Frisoni, G B; Beltramello, A; Geroldi, C; Weiss, C; Bianchetti, A; Trabucchi, M
OBJECTIVES--To evaluate the pattern of regional brain atrophy in patients with frontotemporal dementia by comparing it with that in patients with Alzheimer's disease and normal controls. METHODS--Fourteen patients with frontotemporal dementia, 13 with moderate, and 33 with mild Alzheimer's disease, and 31 controls were studied. Atrophy was evaluated with linear measures in the anterior brain, medial temporal lobe, and hippocampal formation regions using MRI. RESULTS--Patients with frontotemporal dementia had greater atrophy in the anterior brain regions than patients with Alzheimer's disease or controls. Atrophy of the hippocampal formation, which best discriminates Alzheimer's disease from controls, was present also in patients with frontotemporal dementia. By contrast, atrophy of the medial temporal lobe, which is also present in Alzheimer's disease, was absent in frontotemporal dementia. CONCLUSION--A pattern of atrophy in the frontal lobes and hippocampal formation with sparing of the medial temporal lobe might be distinctive of frontotemporal dementia. Hippocampal involvement might not be specific for Alzheimer's disease and specific patterns of atrophy might be distinctive of some forms of degenerative dementia. Images PMID:8708683
Boxer, Adam L.
Opinion statement Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative diseases with heterogeneous clinical presentations and two predominant types of underlying neuropathology. FTD typically comprises three distinct clinical syndromes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA). FTD also frequently overlaps both clinically and neuropathologically with three other neurodegenerative syndromes: corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). Each syndrome can be associated with one or more underlying neuropathological diagnoses and are referred to as frontotemporal lobar degeneration (FTLD). Although the various FTD syndromes can substantially differ in terms of clinical symptoms and underlying pathology, the symptoms can be broadly categorized into behavioral, cognitive and motor domains. Currently there are no Food and Drug Administration (FDA) approved therapies for the above syndromes except riluzole for ALS. FTD treatment strategies generally rely on off-label use of medications for symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. For behavioral symptoms, selective serotonin reuptake inhibitors may be effective, while case reports hint at possible efficacy with antipsychotics or antiepileptics, but use of these latter agents is limited due to concerns regarding side effects. There are no effective therapies for cognitive complaints in FTD, which frequently involve executive function, memory, and language. Motor difficulties associated with FTD may present with parkinsonian symptoms or motor neuron disease, for which riluzole is indicated as therapy. Compared to idiopathic Parkinson’s disease, FTD-related atypical parkinsonism is generally not responsive to dopamine replacement therapies, but a
MacKinley, Julia; Blair, Mervin; Oliver, Lindsay D.; Jesso, Sarah; Tartaglia, Maria C.; Borrie, Michael; Wells, Jennie; Dziobek, Isabel; Pasternak, Stephen; Mitchell, Derek G.V.; Rankin, Katherine; Kertesz, Andrew; Boxer, Adam
Objective: To determine the safety and tolerability of 3 doses of intranasal oxytocin (Syntocinon; Novartis, Bern, Switzerland) administered to patients with frontotemporal dementia (FTD). Methods: We conducted a randomized, parallel-group, double-blind, placebo-controlled study using a dose-escalation design to test 3 clinically feasible doses of intranasal oxytocin (24, 48, or 72 IU) administered twice daily for 1 week to 23 patients with behavioral variant FTD or semantic dementia (clinicaltrials.gov registration number NCT01386333). Primary outcome measures were safety and tolerability at each dose. Secondary measures explored efficacy across the combined oxytocin vs placebo groups and examined potential dose-related effects. Results: All 3 doses of intranasal oxytocin were safe and well tolerated. Conclusions: A multicenter trial is warranted to determine the therapeutic efficacy of long-term intranasal oxytocin for behavioral symptoms in FTD. Classification of evidence: This study provides Class I evidence that for patients with FTD, intranasal oxytocin is not significantly associated with adverse events or significant changes in the overall neuropsychiatric inventory. PMID:25503617
Burrell, James R; Kiernan, Matthew C; Vucic, Steve; Hodges, John R
Frontotemporal dementia and motor neuron disease share clinical, genetic and pathological characteristics. Motor neuron disease develops in a proportion of patients with frontotemporal dementia, but the incidence, severity and functional significance of motor system dysfunction in patients with frontotemporal dementia has not been determined. Neurophysiological biomarkers have been developed to document motor system dysfunction including: short-interval intracortical inhibition, a marker of corticospinal motor neuron dysfunction and the neurophysiological index, a marker of lower motor neuron dysfunction. The present study performed detailed clinical and neurophysiological assessments on 108 participants including 40 consecutive patients with frontotemporal dementia, 42 age- and gender-matched patients with motor neuron disease and 26 control subjects. Of the 40 patients with frontotemporal dementia, 12.5% had concomitant motor neuron disease. A further 27.3% of the patients with frontotemporal dementia had clinical evidence of minor motor system dysfunction such as occasional fasciculations, mild wasting or weakness. Biomarkers of motor system function were abnormal in frontotemporal dementia. Average short-interval intracortical inhibition was reduced in frontotemporal dementia (4.3 ± 1.7%) compared with controls (9.1 ± 1.1%, P < 0.05). Short-interval intracortical inhibition was particularly reduced in the progressive non-fluent aphasia subgroup, but was normal in patients with behavioural variant frontotemporal dementia and semantic dementia. The neurophysiological index was reduced in frontotemporal dementia (1.1) compared with controls (1.9, P < 0.001), indicating a degree of lower motor neuron dysfunction, although remained relatively preserved when compared with motor neuron disease (0.7, P < 0.05). Motor system dysfunction in frontotemporal dementia may result from pathological involvement of the primary motor cortex, with secondary
Ibáñez, Agustín; Velásquez, María Marcela; Caro, Miguel Martorell; Manes, Facundo
The preserved "implicit awareness" in patients with Alzheimer disease (AD) presenting anosognosia has opened a new branch of research regarding explicit-implicit integration. The behavioral variant of frontotemporal dementia (bvFTD), contrary to AD, would present impaired anosognosia-related implicit awareness due to a dysfunctional implicit integration of contextual information caused by an abnormal fronto-insular-temporal network. Loss of insight and anosognosia are pervasive in bvFTD, but no reports have assessed the implicit emotional awareness in this condition. We emphasize the need to investigate and extend our knowledge of implicit contextual integration impairments and their relation with anosognosia in bvFTD vs AD.
Halabi, Cathra; Halabi, Anasheh; Dean, David L.; Wang, Pei-Ning; Boxer, Adam L.; Trojanowski, John Q.; DeArmond, Stephen J.; Miller, Bruce L.; Kramer, Joel H.; Seeley, William W.
Behavioral variant frontotemporal dementia and semantic dementia have been associated with striatal degeneration, but few studies have delineated striatal subregion volumes in vivo or related them to clinical phenotype. We traced caudate, putamen, and nucleus accumbens on MR images to quantify volumes of these structures in behavioral variant frontotemporal dementia, semantic dementia, Alzheimer’s disease, and healthy controls (n = 12 per group). We further related these striatal volumes to clinical deficits and neuropathological findings in a subset of patients. Behavioral variant frontotemporal dementia and semantic dementia showed significant overall striatal atrophy compared with controls. Moreover, behavioral variant frontotemporal dementia showed panstriatal degeneration whereas semantic dementia featured a more focal pattern involving putamen and accumbens. Right-sided striatal atrophy, especially in the putamen, correlated with overall behavioral symptom severity and with specific behavioral domains. At autopsy, patients with behavioral variant frontotemporal dementia and semantic dementia showed striking and severe tau or TAR DNA-binding protein of 43 kDa pathology, especially in ventral parts of the striatum. These results demonstrate that ventral striatum degeneration is a prominent shared feature in behavioral variant frontotemporal dementia and semantic dementia and may contribute to social-emotional deficits common to both disorders. PMID:22367382
Rosso, S M; Heutink, P; Tibben, A; Niermeijer, M F; van Swieten, J C
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterised by progressive behavioural disturbance, aphasia and a decline in frontal cognitive functions. Frontotemporal atrophy on CT and MRI, and hypoperfusion of the frontal brain regions on single-photon emission computed tomography (SPECT), are characteristic findings. Neuropathological examination reveals deposition of abnormally phosphorylated tau protein in neurons and glial cells in a number of the sporadic and familial cases, while aspecific changes with neuronal loss, spongiosis and gliosis are found in the remaining cases. A familial form with an autosomal dominant pattern of inheritance is seen in 20% of FTD patients. Mutations in the tau gene have been identified in a number of families with deposition of abnormal tau protein in affected brain regions. Presymptomatic DNA testing is now available for relatives of patients with tau mutations, but must only be considered after extensive genetic counselling in a centre with neurogenetic expertise.
... the hallmark of Alzheimer’s disease is loss of memory. FTD often begins earlier than AD with an ... their own behaviors), but retain cardinal features of memory (keeping track of day-to-day events, orientation ...
Repetto, Claudia; Manenti, Rosa; Cappa, Stefano; Miniussi, Carlo; Riva, Giuseppe
Modifications of language processing can be observed both in normal aging and in the most common forms of degenerative dementia, such as Alzheimer's disease and the spectrum of frontotemporal dementias. The present experiment tests at the same time semantic and syntactic aspects of language processing in patients with frontotemporal dementia, using an online paradigm that allows researchers to evaluate the real linguistic competence of the patients.
Downey, Laura E; Blezat, Alice; Nicholas, Jennifer; Omar, Rohani; Golden, Hannah L; Mahoney, Colin J; Crutch, Sebastian J; Warren, Jason D
Despite considerable recent interest, the biological basis and clinical diagnosis of behavioural variant frontotemporal dementia (bvFTD) pose unresolved problems. Mentalising (the cognitive capacity to interpret the behaviour of oneself and others in terms of mental states) is impaired as a prominent feature of bvFTD, consistent with involvement of brain regions including ventro-medial prefrontal cortex (PFC), orbitofrontal cortex and anterior temporal lobes. Here, we investigated mentalising ability in a cohort of patients with bvFTD using a novel modality: music. We constructed a novel neuropsychological battery requiring attribution of affective mental or non-mental associations to musical stimuli. Mentalising performance of patients with bvFTD (n = 20) was assessed in relation to matched healthy control subjects (n = 20); patients also had a comprehensive assessment of behaviour and general neuropsychological functions. Neuroanatomical correlates of performance on the experimental tasks were investigated using voxel-based morphometry of patients' brain magnetic resonance imaging (MRI) scans. Compared to healthy control subjects, patients showed impaired ability to attribute mental states but not non-mental characteristics to music, and this deficit correlated with performance on a standard test of social inference and with carer ratings of patients' empathic capacity, but not with other potentially relevant measures of general neuropsychological function. Mentalising performance in the bvFTD group was associated with grey matter changes in anterior temporal lobe and ventro-medial PFC. These findings suggest that music can represent surrogate mental states and the ability to construct such mental representations is impaired in bvFTD, with potential implications for our understanding of the biology of bvFTD and human social cognition more broadly.
Downey, Laura E.; Blezat, Alice; Nicholas, Jennifer; Omar, Rohani; Golden, Hannah L.; Mahoney, Colin J.; Crutch, Sebastian J.; Warren, Jason D.
Despite considerable recent interest, the biological basis and clinical diagnosis of behavioural variant frontotemporal dementia (bvFTD) pose unresolved problems. Mentalising (the cognitive capacity to interpret the behaviour of oneself and others in terms of mental states) is impaired as a prominent feature of bvFTD, consistent with involvement of brain regions including ventro-medial prefrontal cortex (PFC), orbitofrontal cortex and anterior temporal lobes. Here, we investigated mentalising ability in a cohort of patients with bvFTD using a novel modality: music. We constructed a novel neuropsychological battery requiring attribution of affective mental or non-mental associations to musical stimuli. Mentalising performance of patients with bvFTD (n = 20) was assessed in relation to matched healthy control subjects (n = 20); patients also had a comprehensive assessment of behaviour and general neuropsychological functions. Neuroanatomical correlates of performance on the experimental tasks were investigated using voxel-based morphometry of patients' brain magnetic resonance imaging (MRI) scans. Compared to healthy control subjects, patients showed impaired ability to attribute mental states but not non-mental characteristics to music, and this deficit correlated with performance on a standard test of social inference and with carer ratings of patients' empathic capacity, but not with other potentially relevant measures of general neuropsychological function. Mentalising performance in the bvFTD group was associated with grey matter changes in anterior temporal lobe and ventro-medial PFC. These findings suggest that music can represent surrogate mental states and the ability to construct such mental representations is impaired in bvFTD, with potential implications for our understanding of the biology of bvFTD and human social cognition more broadly. PMID:23107380
D’Alton, Simon; Lewis, Jada
In the search for therapeutic modifiers, frontotemporal dementia (FTD) has traditionally been overshadowed by other conditions such as Alzheimer’s disease (AD). A clinically and pathologically diverse condition, FTD has been galvanized by a number of recent discoveries such as novel genetic variants in familial and sporadic forms of disease and the identification of TAR DNA binding protein of 43 kDa (TDP-43) as the defining constituent of inclusions in more than half of cases. In combination with an ever-expanding knowledge of the function and dysfunction of tau—a protein which is pathologically aggregated in the majority of the remaining cases—there exists a greater understanding of FTD than ever before. These advances may indicate potential approaches for the development of hypothetical therapeutics, but FTD remains highly complex and the roles of tau and TDP-43 in neurodegeneration are still wholly unclear. Here the challenges facing potential therapeutic strategies are discussed, which include sufficiently accurate disease diagnosis and sophisticated technology to deliver effective therapies. PMID:25191265
Wood, Kristie A.; Beagle, Alexander J.; Hsu, Ming; Kayser, Andrew S.; Miller, Bruce L.; Kramer, Joel H.
Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients’ subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer’s disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders. PMID:26667277
Ng, Adeline SL; Rademakers, Rosa; Miller, BL
The concept that frontotemporal dementia (FTD) is a purely “cortical” dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery of the C9ORF72 locus as responsible for majority of hereditary FTD, ALS and FTD-ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE) given its association with TDP-43 pathology, increased dementia risk and reports of ALS in CTE patients. Additionally we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget’s disease and frontotemporal dementia (IBMPFD). PMID:25557955
Nakamagoe, Kiyotaka; Kadono, Kotarou; Koganezawa, Tadachika; Takiguchi, Mao; Terada, Makoto; Yamamoto, Fumiko; Moriyama, Tetsuya; Yanagiha, Kumi; Nohara, Seitaro; Tozaka, Naoki; Miyake, Zenshi; Aizawa, Satoshi; Furusho, Kentaro; Tamaoka, Akira
Background No studies to date have attempted to evaluate frontotemporal lobar degeneration from the perspective of the vestibular system. Objective The present study examined vestibular function in patients with frontotemporal dementia (FTD) clinical syndrome and evaluated whether vestibular disorders are involved in the clinical symptoms due to FTD. Methods Fourteen patients with FTD syndrome, as well as healthy elderly controls without dementia, were included in the present study. All subjects underwent vestibular function tests using electronystagmography, such as caloric tests and visual suppression (VS) tests, in which the induced caloric nystagmus was suppressed by visual stimuli. The association between clinical symptoms and vestibular function in the FTD syndrome group was further examined. Results In the FTD syndrome group, caloric nystagmus was not necessarily suppressed during VS tests. Furthermore, VS was observed to be significantly impaired in FTD syndrome patients with gait disturbance as compared to those without such disturbance. Conclusion The present study revealed that impairment of VS in patients with FTD results in an inability to regulate vestibular function by means of visual perception, regardless of multiple presumed neuropathological backgrounds. This could also be associated with gait disturbance in patients with FTD syndrome. PMID:27350780
Benussi, Alberto; Padovani, Alessandro; Borroni, Barbara
Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease. PMID:26388768
Mioshi, Eneida; Foxe, David; Leslie, Felicity; Savage, Sharon; Hsieh, Sharpley; Miller, Laurie; Hodges, John R; Piguet, Olivier
Caregiver burden is greater in frontotemporal dementia (FTD) than in Alzheimer disease (AD). However, little is known of the impact of the 3 main clinical variants of FTD- behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SemDem), and progressive nonfluent aphasia (PNFA)-or the role of disease severity in caregiver burden. The Zarit Burden Inventory was used to measure caregiver burden of bvFTD (n=17), SemDem (n=20), PNFA (n=20), and AD (n=19) patients. Symptom duration, caregiver age, and relationship type were matched across groups. Moreover, a number of caregiver (mood, social network) and patient variables (functional disability, behavioral changes, relationship with caregiver, and dementia stage) were addressed to investigate their impact on caregiver burden. Caregivers of bvFTD patients reported the highest burden, whereas SemDem and PNFA caregivers reported burden similar to AD. A regression analysis revealed that caregiver burden in FTD, regardless of subtype, was explained by a model combining disease staging, relationship changes, and caregiver depression. Burden increased with disease severity in FTD. This study is the first to show that caregivers of SemDem, PNFA, and AD patients show similar burden, while confirming that bvFTD caregivers show higher burden than AD caregivers. More importantly, this study demonstrates that burden worsens with disease progression in FTD.
Bott, Nicholas T; Radke, Anneliese; Stephens, Melanie L; Kramer, Joel H
Summary Frontotemporal dementia (FTD) is a progressive neurologic syndrome with diverse clinical presentations and attendant underlying pathologies. Psychiatric prodrome, neuropsychiatric symptoms and language difficulties are common in FTD, but the diversity of presentation raises unique diagnostic challenges that can significantly impact patient care and counsel for caregivers regarding clinical status and prognosis. While neuropsychiatric symptom measures are helpful, more sensitive assessments delineating the specific behavioral and linguistic deficits accompanying FTD are needed. Comprehensive clinical assessment in combination with evaluation of language, socio-emotional functioning, cognition and neuroimaging aid in accurate and early diagnosis and treatment planning. In what follows, we review each of the FTD syndromes, highlight current research investigating the cognitive, behavioral and socio-emotional deficits observed with this disease, address common diagnostic challenges and summarize best practices associated with management of FTD. PMID:25531687
Wang, Pan; Zhang, Huihong; Han, Lu
Abstract Objectives Alzheimer’s disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD) are the most common causes of dementia; however, their overlapping clinical syndromes and involved brain regions make a differential diagnosis difficult. We aimed to identify the differences in the cognition and motor cortex excitability between AD and bvFTD patients. Methods Twenty-seven AD patients and 30 bvFTD patients were included in the study. Each participant received a neurological evaluation. Cognitive event-related potentials (P300) were recorded during an auditory oddball task. Next, the excitability of the motor cortex, including the resting, facilitated motor threshold (RMT and FMT) and cortical silent period (CSP), were assessed during transcranial magnetic stimulation (TMS). Results The bvFTD patients exhibited significantly longer P300 latencies compared with AD patients. There was a significant negative correlation between cognition and P300 latency in the bvFTD group. The AD patients showed significantly reduced RMT and FMT values compared to the bvFTD group; however, no significant correlation was found between AD severity and the excitability of the motor cortex. Conclusions Cognition and motor cortical functions are different between AD and bvFTD patients. Noninvasive electrophysiological examinations have the potential to identify unique pathophysiological features that can be used to differentially diagnose AD and bvFTD patients. PMID:28123831
Price, C.C.; Grossman, M.
An on-line ''word detection'' paradigm was used to assess the comprehension of thematic and transitive verb agreements during sentence processing in individuals diagnosed with probable Alzheimer's Disease (AD, n=15) and Frontotemporal Dementia (FTD, n=14). AD, FTD, and control participants (n=17) were asked to listen for a word in a sentence.…
Tampi, Rajesh R.; Maksimowski, Michael; Ahmed, Mohsina; Tampi, Deena J.
Background: The aim of this systematic review is to identify published randomized controlled trials (RCTs) that evaluated the use of oxytocin in individuals with frontotemporal dementia (FTD). Methods: A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases for RCTs in any language that evaluated the use of oxytocin in individuals with FTD. Bibliographic databases of published articles were also searched for additional studies. Results: A total of two RCTs that evaluated the use of oxytocin in individuals with FTD were identified. In one study, the use of oxytocin in individuals with FTD produced a reduction in identification of negative facial expressions (anger and fear) which can be hypothesized to improve trust and increase cooperation in these individuals. Both studies noted oxytocin was well tolerated and showed short term benefits on behavioral symptoms in individuals with FTD. Conclusions: Oxytocin appears to improve social aspects of cognition and behavioral symptoms in individuals with FTD and is well tolerated. However, positive data from larger and longer duration RCTs are needed before the routine use of oxytocin in individuals with FTD can be recommended. PMID:28101324
Roca, María; Manes, Facundo; Gleichgerrcht, Ezequiel; Watson, Peter; Ibáñez, Agustín; Thompson, Russell; Torralva, Teresa; Duncan, John
Recently (Roca et al. (2010), we used the relationship with general intelligence (Spearman’s g) to define two sets of frontal lobe or “executive” tests. For one group, including Wisconsin card sorting and verbal fluency, reduction in g entirely explained the deficits found in frontal patients. For another group, including tests of social cognition and multitasking, frontal deficits remained even after correction for g. Preliminary evidence suggested a link of the latter tasks to more anterior frontal regions. Here we develop this distinction in the context of behavioural-variant frontotemporal dementia (bvFTD), a disorder which progressively affects frontal lobe cortices. In bvFTD, some executive tests, including tests of social cognition and multitasking, decline from the early stage of the disease, while others, including classical executive tests such as Wisconsin card sorting, verbal fluency or Trail Making Test part B, show deficits only later on. Here we show that, while deficits in the classical executive tests are entirely explained by g, deficits in the social cognition and multitasking tests are not. The results suggest a relatively selective cognitive deficit at mild stages of the disease, followed by more widespread cognitive decline well predicted by g. PMID:23347963
Siuda, Joanna; Fujioka, Shinsuke; Wszolek, Zbigniew K
Parkinsonism in frontotemporal dementia (FTD) was first described in families with mutations in the microtubule-associated protein tau (MAPT) and progranulin (PRGN) genes. Since then, mutations in several other genes have been identified for FTD with parkinsonism, including chromosome 9 open reading frame 72 (C9ORF72), chromatin modifying protein 2B (CHMP2B), valosin-containing protein (VCP), fused in sarcoma (FUS) and transactive DNA-binding protein (TARDBP). The clinical presentation of patients with familial forms of FTD with parkinsonism is highly variable. The parkinsonism seen in FTD patients is usually characterized by akinetic-rigid syndrome and is mostly associated with the behavioral variant of FTD (bvFTD); however, some cases may present with classical Parkinson's disease. In other cases, atypical parkinsonism resembling progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) has also been described. Although rare, parkinsonism in FTD may coexist with motor neuron disease. Structural neuroimaging, which is crucial for the diagnosis of FTD, shows characteristic patterns of brain atrophy associated with specific mutations. Structural neuroimaging is not helpful in distinguishing among patients with parkinsonian features. Furthermore, dopaminergic imaging that shows nigrostriatal neurodegeneration in FTD with parkinsonism cannot discriminate parkinsonian syndromes that arise from different mutations. Generally, parkinsonism in FTD is levodopa unresponsive, but there have been cases where a temporary benefit has been reported, so dopaminergic treatment is worth trying, especially, when motor and non-motor manifestations can cause significant problems with daily functioning. In this review, we present an update on the clinical and genetic correlations of FTD with parkinsonism.
Baez, Sandra; Manes, Facundo; Huepe, David; Torralva, Teresa; Fiorentino, Natalia; Richter, Fabian; Huepe-Artigas, Daniela; Ferrari, Jesica; Montañes, Patricia; Reyes, Pablo; Matallana, Diana; Vigliecca, Nora S; Decety, Jean; Ibanez, Agustin
Loss of empathy is an early central symptom and diagnostic criterion of the behavioral variant frontotemporal dementia (bvFTD). Although changes in empathy are evident and strongly affect the social functioning of bvFTD patients, few studies have directly investigated this issue by means of experimental paradigms. The current study assessed multiple components of empathy (affective, cognitive and moral) in bvFTD patients. We also explored whether the loss of empathy constitutes a primary deficit of bvFTD or whether it is explained by impairments in executive functions (EF) or other social cognition domains. Thirty-seven bvFTD patients with early/mild stages of the disease and 30 healthy control participants were assessed with a task that involves the perception of intentional and accidental harm. Participants were also evaluated on emotion recognition, theory of mind (ToM), social norms knowledge and several EF domains. BvFTD patients presented deficits in affective, cognitive and moral aspects of empathy. However, empathic concern was the only aspect primarily affected in bvFTD that was neither related nor explained by deficits in EF or other social cognition domains. Deficits in the cognitive and moral aspects of empathy seem to depend on EF, emotion recognition and ToM. Our findings highlight the importance of using tasks depicting real-life social scenarios because of their greater sensitivity in the assessment of bvFTD. Moreover, our results contribute to the understanding of primary and intrinsic empathy deficits of bvFTD and have important theoretical and clinical implications.
Baez, Sandra; Manes, Facundo; Huepe, David; Torralva, Teresa; Fiorentino, Natalia; Richter, Fabian; Huepe-Artigas, Daniela; Ferrari, Jesica; Montañes, Patricia; Reyes, Pablo; Matallana, Diana; Vigliecca, Nora S.; Decety, Jean; Ibanez, Agustin
Loss of empathy is an early central symptom and diagnostic criterion of the behavioral variant frontotemporal dementia (bvFTD). Although changes in empathy are evident and strongly affect the social functioning of bvFTD patients, few studies have directly investigated this issue by means of experimental paradigms. The current study assessed multiple components of empathy (affective, cognitive and moral) in bvFTD patients. We also explored whether the loss of empathy constitutes a primary deficit of bvFTD or whether it is explained by impairments in executive functions (EF) or other social cognition domains. Thirty-seven bvFTD patients with early/mild stages of the disease and 30 healthy control participants were assessed with a task that involves the perception of intentional and accidental harm. Participants were also evaluated on emotion recognition, theory of mind (ToM), social norms knowledge and several EF domains. BvFTD patients presented deficits in affective, cognitive and moral aspects of empathy. However, empathic concern was the only aspect primarily affected in bvFTD that was neither related nor explained by deficits in EF or other social cognition domains. Deficits in the cognitive and moral aspects of empathy seem to depend on EF, emotion recognition and ToM. Our findings highlight the importance of using tasks depicting real-life social scenarios because of their greater sensitivity in the assessment of bvFTD. Moreover, our results contribute to the understanding of primary and intrinsic empathy deficits of bvFTD and have important theoretical and clinical implications. PMID:25346685
Mahoney, Colin J; Simpson, Ivor J A; Nicholas, Jennifer M; Fletcher, Phillip D; Downey, Laura E; Golden, Hannah L; Clark, Camilla N; Schmitz, Nicole; Rohrer, Jonathan D; Schott, Jonathan M; Zhang, Hui; Ourselin, Sebastian; Warren, Jason D; Fox, Nick C
Objective Novel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD). Methods Twenty-three patients with bvFTD (12 having genetic mutations), and 18 age-matched control participants were assessed using DTI and neuropsychological batteries at baseline and ∼1.3 years later. Baseline and follow-up DTI scans were registered using a groupwise approach. Annualized rates of change for DTI metrics, neuropsychological measures, and whole brain volume were calculated. DTI metric performances were compared, and sample sizes for potential clinical trials were calculated. Results In the bvFTD group as a whole, rates of change in fractional anisotropy (FA) and mean diffusivity (MD) within the right paracallosal cingulum were greatest (FA: −6.8%/yr, p < 0.001; MD: 2.9%/yr, p = 0.01). MAPT carriers had the greatest change within left uncinate fasciculus (FA: −7.9%/yr, p < 0.001; MD: 10.9%/yr, p < 0.001); sporadic bvFTD and C9ORF72 carriers had the greatest change within right paracallosal cingulum (sporadic bvFTD, FA: −6.7%/yr, p < 0.001; MD: 3.8%/yr, p = 0.001; C9ORF72, FA: −6.8%/yr, p = 0.004). Sample size estimates using FA change were substantially lower than neuropsychological or whole brain measures of change. Interpretation Serial DTI scans may be useful for measuring disease progression in bvFTD, with particular trajectories of WM damage emerging. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials. PMID:25363208
Possin, Katherine L.; Laluz, Victor R.; Alcantar, Oscar Z.; Miller, Bruce L.; Kramer, Joel H.
