PET improves early differentiation between multiple-system atrophy and Parkinson disease.

PubMed

Van Laere, Koen; Clerinx, Kristien; D'Hondt, Eduard; de Groot, Tjibbe; Vandenberghe, Wim

2010-04-01

Striatal dopamine D(2) receptor (D2R) PET has been proposed to differentiate between Parkinson disease (PD) and multiple-system atrophy with predominant parkinsonism (MSA-P). However, considerable overlap in striatal D(2) binding may exist between PD and MSA-P. It has been shown that imaging of neuronal activity, as determined by metabolism or perfusion, can also help distinguish PD from MSA-P. We investigated whether the differential diagnostic value of (11)C-raclopride PET could be improved by dynamic scan analysis combining D2R binding and regional tracer influx. (11)C-raclopride PET was performed in 9 MSA-P patients (mean age +/- SD, 56.2 +/- 10.2 y; disease duration, 2.9 +/- 0.8 y; median Hoehn-Yahr score, 3), 10 PD patients (mean age +/- SD, 65.7 +/- 8.1 y; disease duration, 3.3 +/- 1.5 y; median Hoehn-Yahr score, 1.5), and 10 healthy controls (mean age +/- SD, 61.6 +/- 6.5 y). Diagnosis was obtained after prolonged follow-up (MSA-P, 5.5 +/- 2.0 y; PD, 6.0 +/- 2.3 y) using validated clinical criteria. Spatially normalized parametric images of binding potential (BP) and local influx ratio (R(1) = K(1)/K'(1)) of (11)C-raclopride were obtained using a voxelwise reference tissue model with occipital cortex as reference region. Stepwise forward discriminant analysis with cross-validation, with and without the inclusion of regional R(1) values, was performed using a predefined volume-of-interest template. Using conventional BP values, we correctly classified 65.5% (all values given with cross-validation) of 29 cases only. The combination of BP and R(1) information increased discrimination accuracy to 79.3%. When healthy controls were not included and patients only were considered, BP information alone discriminated PD and MSA-P in 84.2% of cases, but the combination with R(1) data increased accuracy to 100%. Discriminant analysis using combined striatal D2R BP and cerebral influx ratio information of a single dynamic (11)C-raclopride PET scan distinguishes MSA-P and PD patients with high accuracy and is superior to conventional methods of striatal D2R binding analysis.

Additional corpus biopsy enhances the detection of Helicobacter pylori infection in a background of gastritis with atrophy

PubMed Central

2012-01-01

Background The best sites for biopsy-based tests to evaluate H. pylori infection in gastritis with atrophy are not well known. This study aimed to evaluate the site and sensitivity of biopsy-based tests in terms of degree of gastritis with atrophy. Methods One hundred and sixty-four (164) uninvestigated dyspepsia patients were enrolled. Biopsy-based tests (i.e., culture, histology Giemsa stain and rapid urease test) and non-invasive tests (anti-H. pylori IgG) were performed. The gold standard of H. pylori infection was defined according to previous criteria. The sensitivity, specificity, positive predictive rate and negative predictive rate of biopsy-based tests at the gastric antrum and body were calculated in terms of degree of gastritis with atrophy. Results The prevalence rate of H. pylori infection in the 164 patients was 63.4%. Gastritis with atrophy was significantly higher at the antrum than at the body (76% vs. 31%; p<0.001). The sensitivity of biopsy-based test decreased when the degree of gastritis with atrophy increased regardless of biopsy site (for normal, mild, moderate, and severe gastritis with atrophy, the sensitivity of histology Giemsa stain was 100%, 100%, 88%, and 66%, respectively, and 100%, 97%, 91%, and 66%, respectively, for rapid urease test). In moderate to severe antrum or body gastritis with atrophy, additional corpus biopsy resulted in increased sensitivity to 16.67% compare to single antrum biopsy. Conclusions In moderate to severe gastritis with atrophy, biopsy-based test should include the corpus for avoiding false negative results. PMID:23272897

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia.