Figure copy is the most common method of visual spatial assessment in dementia evaluations, but performance on this test may be multifactorial. We examined the neuroanatomical substrates of figure copy performance in 46 patients with Alzheimer's disease (AD) and 48 patients with the behavioral variant of Frontotemporal dementia (bvFTD). A group of…
Faber, Raymond; Hill, Victoria M; Kim, Billy J
We present the case of a 51-year-old former U.S. Air Force officer who developed marked behavioral and personality changes over a 9-year period, ultimately leading to his discharge from the Air Force at a rank below that which he achieved during service. Clinical diagnostic features, neuropsychological testing and neuroimaging together confirmed a diagnosis of frontotemporal dementia. This form of presenile dementia is discussed with reference to his case.
de Boysson, C.; Belleville, S.; Phillips, N. A.; Johns, E. K.; Goupil, D.; Souchay, C.; Bouchard, R.; Chertkow, H.
The primary goal of this study was to evaluate the false recognition phenomenon in persons with frontotemporal dementia (FTD) and those with Lewy-body disease (LBD). Patients with LBD (n=10) or FTD (n=15) and their corresponding controls (n=30) were subjected to the Deese-Roediger-McDermott (DRM) paradigm to induce false recognition. Patients were…
Evers, Kathinka; Kilander, Lena; Lindau, Maria
The objective of this study was to suggest a new formulation of the core research diagnostic consensus criterion ''loss of insight'' in frontotemporal dementia (FTD). Eight patients with FTD (diagnoses made by interviews, medical and neuropsychological examination, CT scan, and regional cerebral glucose metabolism measured by positron emission…
Clark, Camilla N; Lashley, Tammaryn; Mahoney, Colin J; Warren, Jason D; Revesz, Tamas; Rohrer, Jonathan D
Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick's disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant.
Eckart, Janet A.; Sturm, Virginia E.; Miller, Bruce L.; Levenson, Robert W.
Frontotemporal dementia is a neurodegenerative disease that impacts emotion and social behavior. Using laboratory measures of emotional reactivity, our past work has found that reactivity to loud noises and to thematically simple happy and sad emotional films are preserved in the early stages of the disease while other emotional responses (e.g., embarrassment) are severely compromised. In the present study we examined disgust, an emotion whose function is to distance us from offending objects and situations. We measured disgust reactivity in 21 patients with behavioral variant frontotemporal dementia (bvFTD, a subtype of frontotemporal dementia characterized by emotional blunting) and 25 neurologically healthy controls. Disgust is an emotion of particular interest in bvFTD, due to caregiver and clinician reports that patients engage in acts that suggest this emotion may be compromised; in addition, the pattern of neurodegeneration in bvFTD includes atrophy of key frontotemporal structures (e.g., anterior insula) with known roles in visceral emotions such as disgust. In the present study, participants had their emotional facial behavior, physiology, and self-reported emotional experience measured while watching a disgust-eliciting film. We found that behavioral, physiological, and self-reported experiential responses were all reduced in bvFTD patients compared to controls (with behavioral and physiological differences still found after controlling for patients’ cognitive deficits). We discuss the implications of these findings for bvFTD patients’ problems in social functioning and their typical patterns of neurodegeneration. PMID:22285794
Fernandez-Duque, Diego; Baird, Jodie A; Black, Sandra E
The ability to understand other people's behavior in terms of mental states, such as beliefs, desires, and intentions, is central to social interaction. It has been argued that the interpersonal problems of patients with behavioral variant of frontotemporal dementia (FTD-b) are due to a dysfunction of that system. We used first- and second-order false-belief tasks to assess theory-of-mind reasoning in a group of patients with FTD-b and a cognitively matched group of patients with Alzheimer's disease (AD). Both patient groups were equally impaired relative to a healthy elderly group in the cognitively demanding second-order false-belief tasks, revealing that cognitive demands are an important factor in false-belief task performance. Both patient groups reached ceiling performance in the first-order false-belief tasks with minimal cognitive demands, despite the striking difference in their social graces. These results suggest that a conceptual deficit in theory of mind-as measured by the false-belief task-is not at the core of the differences between FTD-b and AD.
Agustus, Jennifer L; Mahoney, Colin J; Downey, Laura E; Omar, Rohani; Cohen, Miriam; White, Mark J; Scott, Sophie K; Mancini, Laura; Warren, Jason D
Frontotemporal dementia is an important neurodegenerative disorder of younger life led by profound emotional and social dysfunction. Here we used fMRI to assess brain mechanisms of music emotion processing in a cohort of patients with frontotemporal dementia (n = 15) in relation to healthy age-matched individuals (n = 11). In a passive-listening paradigm, we manipulated levels of emotion processing in simple arpeggio chords (mode versus dissonance) and emotion modality (music versus human emotional vocalizations). A complex profile of disease-associated functional alterations was identified with separable signatures of musical mode, emotion level, and emotion modality within a common, distributed brain network, including posterior and anterior superior temporal and inferior frontal cortices and dorsal brainstem effector nuclei. Separable functional signatures were identified post-hoc in patients with and without abnormal craving for music (musicophilia): a model for specific abnormal emotional behaviors in frontotemporal dementia. Our findings indicate the potential of music to delineate neural mechanisms of altered emotion processing in dementias, with implications for future disease tracking and therapeutic strategies. PMID:25773639
Agustus, Jennifer L; Mahoney, Colin J; Downey, Laura E; Omar, Rohani; Cohen, Miriam; White, Mark J; Scott, Sophie K; Mancini, Laura; Warren, Jason D
Frontotemporal dementia is an important neurodegenerative disorder of younger life led by profound emotional and social dysfunction. Here we used fMRI to assess brain mechanisms of music emotion processing in a cohort of patients with frontotemporal dementia (n = 15) in relation to healthy age-matched individuals (n = 11). In a passive-listening paradigm, we manipulated levels of emotion processing in simple arpeggio chords (mode versus dissonance) and emotion modality (music versus human emotional vocalizations). A complex profile of disease-associated functional alterations was identified with separable signatures of musical mode, emotion level, and emotion modality within a common, distributed brain network, including posterior and anterior superior temporal and inferior frontal cortices and dorsal brainstem effector nuclei. Separable functional signatures were identified post-hoc in patients with and without abnormal craving for music (musicophilia): a model for specific abnormal emotional behaviors in frontotemporal dementia. Our findings indicate the potential of music to delineate neural mechanisms of altered emotion processing in dementias, with implications for future disease tracking and therapeutic strategies.
Lima-Silva, Thais Bento; Bahia, Valéria Santoro; Nitrini, Ricardo; Yassuda, Mônica Sanches
The aim was to conduct a systematic review of studies that described the functional profile of patients with behavioral variant frontotemporal dementia (bvFTD), published between 2000 and 2013. The bibliographic search was conducted using the terms “frontotemporal dementia” and “frontotemporal lobar degeneration” in combination with “independence,” “functionality,” “basic activities of daily living,” “disability,” and scales that measure functional performance: “Disability Assessment for Dementia-DAD,” “Functional Activities Questionnaire (FAQ),” “Direct Assessment of Functional Status (DAFS).” To be included in the review, the study had to mention the characterization of the functional status of patients with bvFTD in the objectives of the study, using a previously validated instrument of functional assessment. Fourteen studies met this criterion. The reviewed studies suggested that individuals with bvFTD have greater functional impairment when compared to those with other subtypes of frontotemporal lobar degeneration or Alzheimer's disease. The studies documented a significant association between cognitive impairment and measures of functionality in these patients. The cognitive profile of patients may predict faster functional decline. PMID:24308008
Henley, Susie M.D.; Downey, Laura E.; Nicholas, Jennifer M.; Kinnunen, Kirsi M.; Golden, Hannah L.; Buckley, Aisling; Mahoney, Colin J.; Crutch, Sebastian J.
The current study examined motor timing in frontotemporal dementia (FTD), which manifests as progressive deterioration in social, behavioural and cognitive functions. Twenty-patients fulfilling consensus clinical criteria for behavioural variant FTD (bvFTD), 11 patients fulfilling consensus clinical criteria for semantic-variant primary progressive aphasia (svPPA), four patients fulfilling criteria for nonfluent/agrammatic primary progressive aphasia (naPPA), eight patients fulfilling criteria for Alzheimer׳s disease (AD), and 31 controls were assessed on both an externally- and self-paced finger-tapping task requiring maintenance of a regular, 1500 ms beat over 50 taps. Grey and white matter correlates of deficits in motor timing were examined using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). bvFTD patients exhibited significant deficits in aspects of both externally- and self-paced tapping. Increased mean inter-response interval (faster than target tap time) in the self-paced task was associated with reduced grey matter volume in the cerebellum bilaterally, right middle temporal gyrus, and with increased axial diffusivity in the right superior longitudinal fasciculus, regions and tracts which have been suggested to be involved in a subcortical–cortical network of structures underlying timing abilities. This suggests that such structures can be affected in bvFTD, and that impaired motor timing may underlie some characteristics of the bvFTD phenotype. PMID:25447066
Calabrò, Rocco Salvatore; Spadaro, Letteria; Marra, Angela; Balletta, Tina; Cammaroto, Simona; Bramanti, Placido
Agenesis of corpus callosum (AgCC) is a congenital malformation characterized by total or partial absence of corpus callosum with a good neuropsychological profile. Frontotemporal dementia (FTD) is the third most common cause of cortical dementia, and it is characterized by alterations in personality and social relationship, often associated with deficits in attention, abstraction, planning, and problem solving. Herein, we report a case of a 73-year-old woman presenting with FTD associated with primary AgCC. The possible "causal or casual" relationship between these 2 different conditions should be investigated in large prospective studies.
Le Ber, Isabelle; Camuzat, Agnès; Guerreiro, Rita; Bouya-Ahmed, Kawtar; Bras, Jose; Nicolas, Gael; Gabelle, Audrey; Didic, Mira; De Septenville, Anne; Millecamps, Stéphanie; Lenglet, Timothée; Latouche, Morwena; Kabashi, Edor; Campion, Dominique; Hannequin, Didier; Hardy, John; Brice, Alexis
IMPORTANCE Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. OBJECTIVE To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. DESIGN A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. SETTING Primary care or referral center. PARTICIPANTS An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. MAIN OUTCOMES AND MEASURES Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. RESULTS We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. CONCLUSIONS AND RELEVANCE Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD. PMID:24042580
DeLozier, Sarah J; Davalos, Deana
Clinicians often have difficulty distinguishing between various forms of dementia to achieve a correct diagnosis. Little research has been done to examine whether awareness of one's cognitive deficits, or metacognitive monitoring, might differ between dementia diagnoses, thereby providing an additional means of differentiating between dementia subtypes. We review articles examining metacognitive comparisons between two of the most common dementia subtypes: Alzheimer's disease and frontotemporal dementia. Greater monitoring deficits were apparent in frontotemporal dementia than in Alzheimer's disease, and participants with frontotemporal dementia were less likely to utilize task experience to update and improve the accuracy of subsequent monitoring judgments. Results provide evidence for the utility of metacognitive measures as a means of distinguishing between Alzheimer's disease and frontotemporal dementia.
Goetzl, Edward J; Kapogiannis, Dimitrios; Schwartz, Janice B; Lobach, Iryna V; Goetzl, Laura; Abner, Erin L; Jicha, Gregory A; Karydas, Anna M; Boxer, Adam; Miller, Bruce L
Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia in patients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid β-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias.-Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., Jicha, G. A., Karydas, A. M., Boxer, A., Miller, B. L. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.
Kirshner, Howard S
Frontotemporal dementias are neurodegenerative diseases in which symptoms of frontal and/or temporal lobe disease are the first signs of the illness, and as the diseases progress, they resemble a focal left hemisphere process such as stroke or traumatic brain injury, even more than a neurodegenerative disease. Over time, some patients develop a more generalized dementia. Four clinical subtypes characterize the predominant presentations of this illness: behavioral or frontal variant FTD, progressive nonfluent aphasia, semantic dementia, and logopenic primary progressive aphasia. These clinical variants correlate with regional patterns of atrophy on brain imaging studies such as MRI and PET scanning, as well as with biochemical and molecular genetic variants of the disorder. The treatment is as yet only symptomatic, but advances in molecular genetics promise new therapies. PMID:24966676
Borroni, B; Turrone, R; Galimberti, D; Nacmias, B; Alberici, A; Benussi, A; Caffarra, P; Caltagirone, C; Cappa, S F; Frisoni, G B; Ghidoni, R; Marra, C; Padovani, A; Rainero, I; Scarpini, E; Silani, V; Sorbi, S; Tagliavini, F; Tremolizzo, L; Bruni, A C
In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.
Rostgaard, Nina; Waldemar, Gunhild; Nielsen, Jørgen Erik; Simonsen, Anja Hviid
As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.
Evers, Kathinka; Kilander, Lena; Lindau, Maria
The objective of this study was to suggest a new formulation of the core research diagnostic consensus criterion "loss of insight" in frontotemporal dementia (FTD). Eight patients with FTD (diagnoses made by interviews, medical and neuropsychological examination, CT scan, and regional cerebral glucose metabolism measured by positron emission tomography (PET) participated in the study). The results indicated that insight was present in three out of eight patients, and that insight appears to be a heterogeneous concept. Two types of insight emerged: Emotional insight associated with frontotemporal functions, and cognitive insight, related to posterior cognitive functions. These results suggest that loss of insight should not serve as a core criterion on FTD, but serves well as a supportive criterion of the disease.
Wittenberg, D.; Possin, K.L.; Rascovsky, K.; Rankin, K.P.; Miller, B.L.; Kramer, J.H.
Frontotemporal lobe dementias (FTLD) represent a constellation of disorders that may be overlooked or misdiagnosed, despite being a fairly common presenile neurodegenerative diseases. Although the cognitive disorder can be difficult to document, particularly early in the dementia course, neuropsychological evaluation can assist in the diagnosis. Neuropsychologists are in an excellent position to draw from related disciplines like personality theory and social psychology to better assess the types of changes that characterize the prodromal and early phases of the disease. This review summarizes the current state of the field in the diagnosis of FTLD and discusses the emerging role of neuropsychology in elucidating the brain organization of complex processes including empathy, behavioral control and inhibition, reward systems, appetitive behaviors, emotional regulation, and goal-orientation. As this review underscores, FTD remains a powerful model for studying brain-behavior relationships. PMID:18311522
Alexander, S K; Brown, J M; Graham, A; Nestor, P J
The behavioural variant of frontotemporal dementia (bvFTD) is characterised by personality change with a decline in cognition. We describe two patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) who presented with behavioural phenotypes similar to bvFTD. The first patient presented with progressive personality and behavioural change, had florid white matter hyperintensity, and had a novel missense mutation C366W in exon 7 of the Notch3 gene. The second patient presented with progressive memory impairment and marked personality changes after a transient ischaemic attack. In this second patient, the radiological features were subtle and only the family history of stroke prompted testing for CADASIL using Notch3 genotyping. We present these patients to demonstrate that CADASIL may mimic bvFTD, with little clinical or radiological evidence to distinguish the two. CADASIL may be an under-recognised diagnosis in apparent bvFTD. Screening Notch3 in a substantial and unselected cohort of frontotemporal dementia patients might be appropriate to investigate this possibility.
Torralva, Teresa; Sposato, Luciano A.; Riccio, Patricia M.; Gleichgerrcht, Ezequiel; Roca, María; Toledo, Jon B.; Trojanowski, John Q.; Kukull, Walter A.; Manes, Facundo; Hachinski, Vladimir
Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). We compared demographic data, clinical diagnoses, vascular risk factors, functional status, and normalized neuropsychological z-scores between patients with V-bvFTD vs. bvFTD without concomitant cerebrovascular disease (NV-bvFTD) from the National Alzheimer’s Coordinating Centre database. We included 391 neuropathologically diagnosed cases of frontotemporal lobe degeneration (FTLD). We excluded patients that were diagnosed with aphasic variants of frontotemporal dementia before death. Patients with V-bvFTD (n=62) were older at the time of onset of cognitive decline (71.6 vs. 62.5years, p<0.001) and death (78.7 vs. 69.6, p<0.001), more likely to be hypertensive (75.8 vs. 45.7%, p=0.002), and to have a history of stroke (21.2 vs. 6.1%, p=0.007) than those with NV-bvFTD (n=329). V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that FTLD-related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD. PMID:26220367
Léger, Gabriel C; Banks, Sarah J
Background/Aims Behavioral variant frontotemporal dementia (bvFTD) is pathologically heterogeneous. With emerging therapeutics, determining underlying pathology during life is increasingly important. Neuropsychiatric symptoms are prevalent and diagnostic in bvFTD. Methods We assessed the neuropsychiatric profile in patients with clinically diagnosed bvFTD as a function of pathology at autopsy. Patients with a clinical diagnosis of bvFTD at initial visit were selected from the National Alzheimer's Coordinating Center database. Neuropsychiatric symptoms endorsed on the Neuropsychiatric Inventory Questionnaire were analyzed. Results Of 149 patients with clinically diagnosed bvFTD, pathology was primarily Alzheimer's disease in 20.5%. These patients differed from those with underlying frontotemporal lobar degeneration: patients with AD pathology (plaques and tangles) were more likely to have hallucinations, delusions, or agitation. Patients were further differentiated into tau positive (30 % of cases, including Pick's disease, frontotemporal dementia and parkinsonism with tau-positive, and other tauopathies) or tau-negative (70% of cases including bvFTD tau-negative ubiquitin-positive inclusions). These patients also differed in some of the neuropsychiatric symptoms seen. Tau-negative cases were more likely to demonstrate depression, delusions, and changes in appetite and eating. Conclusions These preliminary findings contribute to our increasing ability to predict, using simple clinical tools the neuropathological underpinnings of bvFTD during life. PMID:24135712
Corticobasal Syndrome; Progressive Supranuclear Palsy; Behavioral Variant Frontotemporal Dementia; Semantic Dementia; Progressive Nonfluent Aphasia; Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia
Lemos, Raquel; Duro, Diana; Simões, Mário R.; Santana, Isabel
Memory impairment is often present in frontotemporal dementia (FTD) as a result of an inefficient use of learning strategies, sometimes leading to a misdiagnosis of Alzheimer's disease (AD). The Free and Cued Selective Reminding Test (FCSRT) is a memory test that controls attention and acquisition, by providing category cues in the learning process. The main goal of this study was to show the usefulness of the FCSRT in the distinction between behavioral (bv-) FTD and AD. Three matched subgroups of participants were considered: bv-FTD (n = 32), AD (n = 32), and a control group of healthy adults (n = 32). Results proved that while AD patients exhibited an overall impairment in FCSRT, bv-FTD subjects showed to benefit more from the controlled learning through category cues. AD patients were 25 times more likely to have an impaired FCSRT. The FCSRT has shown its utility in the distinction between bv-FTD and AD, therefore increasing the diagnostic accuracy. PMID:25062746
Mukherjee, Odity; Wang, Jun; Gitcho, Michael; Chakraverty, Sumi; Taylor-Reinwald, Lisa; Shears, Shantia; Kauwe, John S K; Norton, Joanne; Levitch, Denise; Bigio, Eileen H; Hatanpaa, Kimmo J; White, Charles L; Morris, John C; Cairns, Nigel J; Goate, Alison
Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3' splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.
Seelaar, Harro; Rohrer, Jonathan D; Pijnenburg, Yolande A L; Fox, Nick C; van Swieten, John C
Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will
Caixeta, Leonardo; Vieira, Renata Teles; Paes, Flávia; Carta, Mauro Giovanni; Nardi, Antonio Egidio; Arias-Carrión, Oscar; Rocha, Nuno B. F; Budde, Henning; Machado, Sergio
Objectives : To investigate the severity of subcortical atrophy in frontotemporal dementia (FTD) without extrapyramidal symptoms (EPS) and dementia with EPS. In addition, we aim to verify if there is correlation between demographic and clinical characteristics and subcortical atrophy in the groups. Methodology : The sample was composed of 21 patients with dementia and EPS as well as 19 patients with FTD without EPS. A linear assessment was conducted in order to identify the degree of subcortical atrophy (i.e., bifrontal index - BFI) using MRI. Moreover, the Mini-Mental State Examination (MMSE), Pfeffer Functional Activities Questionnaire (FAQ) and the Clinical Dementia Rating (CDR) were used to investigate clinical aspects. Results : It was verified that patients with dementia and EPS was older than the patients with FTD (p=0.01). The severity of cognitive deficits was associated with BFI, as well as the dementia severity in the EPS group. Conclusion : FTD group presented mean BFI scores above the cutoff for normal elderly population, indicating the presence of subcortical atrophy in this group. Mean BFI was higher (although not statistically significant) in FTD group than in dementia with EPS, which can suggest at least that subcortical pathology in FTD may be as important as in the dementia with EPS group. Subcortical atrophy is a good biological marker for cognitive deterioration in FTD and in dementia with EPS. PMID:25870648
Barsuglia, Joseph P.; Kaiser, Natalie C.; Wilkins, Stacy Schantz; Joshi, Aditi; Barrows, Robin J.; Paholpak, Pongsatorn; Panchal, Hemali Vijay; Jimenez, Elvira E.; Mather, Michelle J.; Mendez, Mario F.
Early social dysfunction is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD); however, validated measures for assessing social deficits in dementia are needed. The purpose of the current study was to examine the utility of a novel informant-based measure of social impairment, the Socioemotional Dysfunction Scale (SDS) in early-onset dementia. Sixteen bvFTD and 18 early-onset Alzheimer’s disease (EOAD) participants received standard clinical neuropsychological measures and neuroimaging. Caregiver informants were administered the SDS. Individuals with bvFTD exhibited greater social dysfunction on the SDS compared with the EOAD group; t(32) = 6.32, p < .001. The scale demonstrated preliminary evidence for discriminating these frequently misdiagnosed groups (area under the curve = 0.920, p = <.001) and internal consistency α = 0.977. The SDS demonstrated initial evidence as an effective measure for detecting abnormal social behavior and discriminating bvFTD from EOAD. Future validation is recommended in larger and more diverse patient groups. PMID:25331776
Barsuglia, Joseph P; Kaiser, Natalie C; Wilkins, Stacy Schantz; Joshi, Aditi; Barrows, Robin J; Paholpak, Pongsatorn; Panchal, Hemali Vijay; Jimenez, Elvira E; Mather, Michelle J; Mendez, Mario F
Early social dysfunction is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD); however, validated measures for assessing social deficits in dementia are needed. The purpose of the current study was to examine the utility of a novel informant-based measure of social impairment, the Socioemotional Dysfunction Scale (SDS) in early-onset dementia. Sixteen bvFTD and 18 early-onset Alzheimer's disease (EOAD) participants received standard clinical neuropsychological measures and neuroimaging. Caregiver informants were administered the SDS. Individuals with bvFTD exhibited greater social dysfunction on the SDS compared with the EOAD group; t(32) = 6.32, p < .001. The scale demonstrated preliminary evidence for discriminating these frequently misdiagnosed groups (area under the curve = 0.920, p = <.001) and internal consistency α = 0.977. The SDS demonstrated initial evidence as an effective measure for detecting abnormal social behavior and discriminating bvFTD from EOAD. Future validation is recommended in larger and more diverse patient groups.
Ghoshal, N.; Dearborn, J.T.; Wozniak, D.F.; Cairns, N.J.
Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-age wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn-/- mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected. PMID:21933710
Whitwell, Jennifer L.; Josephs, Keith A.
Neuroimaging has played an important role in the characterization of the frontotemporal dementia (FTD) syndromes, demonstrating neurodegenerative signatures that can aid in the differentiation of FTD from other neurodegenerative disorders. Recent advances have been driven largely by the refinement of the clinical syndromes that underlie FTD, and by the discovery of new genetic and pathological features associated with FTD. Many new imaging techniques and modalities are also now available that allow the assessment of other aspects of brain structure and function, such as diffusion tensor imaging and resting state functional MRI. Studies have utilized these recent techniques, as well as traditional volumetric MRI, to provide further insight into disease progression across the many clinical, genetic and pathological variants of FTD. Importantly, neuroimaging signatures have been identified that will improve the clinician’s ability to predict underlying genetic and pathological features, and hence ultimately improve patient diagnosis. PMID:23015371
Pressman, Peter; Miller, Bruce L
Frontotemporal dementia (FTD) was documented over a century ago. The last decade, however, has seen substantial changes in our conceptions of this increasingly recognized disorder. Different clinical variants have been delineated, the most common of which is the behavioral variant (bvFTD). Updated diagnostic criteria have been established. New histopathological findings and genetic etiologies have been discovered. Research continues to uncover molecular mechanisms by which abnormal proteins accumulate in degenerating brain tissue. Novel neuroimaging techniques suggest that functional networks are diminished in bvFTD that may be relevant to empathy and social behavior. Despite rapid advances in our understanding of bvFTD, the disease is still under-recognized and commonly misdiagnosed. The result is inappropriate patient care. Recognizing the various presentations of bvFTD and its histological and genetic subtypes may further diagnosis, treatment and research. PMID:24315411
Mendez, Mario F
Brain disorders can lead to criminal violations. Patients with frontotemporal dementia (FTD) are particularly prone to sociopathic behavior while retaining knowledge of their acts and of moral and conventional rules. This report describes four FTD patients who committed criminal violations in the presence of clear consciousness and sufficiently intact cognition. They understood the nature of their acts and the potential consequences, but did not feel sufficiently concerned to be deterred. FTD involves a unique pathologic combination affecting the ventromedial prefrontal cortex, with altered moral feelings, right anterior temporal loss of emotional empathy, and orbitofrontal changes with disinhibited, compulsive behavior. These case histories and the literature indicate that those with right temporal FTD retain the capacity to tell right from wrong but have the slow and insidious loss of the capacity for moral rationality. Patients with early FTD present a challenge to the criminal justice system to consider alterations in moral cognition before ascribing criminal responsibility.
Caroppo, Paola; Camuzat, Agnès; Guillot-Noel, Léna; Thomas-Antérion, Catherine; Couratier, Philippe; Wong, Tsz Hang; Teichmann, Marc; Golfier, Véronique; Auriacombe, Sophie; Belliard, Serge; Laurent, Bernard; Lattante, Serena; Millecamps, Stéphanie; Clot, Fabienne; Dubois, Bruno; van Swieten, John C.; Brice, Alexis
Objectives: We describe the largest series of patients with TARDBP mutations presenting with frontotemporal dementia (FTD) and review the cases in the literature to precisely characterize FTD diseases associated with this genotype. Methods: The phenotypic characteristics of 29 TARDBP patients, including 10 new French and Dutch cases and 19 reviewed from the literature, were evaluated. Results: The most frequent phenotype was a behavioral variant frontotemporal dementia (bvFTD), but a significant proportion (40%) of our patients had semantic (svFTD) or nonfluent variants (nfvFTD) at onset; and svFTD was significantly more frequent in TARDBP carriers than in other FTD genotypes (p < 0.001). Remarkably, only a minority (40%) of our patients secondarily developed amyotrophic lateral sclerosis (ALS). Two patients carried a homozygous mutation but strikingly different phenotypes (bvFTD and ALS) indicating that homozygosity does not result in a specific phenotype. Earlier age at onset in children than parent's generations, mimicking an apparent “anticipation” (21.8 ± 9.3 years, p = 0.001), and possible reduced penetrance were present in most families. Conclusions: This study enlarges the phenotypic spectrum of TARDBP and will have important clinical implications: (1) FTD can be the only clinical manifestation of TARDBP mutations; (2) Initial language or semantic disorders might be indicative of a specific genotype; (3) Mutations should be searched in all FTD phenotypes after exclusion of major genes, even in the absence of ALS in the proband or in family history; (4) reduced penetrance and clinical variability should be considered to deliver appropriate genetic counseling. PMID:27280171
Ferri, Evelyn; Arosio, Beatrice; D'Addario, Claudio; Galimberti, Daniela; Gussago, Cristina; Pucci, Mariangela; Casati, Martina; Fenoglio, Chiara; Abbate, Carlo; Rossi, Paolo Dionigi; Scarpini, Elio; Maccarrone, Mauro; Mari, Daniela
Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) share the accumulation of fibrillar aggregates of misfolded proteins. To better understand these neurodegenerative diseases and identify biomarkers in easily accessible cells, we investigated DNA methylation at Pin1 gene promoter and its expression in peripheral blood mononuclear cells of FTD patients. We found a lower gene expression of Pin1 with a higher DNA methylation in three CpG sites at Pin1 gene promoter analysed in FTD subjects, in contrast to a higher gene expression with a lower methylation in AD subjects and controls. These data suggest an important and distinct involvement of Pin1 in these two types of dementia.