PubMed

Ohm, D T; Kim, G; Gefen, T; Rademaker, A; Weintraub, S; Bigio, E H; Mesulam, M-M; Rogalski, E; Geula, C

2018-04-21

Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05). White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy. © 2018 British Neuropathological Society.

[Chronic atrophic gastritis: endoscopic and histological concordances, associated injuries and application of virtual chromoendoscopy].

PubMed

Liu Bejarano, Humberto

2011-01-01

Due to the poor agreement between endoscopy and histology, the gastric biopsy continues being the gold standard for the diagnosis of atrophic chronic gastritis. The Virtual chromoendoscopy system allows better observation of the gastric mucosa. Evaluate the agreement between the Kimura-Takemoto ´s endoscopic system classification and the histological system of OLGA (Operative for Link Assessment Gastritis), as well as to evaluate the application of the virtual chromoendoscopy. A prospective and longitudinal study of cohorts, 138 patients was include, using endoscopic system of atrophy by Kimura and Takemoto (K-T), with conventional optical and with the use of seventh filter of virtual chromoendoscopy ,then comparing with the histological findings of the OLGA pathology system, also were determinated injuries associated with respect to stage OLGA. The kappa index of agreement between conventional endoscopy and the system OLGA was 0.859 and with the system of virtual chromoendoscopy was 0.822, the preneoplasic and neoplastic gastric lesions were associate to stages III and IV of atrophy. The endoscopic and histological correlation with both systems isvery good, with or without the use of virtual chromoendoscopy. chronic atrophic gastritis, virtual chromoendoscopy, olga system, , kimuratakemoto system.

Masticatory muscles of mouse do not undergo atrophy in space.

PubMed

Philippou, Anastassios; Minozzo, Fabio C; Spinazzola, Janelle M; Smith, Lucas R; Lei, Hanqin; Rassier, Dilson E; Barton, Elisabeth R

2015-07-01

Muscle loading is important for maintaining muscle mass; when load is removed, atrophy is inevitable. However, in clinical situations such as critical care myopathy, masticatory muscles do not lose mass. Thus, their properties may be harnessed to preserve mass. We compared masticatory and appendicular muscles responses to microgravity, using mice aboard the space shuttle Space Transportation System-135. Age- and sex-matched controls remained on the ground. After 13 days of space flight, 1 masseter (MA) and tibialis anterior (TA) were frozen rapidly for biochemical and functional measurements, and the contralateral MA was processed for morphologic measurements. Flight TA muscles exhibited 20 ± 3% decreased muscle mass, 2-fold decreased phosphorylated (P)-Akt, and 4- to 12-fold increased atrogene expression. In contrast, MAs had no significant change in mass but a 3-fold increase in P-focal adhesion kinase, 1.5-fold increase in P-Akt, and 50-90% lower atrogene expression compared with limb muscles, which were unaltered in microgravity. Myofibril force measurements revealed that microgravity caused a 3-fold decrease in specific force and maximal shortening velocity in TA muscles. It is surprising that myofibril-specific force from both control and flight MAs were similar to flight TA muscles, yet power was compromised by 40% following flight. Continued loading in microgravity prevents atrophy, but masticatory muscles have a different set point that mimics disuse atrophy in the appendicular muscle. © FASEB.

The Roots of Alzheimer's Disease: Are High-Expanding Cortical Areas Preferentially Targeted?†.

PubMed

Fjell, Anders M; Amlien, Inge K; Sneve, Markus H; Grydeland, Håkon; Tamnes, Christian K; Chaplin, Tristan A; Rosa, Marcello G P; Walhovd, Kristine B