Barton, Cynthia; Ketelle, Robin; Merrilees, Jennifer; Miller, Bruce
Worldwide prevalence of dementia is predicted to double every 20 years. The most common cause in individuals over 65 is Alzheimer's disease (AD), but in those under 65, frontotemporal dementia (FTD) is as frequent. The physical and cognitive decline that characterizes these diseases is commonly accompanied by troublesome behavioral symptoms. These behavioral symptoms contribute to significant morbidity and mortality among both patients and caregivers. Medications have been largely ineffective in managing these symptoms and carry significant adverse effects. Non-pharmacological interventions have been recommended to precede the utilization of pharmacological treatments. This article reviews the research about these interventions with special attention to the variations by etiology, especially FTD. The authors offer recommendations for improving utilization of these strategies and future research recommendations. PMID:26750129
Johnen, Andreas; Brandstetter, Lisa; Kärgel, Christian; Wiendl, Heinz; Lohmann, Hubertus; Duning, Thomas
Limb apraxia denotes a cognitive impairment of gesture production. Lesion studies in patients with stroke point towards distinct neural processing streams for limb imitation and object-pantomime within left parietal and temporal cortex, respectively. Despite its frequent occurrence as an early symptom in both, Alzheimer's dementia (AD) and behavioural variant frontotemporal dementia (bvFTD), neural correlates of limb apraxia within these patient groups remain unexplored. Using voxel-based morphometry and multiple regression models, associations between limb apraxia and gray matter (GM) volume were investigated in 36 dementia patients (18 AD, 18 bvFTD) in early disease stages. Both dementia subtypes showed a comparable degree of limb apraxia. Although the patient groups showed distinct atrophy patterns with significantly more severe frontal GM loss in bvFTD, we found similar neural correlates of limb apraxia within posterior brain regions for both dementia subtypes: limb-imitation was associated with bilateral atrophy of superior, inferior and medial parietal cortex. Object-pantomime showed associations with GM volume in right middle temporal and angular gyrus. Our results argue for shared neural correlates of limb apraxia in AD and bvFTD and validate the syndrome as an important neuropsychological feature across different etiologies. Moreover, our results are compatible with neural models derived from patients with stroke, suggesting partly distinct neural representations of imitation and pantomime. Compared to patients with stroke however, AD and bvFTD showed more bilateral or even right lateralized neural representations of limb apraxia, proposing a greater influence of visuospatial impairments and spatial body representation deficits on praxis performance.
Zhou, Juan; Greicius, Michael D.; Gennatas, Efstathios D.; Growdon, Matthew E.; Jang, Jung Y.; Rabinovici, Gil D.; Kramer, Joel H.; Weiner, Michael; Miller, Bruce L.
Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer’s disease cause atrophy within two major networks, an anterior ‘Salience Network’ (atrophied in behavioural variant frontotemporal dementia) and a posterior ‘Default Mode Network’ (atrophied in Alzheimer’s disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer’s disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer’s disease) and the Default Mode Network (disrupted in Alzheimer’s disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer’s disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer’s disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic
Muñoz-Ruiz, Miguel Ángel; Hall, Anette; Mattila, Jussi; Koikkalainen, Juha; Herukka, Sanna-Kaisa; Husso, Minna; Hänninen, Tuomo; Vanninen, Ritva; Liu, Yawu; Hallikainen, Merja; Lötjönen, Jyrki; Remes, Anne M.; Alafuzoff, Irina; Soininen, Hilkka; Hartikainen, Päivi
Background Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. Aims To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). Methods The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases. We utilized data from neuropsychological tests, volumetric magnetic resonance imaging, single-photon emission tomography, cerebrospinal fluid biomarkers and the APOE genotype. The DSI classification results were calculated with a combination of leave-one-out cross-validation and bootstrapping. A DSF visualization of a FTD patient is presented as an example. Results The DSI distinguishes controls from FTD (area under the receiver-operator curve, AUC = 0.99) and AD (AUC = 1.00) very well and achieves a good differential diagnosis between AD and FTD (AUC = 0.89). In subsamples of autopsy-confirmed cases (AUC = 0.97) and clinically diagnosed cases (AUC = 0.94), differential diagnosis of AD and FTD performs very well. Conclusions DSI is a promising computer-assisted biomarker approach for aiding in the diagnostic process of dementing diseases. Here, DSI separates controls from dementia and differentiates between AD and FTD. PMID:27703465
Barrows, Robin J; Barsuglia, Joseph; Paholpak, Pongsatorn; Eknoyan, Donald; Sabodash, Valeriy; Lee, Grace J; Mendez, Mario F
The clock-drawing test (CDT) is widely used in clinical practice to diagnose and distinguish patients with dementia. It remains unclear, however, whether the CDT can distinguish among the early-onset dementias. Accordingly, we examined the ability of both quantitative and qualitative CDT analyses to distinguish behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer disease (eAD), the 2 most common neurodegenerative dementias with onset <65 years of age. We hypothesized that executive aspects of the CDT would discriminate between these 2 disorders. The study compared 15 patients with bvFTD and 16 patients with eAD on the CDT using 2 different scales and correlated the findings with neuropsychological testing and magnetic resonance imaging. The total CDT scores did not discriminate bvFTD and eAD; however, specific analysis of executive hand placement items successfully distinguished the groups, with eAD exhibiting greater errors than bvFTD. The performance on those executive hand placement items correlated with measures of naming as well as visuospatial and executive function. On tensor-based morphometry of the magnetic resonance images, executive hand placement correlated with right frontal volume. These findings suggest that lower performance on executive hand placement items occurs with involvement of the right dorsolateral frontal-parietal network for executive control in eAD, a network disproportionately affected in AD of early onset. Rather than the total performance on the clock task, the analysis of specific errors, such as executive hand placement, may be useful for early differentiation of eAD, bvFTD, and other conditions.
Hodges, John R.; Knopman, David; Mendez, Mario F.; Kramer, Joel H.; Neuhaus, John; van Swieten, John C.; Seelaar, Harro; Dopper, Elise G. P.; Onyike, Chiadi U.; Hillis, Argye E.; Josephs, Keith A.; Boeve, Bradley F.; Kertesz, Andrew; Seeley, William W.; Rankin, Katherine P.; Johnson, Julene K.; Gorno-Tempini, Maria-Luisa; Rosen, Howard; Prioleau-Latham, Caroline E.; Lee, Albert; Kipps, Christopher M.; Lillo, Patricia; Piguet, Olivier; Rohrer, Jonathan D.; Rossor, Martin N.; Warren, Jason D.; Fox, Nick C.; Galasko, Douglas; Salmon, David P.; Black, Sandra E.; Mesulam, Marsel; Weintraub, Sandra; Dickerson, Brad C.; Diehl-Schmid, Janine; Pasquier, Florence; Deramecourt, Vincent; Lebert, Florence; Pijnenburg, Yolande; Chow, Tiffany W.; Manes, Facundo; Grafman, Jordan; Cappa, Stefano F.; Freedman, Morris; Grossman, Murray; Miller, Bruce L.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised
Tsai, Richard M.; Boxer, Adam L.
Frontotemporal dementia (FTD) is a common form of dementia with heterogeneous clinical presentations and distinct clinical syndromes. This article will review currently available therapies for FTD, its related disorders and their clinical evidence. It will also discuss recent advancements in FTD pathophysiology, treatment development, biomarker advancement and their relation to recently completed or currently ongoing clinical trials as well as future implications. PMID:27306957
Griffin, Julie; Oyebode, Jan R; Allen, Joanne
Research investigating behavioural-variant frontotemporal dementia has concentrated on identifying and quantifying people's difficulties; yet few studies have considered how people with behavioural-variant frontotemporal dementia make sense of their difficulties. Five participants were interviewed and interpretive phenomenological analysis used to analyse the data. Two superordinate themes emerged: 'Bewilderment' and 'Relationships with others'. 'Bewilderment' reflected the feelings of the participants from the start of their dementia, and was divided into two main themes (1) 'Awareness of change: What's the problem? and (2) Threats to self: This is not me. The superordinate theme, 'Relationships with others', reflected difficulties with social relationships and comprised two main themes (1) 'Family and friends: Things haven't changed… but do I say anything wrong?' and (2) Coping with threats to self: Blame others or just avoid them. The themes were discussed in relation to literature evaluating the difficulties associated with behavioural-variant frontotemporal dementia together with implications for clinical practice.
Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia (FTD). Targets for intervention have been identified, therapies are being developed, and clinical trials are advancing. A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes. The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction, language impairments and behavioral disturbance. Behavioral variant FTD is characterized by an initial presentation of changes in personality, behavior and/or emotion, which are often difficult to objectively capture using traditional neuropsychological measures. The two principal language variants of FTD are Progressive Nonfluent Aphasia (PNFA) with predominant agrammatic/non-fluent impairments and Semantic Dementia (SD) with semantic impairments and visual agnosia. Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change, yet specific enough to isolate signal from noise, and acceptable to regulatory agencies. Given the anticipated potential for small effect sizes, measures must be able to identify small incremental changes over time. It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest. Selected outcome measures should be suitable for repeat administration, yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability. To facilitate widespread adoption as an endpoint, measures should be readily accessible. We provide several examples of potential global, composite, and individual cognitive measures, as well as behavioral measures promising for FTD trials. Development and application of appropriate trial outcomes is critically important to success in advancing new
Irish, Muireann; Landin-Romero, Ramon; Mothakunnel, Annu; Ramanan, Siddharth; Hsieh, Sharpley; Hodges, John R; Piguet, Olivier
Compromised autobiographical memory (ABM) retrieval is well established in dementia, attributable to degeneration of a core memory brain network. It remains unclear, however, how the progressive spread of atrophy with advancing disease severity impacts ABM retrieval across life epochs. To this end, we conducted a longitudinal study of recent and remote ABM in Alzheimer's disease (AD, n =11), and a frontotemporal lobar degeneration group (FTD, n =13) comprising 7 behavioral variant FTD and 6 semantic dementia patients, in comparison with 23 healthy older Controls. Patients were re-assessed approximately one year following their initial visit and underwent repeat testing and brain imaging. Linear mixed modeling neuroimaging analyses explored disease-specific cortical changes driving ABM alterations over time. AD patients showed comparable ABM profiles across assessment periods however, follow-up performance correlated strongly with lateral temporal lobe integrity. In contrast, recent ABMs were disproportionately disrupted at follow-up relative to baseline in the FTD group, attributable to cortical thinning in posterior brain regions, including the right posterior cingulate cortex. Our findings offer new insights regarding the potential time-specific role of discrete cortical regions in ABM retrieval and the differential fate of formerly evocative memories with advancing disease severity in dementia syndromes.
The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders. PMID:22529204
Williams, Kelly L.; Topp, Simon; Yang, Shu; Smith, Bradley; Fifita, Jennifer A.; Warraich, Sadaf T.; Zhang, Katharine Y.; Farrawell, Natalie; Vance, Caroline; Hu, Xun; Chesi, Alessandra; Leblond, Claire S.; Lee, Albert; Rayner, Stephanie L.; Sundaramoorthy, Vinod; Dobson-Stone, Carol; Molloy, Mark P.; van Blitterswijk, Marka; Dickson, Dennis W.; Petersen, Ronald C.; Graff-Radford, Neill R.; Boeve, Bradley F.; Murray, Melissa E.; Pottier, Cyril; Don, Emily; Winnick, Claire; McCann, Emily P.; Hogan, Alison; Daoud, Hussein; Levert, Annie; Dion, Patrick A.; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Kost, Jason; Gellera, Cinzia; Gkazi, Athina Soragia; Miller, Jack; Stockton, Joanne; Brooks, William S.; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luis; Esteban-Pérez, Jesús; Rábano, Alberto; Hardiman, Orla; Morrison, Karen E.; Ticozzi, Nicola; Silani, Vincenzo; de Belleroche, Jacqueline; Glass, Jonathan D.; Kwok, John B. J.; Guillemin, Gilles J.; Chung, Roger S.; Tsuji, Shoji; Brown, Robert H.; García-Redondo, Alberto; Rademakers, Rosa; Landers, John E.; Gitler, Aaron D.; Rouleau, Guy A.; Cole, Nicholas J.; Yerbury, Justin J.; Atkin, Julie D.; Shaw, Christopher E.; Nicholson, Garth A.; Blair, Ian P.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration. PMID:27080313
Ruby, Perrine; Schmidt, Christina; Hogge, Michaël; D'Argembeau, Arnaud; Collette, Fabienne; Salmon, Eric
We aimed at investigating social disability and its cerebral correlates in frontotemporal dementia (FTD). To do so, we contrasted answers of patients with early-stage FTD and of their relatives on personality trait judgment and on behavior prediction in social and emotional situations. Such contrasts were compared to control contrasts calculated with answers of matched controls tested with their relatives. In addition, brain metabolism was measured in patients with positron emission tomography and the [(18)F]fluorodeoxyglucose method. Patients turned out to be as accurate as controls in describing their relative's personality, but they failed to predict their relative's behavior in social and emotional circumstances. Concerning the self, patients were impaired both in current personality assessment and in prediction of their own behavior. Those two self-evaluation measures did not correlate. Only patients' anosognosia for social behavioral disability was found to be related to decreased metabolic activity in the left temporal pole. Such results suggest that anosognosia for social disability in FTD originates in impaired processing of emotional autobiographical information, leading to a self-representation that does not match current behavior. Moreover, we propose that perspective-taking disability participates in anosognosia, preventing patients from correcting their inaccurate self-representation based on their relative's perspective.
Baizabal-Carvallo, José Fidel; Jankovic, Joseph
Frontotemporal dementia (FTD) refers to a group of clinically and genetically heterogeneous neurodegenerative disorders that are a common cause of adult-onset behavioural and cognitive impairment. FTD often presents in combination with various hyperkinetic or hypokinetic movement disorders, and evidence suggests that various genetic mutations underlie these different presentations. Here, we review the known syndromatic-genetic correlations in FTD. Although no direct genotype-phenotype correlations have been identified, mutations in multiple genes have been associated with various presentations. Mutations in the genes that encode microtubule-associated protein tau (MAPT) and progranulin (PGRN) can manifest as symmetrical parkinsonism, including the phenotypes of Richardson syndrome and corticobasal syndrome (CBS). Expansions in the C9orf72 gene are most frequently associated with familial FTD, typically combined with motor neuron disease, but other manifestations, such as symmetrical parkinsonism, CBS and multiple system atrophy-like presentations, have been described in patients with these mutations. Less common gene mutations, such as those in TARDBP, CHMP2B, VCP, FUS and TREM2, can also present as atypical parkinsonism. The most common hyperkinetic movement disorders in FTD are motor and vocal stereotypies, which have been observed in up to 78% of patients with autopsy-proven FTD. Other hyperkinetic movements, such as chorea, orofacial dyskinesias, myoclonus and dystonia, are also observed in some patients with FTD.