2015-09-01

Alzheimer's disease (AD) is regarded a human-specific condition, and it has been suggested that brain regions highly expanded in humans compared with other primates are selectively targeted. We calculated shared and unique variance in the distribution of AD atrophy accounted for by cortical expansion between macaque and human, affiliation to the default mode network (DMN), ontogenetic development and normal aging. Cortical expansion was moderately related to atrophy, but a critical discrepancy was seen in the medial temporo-parietal episodic memory network. Identification of "hotspots" and "coldspots" of expansion across several primate species did not yield compelling evidence for the hypothesis that highly expanded regions are specifically targeted. Controlling for distribution of atrophy in aging substantially attenuated the expansion-AD relationship. A path model showed that all variables explained unique variance in AD atrophy but were generally mediated through aging. This supports a systems-vulnerability model, where critical networks are subject to various negative impacts, aging in particular, rather than being selectively targeted in AD. An alternative approach is suggested, focused on the interplay of the phylogenetically old and preserved medial temporal lobe areas with more highly expanded association cortices governed by different principles of plasticity and stability. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Abnormal metabolic brain networks in Parkinson's disease from blackboard to bedside.

PubMed

Tang, Chris C; Eidelberg, David

2010-01-01

Metabolic imaging in the rest state has provided valuable information concerning the abnormalities of regional brain function that underlie idiopathic Parkinson's disease (PD). Moreover, network modeling procedures, such as spatial covariance analysis, have further allowed for the quantification of these changes at the systems level. In recent years, we have utilized this strategy to identify and validate three discrete metabolic networks in PD associated with the motor and cognitive manifestations of the disease. In this chapter, we will review and compare the specific functional topographies underlying parkinsonian akinesia/rigidity, tremor, and cognitive disturbance. While network activity progressed over time, the rate of change for each pattern was distinctive and paralleled the development of the corresponding clinical symptoms in early-stage patients. This approach is already showing great promise in identifying individuals with prodromal manifestations of PD and in assessing the rate of progression before clinical onset. Network modulation was found to correlate with the clinical effects of dopaminergic treatment and surgical interventions, such as subthalamic nucleus (STN) deep brain stimulation (DBS) and gene therapy. Abnormal metabolic networks have also been identified for atypical parkinsonian syndromes, such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Using multiple disease-related networks for PD, MSA, and PSP, we have developed a novel, fully automated algorithm for accurate classification at the single-patient level, even at early disease stages. Copyright © 2010 Elsevier B.V. All rights reserved.

Ultra-wide-field and autofluorescence imaging of choroidal dystrophies.

PubMed

Yuan, Alex; Kaines, Andrew; Jain, Atul; Reddy, Shantan; Schwartz, Steven D; Sarraf, David

2010-10-28

The authors retrospectively identified 2 cases of gyrate atrophy, 3 cases of choroideremia, and 1 case of the carrier state of choroideremia who underwent ultra-wide-field fundus photography and fluorescein angiography. The findings were studied and compared to standard fundus photography and fluorescein angiography. Gyrate atrophy demonstrated a diffuse confluent extent of chorioretinal atrophy extending from the anterior to the posterior pole to the periphery. Choroideremia demonstrated a patchy irregular pattern of chorioretinal atrophy extending from the posterior pole to the periphery. Peripheral reticular degeneration without chorioretinal atrophy was appreciated in the carrier state. Ultra-wide-field imaging of these choroidal dystrophies demonstrated distinctive patterns that may aid in their identification and diagnosis. Copyright 2010, SLACK Incorporated.

Man Versus Machine Part 2: Comparison of Radiologists' Interpretations and NeuroQuant Measures of Brain Asymmetry and Progressive Atrophy in Patients With Traumatic Brain Injury.

PubMed

Ross, David E; Ochs, Alfred L; DeSmit, Megan E; Seabaugh, Jan M; Havranek, Michael D

2015-01-01

This study is an expanded version of an earlier study, which compared NeuroQuant measures of MRI brain volume with the radiologist's traditional approach in outpatients with mild or moderate traumatic brain injury. NeuroQuant volumetric analyses were compared with the radiologists' interpretations. NeuroQuant found significantly higher rates of atrophy (50.0%), abnormal asymmetry (83.3%), and progressive atrophy (70.0%) than the radiologists (12.5%, 0% and 0%, respectively). Overall, NeuroQuant was more sensitive for detecting at least one sign of atrophy, abnormal asymmetry, or progressive atrophy (95.8%) than the traditional radiologist's approach (12.5%).

Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition.

PubMed

MacDonald, Elizabeth M; Andres-Mateos, Eva; Mejias, Rebeca; Simmers, Jessica L; Mi, Ruifa; Park, Jae-Sung; Ying, Stephanie; Hoke, Ahmet; Lee, Se-Jin; Cohn, Ronald D

2014-04-01

The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mouse induces profound muscle hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and denervation (sciatic nerve resection) atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from disuse atrophy is regulated by serum and glucocorticoid-induced kinase (SGK) rather than by Akt. Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the atrophy phenotype. Additionally, rapamycin prevented the denervation-induced upregulation of the mTORC2 substrates Akt and SGK. Thus, our studies show that denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy.

Early metabolic crisis-related brain atrophy and cognition in traumatic brain injury.

PubMed

Wright, Matthew J; McArthur, David L; Alger, Jeffry R; Van Horn, Jack; Irimia, Andrei; Filippou, Maria; Glenn, Thomas C; Hovda, David A; Vespa, Paul

2013-09-01

Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as 'frontal-temporal' in nature, suggesting a possible link between acute metabolic crisis-related brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis-related brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis-related atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors.

The influence of exercise on bone atrophy

NASA Technical Reports Server (NTRS)

1978-01-01

The relationship between the skeletal system, the muscular system, and exercise in bed rest studies are described. The regime of exercises performed, the mineral balance data derived, and the bone densitometric data obtained are discussed. A brief review of some of the histological results are also given.

Chaos theory for clinical manifestations in multiple sclerosis.

PubMed

Akaishi, Tetsuya; Takahashi, Toshiyuki; Nakashima, Ichiro

2018-06-01

Multiple sclerosis (MS) is a demyelinating disease which characteristically shows repeated relapses and remissions irregularly in the central nervous system. At present, the pathological mechanism of MS is unknown and we do not have any theories or mathematical models to explain its disseminated patterns in time and space. In this paper, we present a new theoretical model from a viewpoint of complex system with chaos model to reproduce and explain the non-linear clinical and pathological manifestations in MS. First, we adopted a discrete logistic equation with non-linear dynamics to prepare a scalar quantity for the strength of pathogenic factor at a specific location of the central nervous system at a specific time to reflect the negative feedback in immunity. Then, we set distinct minimum thresholds in the above-mentioned scalar quantity for demyelination possibly causing clinical relapses and for cerebral atrophy. With this simple model, we could theoretically reproduce all the subtypes of relapsing-remitting MS, primary progressive MS, and secondary progressive MS. With the sensitivity to initial conditions and sensitivity to minute change in parameters of the chaos theory, we could also reproduce the spatial dissemination. Such chaotic behavior could be reproduced with other similar upward-convex functions with appropriate set of initial conditions and parameters. In conclusion, by applying chaos theory to the three-dimensional scalar field of the central nervous system, we can reproduce the non-linear outcome of the clinical course and explain the unsolved disseminations in time and space of the MS patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

Visual Evoked Potential and Magnetic Resonance Imaging are More Effective Markers of Multiple Sclerosis Progression than Laser Polarimetry with Variable Corneal Compensation.

PubMed

Kantorová, Ema; Ziak, Peter; Kurča, Egon; Koyšová, Mária; Hladká, Mária; Zeleňák, Kamil; Michalik, Jozef