Ibañez, Agustin; Manes, Facundo
The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders.
Mishra, Aniket; Ferrari, Raffaele; Heutink, Peter; Hardy, John; Pijnenburg, Yolande; Posthuma, Danielle
Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.
Grossman, Murray; McMillan, Corey; Moore, Peachie; Ding, Lijun; Glosser, Guila; Work, Melissa; Gee, James
Confrontation naming is impaired in neurodegenerative conditions like Alzheimer's disease (AD), frontotemporal dementia (FTD) and corticobasal degeneration (CBD). Some behavioural observations suggest a common source of impaired naming across these patient groups, while others find partially unique patterns of naming difficulty. We hypothesized…
Zhang, Weiwei; Jiao, Bin; Xiao, Tingting; Pan, Chuzheng; Liu, Xixi; Zhou, Lin; Tang, Beisha; Shen, Lu
The prion protein (PRNP) gene is associated with prion diseases, whereas variants of the PRNP gene may also explain some cases of Alzheimer disease (AD) and frontotemporal dementia (FTD) in Caucasian populations. To determine the prevalence of the PRNP gene in patients with AD and FTD in China, we screened all exons of the PRNP gene in a cohort of 683 cases (606 AD and 77 FTD) in the Chinese Han population and we detected a novel missense mutation p.S17G in a late-onset AD (LOAD) patient. Furthermore, we analyzed the PRNP M/V polymorphism at codon 129, which was previously reported as a risk factor. However, there were no significant differences in genotype and allele frequency either in AD (OR = 0.75[0.378–1.49], P = 0.492), or FTD patients (OR = 2.046[0.265–15.783], P = 0.707). To our knowledge, this is the first study to reveal a correlation between the PRNP gene and Chinese AD and FTD patients in a large cohort. This study reports a novel p.S17G mutation in a clinically diagnosed LOAD patient, suggesting that the PRNP mutation is present in Chinese AD patients, whereas, M129V polymorphism is not a risk factor for AD or FTD in the Chinese Han population. PMID:27910931
Santos, Rodrigo Ribeiro; Torres, Karen C; Lima, Giselle S; Fiamoncini, Carolina M; Mapa, Filipe C; Pereira, Patricia A; Rezende, Vitor B; Martins, Luiza C; Bicalho, Maria A; Moraes, Edgar N; Reis, Helton J; Teixeira, Antonio L; Romano-Silva, Marco A
Studies suggest that inflammation is involved in the neurodegenerative cascade of dementias. Immunological mechanisms may be part of the pathophysiological process in frontotemporal dementia (FTD), but up till now only vague evidence of such mechanisms has been presented. The B7- CD28/CTLA-4 pathway is an important immunological signaling pathway involved in modulation of T cell activation. The aim of this study was to compare the expression of molecules associated with co-stimulatory signaling in peripheral blood mononuclear cells (PBMC) of FTD to Alzheimer disease (AD) and control groups. Our results confirm the previous demonstrated increased expression of CD80 in CD14+ Alzheimer patients T cells but show, for the first time, a reduction in the expression of CTLA-4 in CD4+ FTD cells. As CTLA-4 is the most potent negative regulators of T-cell activation we speculated that peripheral T lymphocytes in FTD are more activated and this could be involved in the neurodegeneration observed in this dementia.
Bora, Emre; Walterfang, Mark; Velakoulis, Dennis
Current evidence suggests that neurocognitive testing has limited practical benefit in distinguishing behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). In this meta-analysis of 30 studies, theory of mind (ToM) performances of 784 individuals with bvFTD (n=273) and AD (n=511) were compared with 671 healthy controls. ToM performances of 227 patients with bvFTD and 229 with AD were also compared in studies matched for general cognition. ToM was impaired in both bvFTD (d=1.79) and AD (d=1.15). In bvFTD, patients were particularly impaired in advanced tasks such as recognition of faux pas and sarcasm (d>2.0). In AD, ToM deficits were relatively modest. In studies matched for general cognition, ToM was significantly impaired in bvFTD in comparision to AD (d=1.29), especially for faux pas recognition (d=1.75). ToM dysfunction is a robust and more specific feature of bvFTD. In contrast, ToM deficits are modest compared with level of general cognitive impairment in AD. In both disorders, longer duration of disease and level of general cognitive impairment are related to relatively more severe ToM deficits. Assessment of ToM can be beneficial for early identification of bvFTD.
Hardy, Chris J. D.; Buckley, Aisling H.; Downey, Laura E.; Lehmann, Manja; Zimmerer, Vitor C.; Varley, Rosemary A.; Crutch, Sebastian J.; Rohrer, Jonathan D.; Warrington, Elizabeth K; Warren, Jason D.
Background The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. Objective We aimed to quantify the extent of language deficits in this patient group. Methods We assessed a cohort of patients with bvFTD (n=24) in relation to patents with semantic variant primary progressive aphasia (svPPA; n=14), nonfluent variant primary progressive aphasia (nfvPPA; n=18) and healthy age-matched individuals (n=24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients’ brain magnetic resonance images. Results Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. Conclusions bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker. PMID:26682693
Sjogren, M; Folkesson, S; Blennow, K; Tarkowski, E
Objective: Immunological mechanisms may be part of the pathophysiological mechanisms in frontotemporal dementia (FTD), but hitherto only vague evidence of such mechanisms has been presented. The aim of this study was to compare the cerebrospinal fluid (CSF) levels of the pro-inflammatory cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α, and the anti-inflammatory cytokine transforming growth factor (TGF)-ß in patients with FTD and normal controls. Furthermore, serum levels of TNF-α, TGF-ß, and IL-1ß were measured in FTD patients. Methods: The CSF levels of IL-1ß, TNFα, and TGF-ß were measured using ELISA in 19 patients with FTD and 24 sex and age matched healthy controls. Results: The CSF levels of TNF-α (FTD 0.6 pg/mL (median: lower, upper quartile 0.3, 0.7); controls: 0.0 pg/mL (0.0, 0.0); p = 0.008) and TGF-ß (FTD 266 pg/mL (157, 371), controls: 147 pg/mL (119, 156); p = 0.0001) were significantly increased in FTD patients compared with controls. No correlations were found between CSF and serum levels of the cytokines. In the controls, but not in the FTD patients, a positive correlation was found between the CSF levels of TGF-ß and age (r = 0.42, p<0.05). No correlation was found between any of the cytokines and degree of brain atrophy or white matter changes. No differences between the groups were found for age, gender, or CSF/serum albumin ratio. Conclusions: The results suggest an increased intrathecal production of both pro- and anti-inflammatory cytokines in FTD. As no correlations were found with the albumin ratio, and no correlations between CSF and serum levels of the cytokines were found, these changes in the CSF cannot be explained by a systemic overproduction of cytokines. PMID:15258209
Bocchetta, Martina; Cardoso, M. Jorge; Cash, David M.; Ourselin, Sebastien; Warren, Jason D.; Rohrer, Jonathan D.
Background Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with a strong genetic component. The cerebellum has not traditionally been felt to be involved in FTD but recent research has suggested a potential role. Methods We investigated the volumetry of the cerebellum and its subregions in a cohort of 44 patients with genetic FTD (20 MAPT, 7 GRN, and 17 C9orf72 mutation carriers) compared with 18 cognitively normal controls. All groups were matched for age and gender. On volumetric T1-weighted magnetic resonance brain images we used an atlas propagation and label fusion strategy of the Diedrichsen cerebellar atlas to automatically extract subregions including the cerebellar lobules, the vermis and the deep nuclei. Results The global cerebellar volume was significantly smaller in C9orf72 carriers (mean (SD): 99989 (8939) mm3) compared with controls (108136 (7407) mm3). However, no significant differences were seen in the MAPT and GRN carriers compared with controls (104191 (6491) mm3 and 107883 (6205) mm3 respectively). Investigating the individual subregions, C9orf72 carriers had a significantly lower volume than controls in lobule VIIa-Crus I (15% smaller, p < 0.0005), whilst MAPT mutation carriers had a significantly lower vermal volume (10% smaller, p = 0.001) than controls. All cerebellar subregion volumes were preserved in GRN carriers compared with controls. Conclusion There appears to be a differential pattern of cerebellar atrophy in the major genetic forms of FTD, being relatively spared in GRN, localized to the lobule VIIa-Crus I in the superior-posterior region of the cerebellum in C9orf72, the area connected via the thalamus to the prefrontal cortex and involved in cognitive function, and localized to the vermis in MAPT, the ‘limbic cerebellum’ involved in emotional processing. PMID:26977398
Ishiki, Aiko; Kamada, Maki; Kawamura, Yuki; Terao, Chiaki; Shimoda, Fumiko; Tomita, Naoki; Arai, Hiroyuki; Furukawa, Katsutoshi
Biomarkers in the cerebrospinal fluid (CSF) are currently regarded as indispensable indicators for accurate differential diagnosis of neurodegenerative disorders. Although high levels of astrocyte-secreted glial fibrillar acidic protein (GFAP) in the CSF of patients with Alzheimer's disease (AD) have been reported, the levels of GFAP in the CSF have not been fully investigated in other neurological disorders that cause dementia, such as dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). In this study, we determined the levels of GFAP in the CSF of healthy control subjects and AD, DLB, and FTLD patients to address two questions: (i) Do the levels of GFAP differ among these disorders? and (ii) Can GFAP be used as a biomarker for the differential diagnosis of these neurodegenerative disorders? The levels of GFAP in AD, DLB, and FTLD patients were significantly higher than those in the healthy control subjects. Although the levels of GFAP were not significantly different between AD and DLB patients, a higher level of GFAP was observed in FTLD patients than in AD and DLB patients. It is concluded that representative neurological disorders causing dementia were associated with higher levels of GFAP in the CSF. We propose the following mechanism concerning the amount of glial fibrillar acidic protein (GFAP) in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). The increase in the release of GFAP into CSF is considered to reflect the sum of degeneration of astrocytes and astrocytosis. The sum of degeneration and astrocytosis or the GFAP release could be in the order of FTLD > DLB > AD > normal condition.
Ranasinghe, Kamalini G.; Lobach, Iryna V.; Kramer, Joel H.; Sturm, Virginia E.; Bettcher, Brianne M.; Possin, Katherine; Christine You, S.; Lamarre, Amanda K.; Shany-Ur, Tal; Stephens, Melanie L.; Perry, David C.; Lee, Suzee E.; Miller, Zachary A.; Gorno-Tempini, Maria L.; Rosen, Howard J.; Boxer, Adam; Seeley, William W.; Rabinovici, Gil D.; Vossel, Keith A.; Miller, Bruce L.
Objective: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease. Methods: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674). Results: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD. Conclusion: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients. PMID:26802093
Rollinson, Sara; Thompson, Jennifer C.; Harris, Jennifer M.; Stopford, Cheryl L.; Richardson, Anna M. T.; Jones, Matthew; Gerhard, Alex; Davidson, Yvonne S.; Robinson, Andrew; Gibbons, Linda; Hu, Quan; DuPlessis, Daniel; Neary, David; Pickering-Brown, Stuart M.
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients’ clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients’ delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all
Lagarde, J; Sarazin, M
Frontotemporal degeneration (FTD) in its behavioral variant (bvFTD) is probably one of the conditions that best illustrates the links between psychiatry and neurology. It is indeed admitted that between a third and half of patients with this condition, especially in early-onset forms, receive an initial diagnosis of psychiatric disorder (depression, schizophrenia, bipolar disorder) and are then referred to a psychiatric ward. BvFTD can thus be considered a neurological disorder with a psychiatric presentation. Among psychiatric symptoms reported in this disease, psychotic symptoms (hallucinations, delusions, especially of persecution), which have long been underestimated in bvFTD and are not part of the current diagnostic criteria, are present in about 20% of cases and may be inaugural. They are particularly common in the genetic forms related to a mutation in the C9orf72 gene (up to 50%), and to a lesser extent in the GRN gene (up to 25%). C9orf72 gene mutation is often associated with a family history of dementia or motor neuron disease but also of psychiatric disorders. It has also been described in sporadic presentation forms. Sometimes, the moderate degree of brain atrophy on MRI described in patients carrying this mutation may complicate the differential diagnosis with late-onset psychiatric diseases. In the present article, we underline the importance of considering that psychiatric - especially psychotic - symptoms are not rare in bvFTD, which should lead to a revision of the diagnostic criteria of this disease by taking greater account of this fact. We also propose a diagnostic chart, based on concerted evaluation by neurologists and psychiatrists for cases of atypical psychiatric symptoms (late-onset or pharmacoresistant troubles) leading to consider the possibility of a neurological disorder, in order to shed a new light on these difficult clinical situations. In the field of research, bvFTD may constitute a model to explore the neural basis of certain
Piquard, Ambre; Lacomblez, Lucette; Derouesne, Christian; Sieroff, Eric
We studied the role of the frontal lobes in orienting spatial attention and inhibiting attentional capture by goal-irrelevant stimuli, using a spatial cueing method in patients with frontotemporal dementia (FTD). Two blocks of trials were presented, one with non-predictive cues and the other with counter-predictive cues. FTD patients showed a…
Mendez, Mario F.; Shapira, Jill S.