2014-01-01

The aim of our study was to assess the role of laser polarimetry and visual evoked potentials (VEP) as potential biomarkers of disease progression in multiple sclerosis (MS). A total of 41 patients with MS (82 eyes) and 22 age-related healthy volunteers (44 eyes) completed the study. MS patients were divided into two groups, one (ON) with a history of optic neuritis (17 patients, 34 eyes) and another group (NON) without it (24 patients, 48 eyes). The MS patients and controls underwent laser polarimetry (GDx) examination of the retinal nerve fiber layer (RNFL). In the MS group, we also examined: Kurtzke "expanded disability status scale" (EDSS), the duration of the disorder, VEP - latency and amplitude, and conventional brain magnetic resonance imaging (MRI). Our results were statistically analyzed using ANOVA, Mann-Whitney, and Spearman correlation analyses. In the MS group, brain atrophy and new T2 brain lesions in MRI correlated with both VEP latencies and amplitudes. Separate comparisons revealed VEP latency testing to be less sensitive in ON than in NON-patients. In ON patients, VEP amplitudes correlated mildly with brain atrophy (r = -0.15) and strongly with brain new MRI lesions (r = -0.8). In NON-patients, highly significant correlation of new MRI brain lesions with VEP latencies (r = 0.63, r = 0.6) and amplitudes (r = -0.3, r = -4.2) was found. EDSS also correlated with brain atrophy in this group (r = 0.5). Our study did not find a correlation of GDx measures with MRI tests. The GDx method was not able to detect whole brain demyelinization and the degeneration process, but was only able to reveal the involvement of optic nerves in ON and NON-patients. In our study, we found that both methods (VEP and GDx) can be used for the detection of optic nerve damage, but VEP was found to be superior in evaluating whole brain demyelinization and axonal degeneration. Both VEP and MRI, but not GDx, have an important role in monitoring disease progression in MS patients, independent of the ON history.

Counting or Chunking?

PubMed Central

Spotorno, Nicola; McMillan, Corey T.; Powers, John P.; Clark, Robin; Grossman, Murray

2014-01-01

A growing amount of empirical data is showing that the ability to manipulate quantities in a precise and efficient fashion is rooted in cognitive mechanisms devoted to specific aspects of numbers processing. The Analog number system (ANS) has a reasonable representation of quantities up to about 4, and represents larger quantities on the basis of a numerical ratio between quantities. In order to represent the precise cardinality of a number, the ANS may be supported by external algorithms such as language, leading to a “Precise Number System”. In the setting of limited language, other number-related systems can appear. For example the Parallel Individuation system (PIS) supports a “chunking mechanism” that clusters units of larger numerosities into smaller subsets. In the present study we investigated number processing in non-aphasic patients with Corticobasal Syndrome (CBS) and Posterior Cortical Atrophy (PCA), two neurodegenerative conditions that are associated with progressive parietal atrophy. The present study investigated these number systems in CBS and PCA by assessing the property of the ANS associated with smaller and larger numerosities, and the chunking property of the PIS. The results revealed that CBS/PCA patients are impaired in simple calculations (e.g., addition and subtraction) and that their performance strongly correlates with the size of the numbers involved in these calculations, revealing a clear magnitude effect. This magnitude effect correlated with gray matter atrophy in parietal regions. Moreover, a numeral-dots transcoding task showed that CBS/PCA patients are able to take advantage of clustering in the spatial distribution of the dots of the array. The relative advantage associated with chunking compared to a random spatial distribution correlated with both parietal and prefrontal regions. These results shed light on the properties of systems for representing number knowledge in non-aphasic patients with CBS and PCA. PMID:25278132

iss028e034978

NASA Image and Video Library

2011-08-30

ISS028-E-034978 (30 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, performs in-flight maintenance on the Muscle Atrophy Research & Exercise System (MARES) in the Columbus laboratory of the International Space Station.

iss028e034993

NASA Image and Video Library

2011-08-30

ISS028-E-034993 (30 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, performs in-flight maintenance on the Muscle Atrophy Research & Exercise System (MARES) in the Columbus laboratory of the International Space Station.

iss028e034980

NASA Image and Video Library

2011-08-30

ISS028-E-034980 (30 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, performs in-flight maintenance on the Muscle Atrophy Research & Exercise System (MARES) in the Columbus laboratory of the International Space Station.

iss028e035002

NASA Image and Video Library

2011-08-30

ISS028-E-035002 (30 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, performs in-flight maintenance on the Muscle Atrophy Research & Exercise System (MARES) in the Columbus laboratory of the International Space Station.