The basis of hypersexual behavior among patients with dementia is not entirely clear. Hypersexual behavior may be a particular feature of behavioral variant frontotemporal dementia (bvFTD), which affects ventromedial frontal and adjacent anterior temporal regions specialized in interpersonal behavior. Recent efforts to define Hypersexual Disorder indicate an increasing awareness of heightened sexual activity as a source of personal distress and functional impairment, and clarification of hypersexuality in bvFTD could contribute to understanding the neurobiology of this behavior. This study reviewed 47 patients with bvFTD compared to 58 patients with Alzheimer’s disease (AD) for the presence of heightened sexual activity to the point of distress to caregivers and others. Hypersexual behavior occurred in 6 (13%) bvFTD patients compared to none of the AD patients. Caregivers judged all six bvFTD patients with hypersexual behavior as having a dramatic increase in sexual frequency from premorbid levels. All had general disinhibition, poor impulse control, and actively sought sexual stimulation. They had widened sexual interests and experienced sexual arousal from previously unexciting stimuli. One patient, with early and predominant right anterior temporal involvement, was easily aroused by slight stimuli, such as touching her palms. Although previously considered to be predominantly disinhibited sexual behavior as part of generalized disinhibition, these patients with dementia illustrate varying degrees of increased sexual desire. We conclude that bvFTD is uniquely associated with hypersexuality; it is more than just cognitive impairment with frontal disinhibition but also involves alterations in sexual drive, possibly from right anterior temporal-limbic involvement in this disease. PMID:23297146
Le Bouc, Raphaël; Lenfant, Pierre; Delbeuck, Xavier; Ravasi, Laura; Lebert, Florence; Semah, Franck; Pasquier, Florence
Theory of mind reasoning-the ability to understand someone else's mental states, such as beliefs, intentions and desires-is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone else's mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimer's disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone else's mental perspective requires two distinct processes: inferring someone else's belief and inhibiting one's own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimer's disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimer's disease were matched for age, gender, education and global cognitive impairment. [(18)F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind
Bannwarth, Sylvie; Ait-El-Mkadem, Samira; Chaussenot, Annabelle; Genin, Emmanuelle C; Lacas-Gervais, Sandra; Fragaki, Konstantina; Berg-Alonso, Laetitia; Kageyama, Yusuke; Serre, Valérie; Moore, David G; Verschueren, Annie; Rouzier, Cécile; Le Ber, Isabelle; Augé, Gaëlle; Cochaud, Charlotte; Lespinasse, Françoise; N'Guyen, Karine; de Septenville, Anne; Brice, Alexis; Yu-Wai-Man, Patrick; Sesaki, Hiromi; Pouget, Jean; Paquis-Flucklinger, Véronique
Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these
Midorikawa, Akira; Leyton, Cristian E.; Foxe, David; Landin-Romero, Ramon; Hodges, John R.; Piguet, Olivier
Background: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. Objective: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). Methods: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. Results: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. Conclusions: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia. PMID:27472884
Kaizik, Cassandra; Caga, Jashelle; Camino, Julieta; O'Connor, Claire M; McKinnon, Colleen; Oyebode, Jan R; Piguet, Olivier; Hodges, John R; Mioshi, Eneida
The objectives of this observational study were to (1) compare spousal and child caregiver burden; (2) compare co-resident and live-out child caregiver burden; and (3) investigate factors influencing spousal and child caregiver burden. Data was collected from 90 caregivers of people with frontotemporal degeneration (FTD) recruited from the Frontotemporal Dementia Research Group (Frontier) at Neuroscience Research, Australia. Of this caregiver group, 43 were spousal caregivers and 47 were child caregivers. Caregiver burden and emotional state were evaluated using the short Zarit Burden Interview and the short version of the Depression, Anxiety and Stress Scale-21. The Social Network Index was applied to ascertain the social network of the caregiver, while the Intimate Bond Measure was used to evaluate the current quality of the relationship between the caregiver and the person with dementia. The Frontotemporal Dementia Rating Scale was used to assess severity of dementia. Spousal and child caregivers experienced similar levels of burden, depression, anxiety, and stress, regardless of disease severity. Co-resident child caregivers had smaller social networks and greater burden than live-out caregivers. Dementia severity was key in spousal caregiver burden, whereas caregiver depression was most important in child caregiver burden. Child and spousal caregivers of individuals with FTD share similar levels of burden, influenced by different factors. Future interventions need to account for these differences.
Kaizik, Cassandra; Caga, Jashelle; Camino, Julieta; O’Connor, Claire M.; McKinnon, Colleen; Oyebode, Jan R.; Piguet, Olivier; Hodges, John R.; Mioshi, Eneida
The objectives of this observational study were to (1) compare spousal and child caregiver burden; (2) compare co-resident and live-out child caregiver burden; and (3) investigate factors influencing spousal and child caregiver burden. Data was collected from 90 caregivers of people with frontotemporal degeneration (FTD) recruited from the Frontotemporal Dementia Research Group (Frontier) at Neuroscience Research, Australia. Of this caregiver group, 43 were spousal caregivers and 47 were child caregivers. Caregiver burden and emotional state were evaluated using the short Zarit Burden Interview and the short version of the Depression, Anxiety and Stress Scale-21. The Social Network Index was applied to ascertain the social network of the caregiver, while the Intimate Bond Measure was used to evaluate the current quality of the relationship between the caregiver and the person with dementia. The Frontotemporal Dementia Rating Scale was used to assess severity of dementia. Spousal and child caregivers experienced similar levels of burden, depression, anxiety, and stress, regardless of disease severity. Co-resident child caregivers had smaller social networks and greater burden than live-out caregivers. Dementia severity was key in spousal caregiver burden, whereas caregiver depression was most important in child caregiver burden. Child and spousal caregivers of individuals with FTD share similar levels of burden, influenced by different factors. Future interventions need to account for these differences. PMID:28106550
Hsiung, Ging-Yuek R; DeJesus-Hernandez, Mariely; Feldman, Howard H; Sengdy, Pheth; Bouchard-Kerr, Phoenix; Dwosh, Emily; Butler, Rachel; Leung, Bonnie; Fok, Alice; Rutherford, Nicola J; Baker, Matt; Rademakers, Rosa; Mackenzie, Ian R A
Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34-74 years) and disease duration (mean = 5.3, range = 1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with M(r) 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor
Goodkind, Madeleine S; Sturm, Virginia E; Ascher, Elizabeth A; Shdo, Suzanne M; Miller, Bruce L; Rankin, Katherine P; Levenson, Robert W
Deficits in recognizing others' emotions are reported in many psychiatric and neurological disorders, including autism, schizophrenia, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Most previous emotion recognition studies have required participants to identify emotional expressions in photographs. This type of assessment differs from real-world emotion recognition in important ways: Images are static rather than dynamic, include only 1 modality of emotional information (i.e., visual information), and are presented absent a social context. Additionally, existing emotion recognition batteries typically include multiple negative emotions, but only 1 positive emotion (i.e., happiness) and no self-conscious emotions (e.g., embarrassment). We present initial results using a new task for assessing emotion recognition that was developed to address these limitations. In this task, respondents view a series of short film clips and are asked to identify the main characters' emotions. The task assesses multiple negative, positive, and self-conscious emotions based on information that is multimodal, dynamic, and socially embedded. We evaluate this approach in a sample of patients with bvFTD, AD, and normal controls. Results indicate that patients with bvFTD have emotion recognition deficits in all 3 categories of emotion compared to the other groups. These deficits were especially pronounced for negative and self-conscious emotions. Emotion recognition in this sample of patients with AD was indistinguishable from controls. These findings underscore the utility of this approach to assessing emotion recognition and suggest that previous findings that recognition of positive emotion was preserved in dementia patients may have resulted from the limited sampling of positive emotion in traditional tests.
Goodkind, Madeleine S.; Sturm, Virginia E.; Ascher, Elizabeth A.; Shdo, Suzanne M.; Miller, Bruce L.; Rankin, Katherine P.; Levenson, Robert W.
Deficits in recognizing others' emotions are reported in many psychiatric and neurological disorders, including autism, schizophrenia, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Most previous emotion recognition studies have required participants to identify emotional expressions in photographs. This type of assessment differs from real-world emotion recognition in important ways: Images are static rather than dynamic, include only 1 modality of emotional information (i.e., visual information), and are presented absent a social context. Additionally, existing emotion recognition batteries typically include multiple negative emotions, but only 1 positive emotion (i.e., happiness) and no self-conscious emotions (e.g., embarrassment). We present initial results using a new task for assessing emotion recognition that was developed to address these limitations. In this task, respondents view a series of short film clips and are asked to identify the main characters' emotions. The task assesses multiple negative, positive, and self-conscious emotions based on information that is multimodal, dynamic, and socially embedded. We evaluate this approach in a sample of patients with bvFTD, AD, and normal controls. Results indicate that patients with bvFTD have emotion recognition deficits in all 3 categories of emotion compared to the other groups. These deficits were especially pronounced for negative and self-conscious emotions. Emotion recognition in this sample of patients with AD was indistinguishable from controls. These findings underscore the utility of this approach to assessing emotion recognition and suggest that previous findings that recognition of positive emotion was preserved in dementia patients may have resulted from the limited sampling of positive emotion in traditional tests. PMID:26010574
Chaunu, Marie-Pierre; Deramecourt, Vincent; Buée-Scherrer, Valérie; Le Ber, Isabelle; Brice, Alexis; Ehrle, Nathalie; El Hachimi, Khalid; Pluot, Michel; Maurage, Claude-Alain; Bakchine, Serge; Buée, Luc
Frontotemporal lobe degeneration includes a large spectrum of neurodegenerative disorders. Patients with frontotemporal dementia with parkinsonism linked to chromosome 17 exhibit heterogeneity in both clinical and neuropathological features. Here, we report the case of a young patient with a G389R mutation. This teenager girl was 17 years old when she progressively developed severe behavioral disturbances. First, she was considered to be suffering from atypical depression. After 2 years, she was referred to the department of neurology. By this time, the patient exhibited typical frontotemporal dementia with mild extrapyramidal disorders. The main behavioral features included apathy and reduced speech output. MRI and SPECT showed a frontotemporal atrophy and hypofixation, respectively. She died 7 years after onset. Three relatives on her father side had also died after early onset dementia. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (Exon 13) of MAPT, the tau gene, resulting in a glycine to arginine substitution, in the patient and her non-affected father. Postmortem neuropathological and biochemical data indicate a Pick-like tau pathology but with phosphoserine 262-positive immunoreactivity. This case is remarkable because of the extremely early onset of the disease.
Flanagan, Emma C.; Wong, Stephanie; Dutt, Aparna; Tu, Sicong; Bertoux, Maxime; Irish, Muireann; Piguet, Olivier; Rao, Sulakshana; Hodges, John R.; Ghosh, Amitabha; Hornberger, Michael
Episodic memory recall processes in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) can be similarly impaired, whereas recognition performance is more variable. A potential reason for this variability could be false-positive errors made on recognition trials and whether these errors are due to amnesia per se or a general over-endorsement of recognition items regardless of memory. The current study addressed this issue by analysing recognition performance on the Rey Auditory Verbal Learning Test (RAVLT) in 39 bvFTD, 77 AD and 61 control participants from two centers (India, Australia), as well as disinhibition assessed using the Hayling test. Whereas both AD and bvFTD patients were comparably impaired on delayed recall, bvFTD patients showed intact recognition performance in terms of the number of correct hits. However, both patient groups endorsed significantly more false-positives than controls, and bvFTD and AD patients scored equally poorly on a sensitivity index (correct hits—false-positives). Furthermore, measures of disinhibition were significantly associated with false positives in both groups, with a stronger relationship with false-positives in bvFTD. Voxel-based morphometry analyses revealed similar neural correlates of false positive endorsement across bvFTD and AD, with both patient groups showing involvement of prefrontal and Papez circuitry regions, such as medial temporal and thalamic regions, and a DTI analysis detected an emerging but non-significant trend between false positives and decreased fornix integrity in bvFTD only. These findings suggest that false-positive errors on recognition tests relate to similar mechanisms in bvFTD and AD, reflecting deficits in episodic memory processes and disinhibition. These findings highlight that current memory tests are not sufficient to accurately distinguish between bvFTD and AD patients. PMID:27489543
Hirano, Shigeki; Shinotoh, Hitoshi; Shimada, Hitoshi; Aotsuka, Akiyo; Tanaka, Noriko; Ota, Tsuneyoshi; Sato, Koichi; Ito, Hiroshi; Kuwabara, Satoshi; Fukushi, Kiyoshi; Irie, Toshiaki; Suhara, Tetsuya
Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both
Chen, Ke-Liang; Sun, Yi-Min; Zhou, Yan; Zhao, Qian-Hua; Ding, Ding
Objective To explore the effect of APOE polymorphisms on patients with cognitive impairments in The Chinese Han population. Materials and methods A total of 1027 cases with Alzheimer’s disease (AD), 40 cases with vascular dementia (VaD), 28 cases with behavioral variant frontotemporal dementia (bvFTD), 54 cases with semantic dementia (SD), 44 cases with dementia with Lewy bodies (DLB), 583 cases with mild cognitive impairment (MCI), and 32 cases with vascular cognitive impairment no dementia (VCIND) were recruited consecutively from memory disorders clinics in Huashan Hospital between January 2010 and December 2014. The 1149 cognitively normal controls were recruited from the community epidemiologic investigations. The APOE genotypes were determined using the TaqMan assay. Results The distribution of genotype and allele frequencies of APOE differed significantly between control and AD or MCI, with ε4 increasing the risk of AD and MCI in a dose-dependent pattern and ε2 decreasing the risk of AD, but not the risk of MCI. As for VaD, significant differences in the APOE genotype distribution were found compared with the controls. E4/4 increased the risk of VaD and ε4 increased the risk of VCIND in women. The allele distribution differed between bvFTD and controls, but genotype and allele frequencies of APOE did not affect the risk of bvFTD, SD, and DLB. Conclusion In The Chinese Han population, APOE ε4 increased the risk of AD and MCI in a dose-dependent manner and ε2 decreased the risk of AD as reported previously. APOE ε4 might increase risk in VaD and female patients with VCIND, but no effects of APOE on bvFTD, DLB, and SD were found. PMID:26981880
Looi, Jeffrey C.L.; Rajagopalan, Priya; Walterfang, Mark; Madsen, Sarah K.; Thompson, Paul M.; Macfarlane, Matthew D.; Ching, Chris; Chua, Phyllis; Velakoulis, Dennis
Objective Direct neuronal loss or deafferentation of the putamen, a critical hub in corticostriatal circuits, may result in diverse and distinct cognitive and motoric dysfunction in neurodegenerative disease. Differential putaminal morphology, as a quantitative measure of corticostriatal integrity, may thus be evident in Huntington disease (HD), Alzheimer Disease (AD) and Frontotemporal Dementia (FTD), diseases with differential clinical dysfunction. Method HD (n=17), FTD (n=33) and AD (n=13) patients were diagnosed according to international consensus criteria, and with healthy controls (n=17), were scanned on the same MRI scanner. Patients underwent brief cognitive testing using the Neuropsychiatry unit cognitive assessment tool (NUCOG). Ten MRI scans from this dataset were manually segmented as a training set for the Adaboost algorithm, which automatically segmented all remaining scans for the putamen, yielding the following subset of the data: 9 left and 12 right putamen segmentations for AD; 25 left and 26 right putamina for FTD; 16 left and 15 right putamina for HD; 12 left and 12 right putamina for controls. Shape analysis was performed at each point on the surface of each structure using a multiple regression controlling for age and sex to compare radial distance across diagnostic groups. Results Age, but not sex and ICV, were significantly different in the segmentation subgroups by diagnosis. The AD group showed significantly poorer performance on cognitive testing than FTD. Mean putaminal volumes were HD
Issac, Thomas Gregor; Chandra, Sadanandavalli Retnaswami; Gupta, Neelesh; Rukmani, Malligurki Raghurama; Deepika, S.; Sathyaprabha, T. N.