MARES Payload Installation

NASA Image and Video Library

2010-09-16

ISS024-E-014952 (16 Sept. 2010) --- NASA astronaut Doug Wheelock, Expedition 24 flight engineer, works with Muscle Atrophy Resistive Exercise System (MARES) hardware during installation of MARES payload in the Columbus laboratory of the International Space Station.

MARES Payload Installation

NASA Image and Video Library

2010-09-16

ISS024-E-014934 (16 Sept. 2010) --- NASA astronaut Shannon Walker, Expedition 24 flight engineer, works with Muscle Atrophy Resistive Exercise System (MARES) hardware during installation of MARES payload in the Columbus laboratory of the International Space Station.

MARES Payload Installation

NASA Image and Video Library

2010-09-16

ISS024-E-014956 (16 Sept. 2010) --- NASA astronaut Shannon Walker, Expedition 24 flight engineer, works with Muscle Atrophy Resistive Exercise System (MARES) hardware during installation of MARES payload in the Columbus laboratory of the International Space Station.

iss028e034984

NASA Image and Video Library

2011-08-30

ISS028-E-034984 (30 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, performs in-flight maintenance on the Muscle Atrophy Research & Exercise System (MARES) in the Columbus laboratory of the International Space Station.

MARES Payload Installation

NASA Image and Video Library

2010-09-16

ISS024-E-014930 (16 Sept. 2010) --- NASA astronaut Doug Wheelock, Expedition 24 flight engineer, works with Muscle Atrophy Resistive Exercise System (MARES) hardware during installation of MARES payload in the Columbus laboratory of the International Space Station.

MARES Payload Installation

NASA Image and Video Library

2010-09-16

ISS024-E-014981 (17 Sept. 2010) --- NASA astronaut Shannon Walker, Expedition 24 flight engineer, works with Muscle Atrophy Resistive Exercise System (MARES) hardware during installation of MARES payload in the Columbus laboratory of the International Space Station.

MARES Payload Installation

NASA Image and Video Library

2010-09-16

ISS024-E-014973 (17 Sept. 2010) --- NASA astronaut Doug Wheelock, Expedition 24 flight engineer, works with Muscle Atrophy Resistive Exercise System (MARES) hardware during installation of MARES payload in the Columbus laboratory of the International Space Station.

iss028e034992

NASA Image and Video Library

2011-08-30

ISS028-E-034992 (30 Aug. 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, performs in-flight maintenance on the Muscle Atrophy Research & Exercise System (MARES) in the Columbus laboratory of the International Space Station.

iss028e035617

NASA Image and Video Library

2011-08-31

ISS028-E-035617 (31 Aug. 2011) --- Japan Aerospace Exploration Agency astronaut Satoshi Furukawa, Expedition 28 flight engineer, works with Muscle Atrophy Research & Exercise System (MARES) hardware in the Columbus laboratory of the International Space Station.

MARES Payload Installation

NASA Image and Video Library

2010-09-16

ISS024-E-014979 (17 Sept. 2010) --- NASA astronaut Doug Wheelock, Expedition 24 flight engineer, works with Muscle Atrophy Resistive Exercise System (MARES) hardware during installation of MARES payload in the Columbus laboratory of the International Space Station.

Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy

PubMed Central

Chua, Jason P.; Lieberman, Andrew P.

2014-01-01

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work. These model systems have revealed critical aspects of the disease, including its hormone dependence, a feature that underlies disease occurrence only in men with the mutant allele. We discuss how this and other findings have been translated to clinical trials for SBMA patients, and examine emerging therapeutic targets that have been identified by recent work. PMID:24040817

Retinal Oximetry Discovers Novel Biomarkers in Retinal and Brain Diseases.

PubMed

Stefánsson, Einar; Olafsdottir, Olof Birna; Einarsdottir, Anna Bryndis; Eliasdottir, Thorunn Scheving; Eysteinsson, Thor; Vehmeijer, Wouter; Vandewalle, Evelien; Bek, Toke; Hardarson, Sveinn Hakon

2017-05-01

Biomarkers for several eye and brain diseases are reviewed, where retinal oximetry may help confirm diagnosis or measure severity of disease. These include diabetic retinopathy, central retinal vein occlusion (CRVO), retinitis pigmentosa, glaucoma, and Alzheimer's disease. Retinal oximetry is based on spectrophotometric fundus imaging and measures oxygen saturation in retinal arterioles and venules in a noninvasive, quick, safe manner. Retinal oximetry detects changes in oxygen metabolism, including those that result from ischemia or atrophy. In diabetic retinopathy, venous oxygen saturation increases and arteriovenous difference decreases. Both correlate with diabetic retinopathy severity as conventionally classified on fundus photographs. In CRVO, vein occlusion causes hypoxia, which is measured directly by retinal oximetry to confirm the diagnosis and measure severity. In both diseases, the change in oxygen levels is a consequence of disturbed blood flow with resulting tissue hypoxia and vascular endothelial growth factor (VEGF) production. In atrophic diseases, such as retinitis pigmentosa and glaucoma, retinal oxygen consumption is reduced and this is detected by retinal oximetry. Retinal oximetry correlates with visual field damage and retinal atrophy. It is an objective metabolic measure of the degree of retinal atrophy. Finally, the retina is part of the central nervous system tissue and reflects central nervous system diseases. In Alzheimer's disease, a change in retinal oxygen metabolism has been discovered. Retinal oximetry is a novel, noninvasive technology that opens the field of metabolic imaging of the retina. Biomarkers in metabolic, ischemic, and atrophic diseases of the retina and central nervous system have been discovered.

Gray matter atrophy in patients with mild cognitive impairment/Alzheimer's disease over the course of developing delusions.

PubMed

Fischer, Corinne E; Ting, Windsor Kwan-Chun; Millikin, Colleen P; Ismail, Zahinoor; Schweizer, Tom A

2016-01-01

We conducted a neuroimaging analysis to understand the neuroanatomical correlates of gray matter loss in a group of mild cognitive impairment and early Alzheimer's disease patients who developed delusions. With data collected as part of the Alzheimer's Disease Neuroimaging Initiative, we conducted voxel-based morphometry to determine areas of gray matter change in the same Alzheimer's Disease Neuroimaging Initiative participants, before and after they developed delusions. We identified 14 voxel clusters with significant gray matter decrease in patient scans post-delusional onset, correcting for multiple comparisons (false discovery rate, p < 0.05). Major areas of difference included the right and left insulae, left precuneus, the right and left cerebellar culmen, the left superior temporal gyrus, the right posterior cingulate, the right thalamus, and the left parahippocampal gyrus. Although contrary to our initial predictions of enhanced right frontal atrophy, our preliminary work identifies several neuroanatomical areas, including the cerebellum and left posterior hemisphere, which may be involved in delusional development in these patients. Copyright © 2015 John Wiley & Sons, Ltd.

On the history of lacunes, etat criblé, and the white matter lesions of vascular dementia.

PubMed

Román, Gustavo C

2002-01-01

The history of lesions associated with vascular dementia (17th to 19th century) is reviewed. Recognition of ischemic and hemorrhagic stroke types dates back to the 17th century; however, at that time a third type ('cerebral congestion') emerged as the most common form of apoplexy. This entity vanished as arterial hypertension became established with the introduction of the sphygmomanometer (1905). Before the 19th century, apoplexy was considered a uniformly fatal disease, although Willis first recognized post-stroke dementia in 1672. Dechambre (1838) first reported 'lacunes' in stroke survivors with small cerebral softenings. Durand-Fardel (1842) described interstitial atrophy of the brain (leukoaraiosis) and état criblé (cribriform state) reflecting chronic cerebral congestion. In 1894, Alzheimer and Binswanger identified 'arteriosclerotic brain atrophy,' a form of vascular dementia characterized by 'miliary apoplexies' (lacunes). Also in 1894, Binswanger described the disease that now bears his name. In 1901, Pierre Marie coined the name état lacunaire (lacunar state) for the clinical syndrome of elderly patients with multiple lacunes. Copyright 2002 S. Karger AG, Basel

Juvenile muscular atrophy of the distal upper extremities associated with x-linked periventricular heterotopia with features of Ehlers-Danlos syndrome.

PubMed

Hommel, Alyson L; Jewett, Tamison; Mortenson, Megan; Caress, James B

2016-10-01

Juvenile muscular atrophy of the distal upper extremities (JMADUE) is a rare, sporadic disorder that affects adolescent males and is characterized by progressive but self-limited weakness of the distal upper extremities. The etiology is unknown, but cervical hyperflexion has been hypothesized. We report a case of an adolescent male who presented with typical JMADUE but also had joint hypermobility and multiple congenital anomalies, including periventricular heterotopias, suggesting a multisystem syndrome. Subsequent diagnostic testing confirmed a diagnosis of JMADUE, and sequencing of the filamin-A gene showed a novel, pathogenic mutation that confirmed an additional diagnosis of X-linked periventricular heterotopias with features of Ehlers-Danlos syndrome (XLPH-EDS). The concurrent diagnosis of these 2 rare conditions suggests a pathogenic connection. It is likely that the joint hypermobility from XLPH-EDS predisposed this patient to developing JMADUE. This supports the cervical hyperflexion theory of pathogenesis. This case also expands the phenotype associated with FLNA mutations. Muscle Nerve 54: 794-797, 2016. © 2016 Wiley Periodicals, Inc.

Multiple fractures and impaired bone metabolism in Wolfram syndrome: a case report.

PubMed

Catalano, Antonino; Bellone, Federica; Cicala, Giuseppe; Giandalia, Annalisa; Morabito, Nunziata; Cucinotta, Domenico; Russo, Giuseppina Tiziana

2017-01-01

Wolfram Syndrome (WS) is a rare and lethal disease characterized by optic atrophy, diabetes mellitus, diabetes insipidus, and hearing loss. To date, osteoporotic related fractures have not been reported in affected patients. Here, we describe the case of a man affected by WS complicated by several bone fragility fractures. A 50-year-old Caucasian man was hospitalized because of tibia and fibula fractures. His clinical features included diabetes mellitus, diabetes insipidus, optic atrophy and deafness that were consistent with an unrecognized WS diagnosis, which was confirmed by the identification of a specific mutation in gene WFS1 encoding wolframin. Bone mineral density by phalangeal quantitative ultrasound demonstrated severe osteoporosis, with high serum levels of surrogate markers of bone turn-over. Previously unidentified rib fractures were also detected. To the best of our knowledge, this is the first report of osteoporotic related fractures in a patient affected by WS. Although no effective treatments are currently available to delay the progression of the disease, this case report suggests to evaluate fracture risk in the diagnostic work-up of WS.

Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS.

PubMed

Da Cruz, Sandrine; Parone, Philippe A; Lopes, Vanda S; Lillo, Concepción; McAlonis-Downes, Melissa; Lee, Sandra K; Vetto, Anne P; Petrosyan, Susanna; Marsala, Martin; Murphy, Anne N; Williams, David S; Spiegelman, Bruce M; Cleveland, Don W

2012-05-02

The transcriptional coactivator PGC-1α induces multiple effects on muscle, including increased mitochondrial mass and activity. Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, adult-onset neurodegenerative disorder characterized by selective loss of motor neurons and skeletal muscle degeneration. An early event is thought to be denervation-induced muscle atrophy accompanied by alterations in mitochondrial activity and morphology within muscle. We now report that elevation of PGC-1α levels in muscles of mice that develop fatal paralysis from an ALS-causing SOD1 mutant elevates PGC-1α-dependent pathways throughout disease course. Mitochondrial biogenesis and activity are maintained through end-stage disease, accompanied by retention of muscle function, delayed muscle atrophy, and significantly improved muscle endurance even at late disease stages. However, survival was not extended. Therefore, muscle is not a primary target of mutant SOD1-mediated toxicity, but drugs increasing PGC-1α activity in muscle represent an attractive therapy for maintaining muscle function during progression of ALS. Copyright © 2012 Elsevier Inc. All rights reserved.