Introduction: In frontotemporal dementia (FTD) and Alzheimer's disease (AD), central autonomic structures get affected early. An insight into autonomic functions in these patients is likely to be of diagnostic importance and thus help in prognosticating and also probably explain unexplained sudden death in some of these patients. Objectives: The objective of this study is to identify autonomic dysfunction prevailing in patients. Then, if there is dysfunction, is the pattern same or different in these two conditions. And if different it will serve as an additional biomarker for specific diagnosis. Patients and Methods: There were 25 patients and 25 controls and six patients and three controls in AD and FTD groups, respectively. The participants who were recruited were assessed for heart rate variability and conventional cardiac autonomic function testing. The parameters were analyzed using LabChart version 7 software and compared with control population using appropriate statistical methods using SPSS version 22 software. Results: The mean overall total power was low in the FTD group (P < 0.001), and there was significant reduction in the standard deviation of normal-to-normal intervals and root mean square of successive differences (P < 0.001) with elevated sympathovagal balance in the FTD group (P = 0.04). Patients with AD also showed sympathetic dominance, but there was in addition parasympathetic suppression unlike in the FTD group. Conclusion: This study reveals autonomic dysfunction in patients with FTD and AD. Both conditions show sympathetic dominance, probably consecutive to the involvement of central autonomic regulatory structures as a shared domain. It remains to be confirmed if these findings are the cause or effect of neurodegeneration and might open up newer territories of research based on the causal role of neurotransmitters in these regions and thus lead to novel therapeutic options such as yoga. The presence of parasympathetic suppression in AD in
... dementia is a progressive brain disorder that affects personality, behavior, and language. The symptoms of this disorder ... years after the appearance of symptoms. Changes in personality and behavior are the most common early signs ...
Harciarek, Michał; Cosentino, Stephanie
Frontotemporal dementia (FTD) represents a spectrum of non-Alzheimer’s degenerative conditions associated with focal atrophy of the frontal and/or temporal lobes. Frontal and temporal regions of the brain have been shown to be strongly involved in executive function, social cognition and language processing and, thus, deficits in these domains are frequently seen in patients with FTD or may even be hallmarks of a specific FTD subtype ( i.e., relatively selective and progressive language impairment in primary progressive aphasia). In this review, we have attempted to delineate how language, executive function, and social cognition may contribute to the diagnosis of FTD syndromes, namely the behavioral variant FTD as well as the language variants of FTD including the three subtypes of primary progressive aphasia (PPA): non-fluent/agrammatic, semantic, and logopenic. This review also addresses the extent to which deficits in these cognitive areas contribute to the differential diagnosis of FTD versus AD. Finally, early clinical determinants of pathology are briefly discussed and contemporary challenges to the diagnosis of FTD are presented. PMID:23611348
Watson, Annie; Pribadi, Mochtar; Chowdari, Kodavali; Clifton, Sue; Joel Wood; Miller, Bruce L; Coppola, Giovanni; Nimgaonkar, Vishwajit
A pathologic hexanucleotide repeat expansion in C9orf72 causes frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). Behavioral abnormalities can also occur among mutation carriers with FTD, but it is uncertain whether such mutations occur among persons with psychoses per se. Among participants in a genetic study of psychoses (N=739), two pairs of related individuals had C9orf72 expansions, of whom three were diagnosed with schizophrenia (SZ) / schizoaffective disorder (SZA), but their clinical features did not suggest dementia or ALS. A few patients with SZ/SZA carry C9orf72 repeat expansions; such individuals are highly likely to develop FTD/ALS.
Santillo, Alexander Frizell; Mårtensson, Johanna; Lindberg, Olof; Nilsson, Markus; Manzouri, Amir; Landqvist Waldö, Maria; van Westen, Danielle; Wahlund, Lars-Olof; Lätt, Jimmy; Nilsson, Christer
MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p=0.031), and borderline significant for fractional anisotropy vs. VBM (p=0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls. PMID:23874403
Irish, Muireann; Hodges, John R; Piguet, Olivier
Remembering the past and imagining the future are complex endeavours proposed to rely on a core neurobiological brain system. In the behavioural variant of frontotemporal dementia (bvFTD), regional patterns of brain atrophy affect medial prefrontal and temporal cortices of this core network. While autobiographical memory impairments have been documented in bvFTD, it remains unknown whether the ability to imagine future events is also compromised. Here, we investigated episodic future thinking in 10 bvFTD patients and contrasted their performance with Alzheimer's disease (AD, n = 10) and healthy matched Control (n = 10) participants. Participants were asked to remember 3 events from the previous year and to envisage 3 possible events that could occur in the next year. Both patient groups showed equivalent episodic detail performance for the retrieval of past events and the simulation of possible future episodes. Patients with bvFTD, however, showed additional impairments for the generation of external (non-episodic) details irrespective of condition. Voxel-based morphometry analyses revealed divergent neural correlates of episodic past and future thinking performance specific to each patient group. Atrophy in the posterior cingulate cortex was implicated in the disruption of past and future thinking in AD. In contrast, in bvFTD, disruption of past retrieval correlated with atrophy in medial prefrontal regions, whereas future thinking deficits were associated with atrophy of frontopolar, medial temporal regions including the right hippocampus, and lateral temporal and occipital cortices. Our results point to the involvement of multiple brain regions in facilitating retrieval of past, and simulation of future, events. Damage to any of these key regions thus adversely affects the ability to engage in personally relevant mental time travel.
Mackenzie, Ian R A; Neumann, Manuela
Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The past decade has seen the discovery of several new FTD-causing genetic mutations and the identification of many of the relevant pathological proteins. The current neuropathological classification is based on the predominant protein abnormality and allows most cases of FTD to be placed into one of three broad molecular subgroups; frontotemporal lobar degeneration with tau, TDP-43 or FET protein accumulation. This review will describe our current understanding of the molecular basis of FTD, focusing on insights gained from the study of human postmortem tissue, as well as some of the current controversies. Most cases of FTD can be subclassified into one of three broad molecular subgroups based on the predominant protein that accumulates as pathological cellular inclusions. Understanding the associated pathogenic mechanisms and recognizing these FTD molecular subtypes in vivo will likely be crucial for the development and use of targeted therapies. This article is part of the Frontotemporal Dementia special issue.
Iizuka, O; Suzuki, K; Endo, K; Fujii, T; Mori, E
A 66-year-old right-handed man developed pure anarthria following pure word deafness. In addition to language disorders, his behavior gradually changed and finally included violence against his wife. Brain magnetic resonance imagings revealed atrophy of the left perisylvian area, which included the inferior half of the precentral gyrus and the upper portion of the superior temporal gyrus, consistent with frontotemporal dementia (FTD). It has been documented as either a disorder of expressive language or as an impaired understanding of word meaning. Unlike with pure anarthria, pure word deafness is not included in the clinical diagnostic current criteria for FTD. However, a large variety of language symptoms can appear in FTD according to the distribution of pathological changes in the frontotemporal cortices. This case suggests that pure word deafness could be a prodomal symptom of FTD.
Alladi, Suvarna; Bak, Thomas H; Shailaja, Mekala; Gollahalli, Divyaraj; Rajan, Amulya; Surampudi, Bapiraju; Hornberger, Michael; Duggirala, Vasanta; Chaudhuri, Jaydip Ray; Kaul, Subhash
Bilingualism has been found to delay onset of dementia and this has been attributed to an advantage in executive control in bilinguals. However, the relationship between bilingualism and cognition is complex, with costs as well as benefits to language functions. To further explore the cognitive consequences of bilingualism, the study used Frontotemporal dementia (FTD) syndromes, to examine whether bilingualism modifies the age at onset of behavioral and language variants of Frontotemporal dementia (FTD) differently. Case records of 193 patients presenting with FTD (121 of them bilingual) were examined and the age at onset of the first symptoms were compared between monolinguals and bilinguals. A significant effect of bilingualism delaying the age at onset of dementia was found in behavioral variant FTD (5.7 years) but not in progressive nonfluent aphasia (0.7 years), semantic dementia (0.5 years), corticobasal syndrome (0.4 years), progressive supranuclear palsy (4.3 years) and FTD-motor neuron disease (3 years). On dividing all patients predominantly behavioral and predominantly aphasic groups, age at onset in the bilingual behavioral group (62.6) was over 6 years higher than in the monolingual patients (56.5, p=0.006), while there was no difference in the aphasic FTD group (60.9 vs. 60.6 years, p=0.851). The bilingual effect on age of bvFTD onset was shown independently of other potential confounding factors such as education, gender, occupation, and urban vs rural dwelling of subjects. To conclude, bilingualism delays the age at onset in the behavioral but not in the aphasic variants of FTD. The results are in line with similar findings based on research in stroke and with the current views of the interaction between bilingualism and cognition, pointing to advantages in executive functions and disadvantages in lexical tasks.
Vorspan, Florence; Bertoux, Maxime; Brichant-Petitjean, Clara; Dubois, Bruno; Lépine, Jean-Pierre
Summary We report the case of a bipolar I patient who was diagnosed with frontotemporal dementia at the age of 54 during a manic episode. Her neurological state improved when this episode ended. Each subsequent thymic relapse was associated with cognitive deficits which subsided when the patient became euthymic, even though SPECT continued to show the same frontal hypoperfusion. We here discuss the hypothesis that the cognitive reserve of this patient, a former journalist, may, except during her mood episodes, have provided her with sufficient resources to meet her life demands despite her underlying neurological disorder. PMID:23402681
Cho, Hanna; Chin, Juhee; Suh, Mee Kyung; Kim, Hee Jin; Kim, Yeo Jin; Ye, Byoung Seok; Lee, Na Kyung; Kim, Eun Joo; Seo, Sang Won; Na, Duk L
Some patients with frontotemporal dementia (FTD) show an artistic enhancement of musical abilities. However, no patients with FTD, to date, have been reported to be able to learn how to play a musical instrument after disease onset. Herein we describe a patient (J. K.) who had never played any musical instruments premorbidly, but who learned to play the saxophone after being diagnosed with a behavioral variant of FTD. He mastered a repertoire that consisted of 10 pieces of Korean folk songs over a period of three years. Furthermore, his saxophone skills were high enough to outperform other students in his class.
Koopman, Karen; Le Bastard, Nathalie; Martin, Jean-Jacques; Nagels, Guy; De Deyn, Peter P; Engelborghs, Sebastiaan
To establish diagnostic accuracy (acc) and optimal cut-off levels of CSF tau phosphorylated at threonine 181 (P-tau(181P)) for discriminating Alzheimer's disease (AD) from non-AD dementias in autopsy-confirmed dementia patients, CSF levels of beta-amyloid peptide (Abeta(1-42)), total tau protein (T-tau) and P-tau(181P) from patients with definite AD (n=95) and non-AD dementias (n=50) were determined with single-parameter ELISA kits. Optimal P-tau(181P) cut-off levels for differentiating AD from pooled non-AD dementias, dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) were 50.4pg/mL (acc=0.73), 52.8pg/mL (acc=0.73) and 35.3pg/mL (acc=0.90), respectively. The optimal CSF P-tau(181P) cut-off level for discriminating AD from non-AD dementias was 50.4pg/mL. Optimal CSF P-tau(181P) cut-off levels differed between non-AD diagnostic dementia categories.
Ahmed, Rebekah M; Irish, Muireann; van Eersel, Janet; Ittner, Arne; Ke, Yazi D; Volkerling, Alexander; van der Hoven, Julia; Tanaka, Kimi; Karl, Tim; Kassiou, Michael; Kril, Jillian J; Piguet, Olivier; Götz, Jürgen; Kiernan, Matthew C; Halliday, Glenda M; Hodges, John R; Ittner, Lars M
Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.
Lashley, Tammaryn; Rohrer, Jonathan D; Mahoney, Colin; Gordon, Elizabeth; Beck, Jon; Mead, Simon; Warren, Jason; Rossor, Martin; Revesz, Tamas
Aims Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease and is the second most common form of young onset dementia after Alzheimer's disease (AD). An autosomal dominant pattern of inheritance is present in around 25–50% of FTLD cases indicating a strong genetic component. Major pathogenic mutations of FTLD have been demonstrated independently in the progranulin (GRN) gene and the C9orf72 hexanucleotide expansion repeat. In this study we present a family that have been identified as carrying both a GRN Cys31fs mutation and the C9orf72 hexanucleotide expansion repeat. Methods In the present study we describe the clinical and genetic details of family members and pathological features of two family members that have come to post-mortem. Results The mean age at disease onset was 57 years (48–61 years) and mean duration 4 years (2–7 years). The most common presenting syndrome was behavioural variant frontotemporal dementia. Brain imaging from available cases showed a symmetrical pattern of atrophy particularly affecting the frontal and temporal lobes. Pathologically two cases were classified as FTLD-TDP type A with TDP-43 positive inclusions, with additional p62-positive ‘star-like’ inclusions found in the hippocampal formation and cerebellum. Conclusions The type and distribution of the pathological lesions in these two cases were in keeping with FTLD cases carrying only the C9orf72 hexanucleotide repeat. However the driving force of the pathological process may be either pathogenic mutation or a combination of both converging on a singular mechanism. PMID:24286341
Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Korada, Suresh Kumar; Teja, Karru Venkata Ravi; Philip, Mariamma
Introduction: About 20–50% of relatively young onset dementia belongs to frontotemporal type. Most of these patients are diagnosed as psychiatric illness as their memory and instrumental activities of daily living remain unaltered till late and most of these patients do not qualify for dementia by the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. In this study, we analyzed the behavioral symptoms in our patients with radiologically and neuropsychologically proven as probable behavioral variant of frontotemporal dementia (FTD). Patients and Methods: Twenty patients qualifying the International Consensus Criteria were included and evaluated using National Institute of Mental Health and Neurosciences neuropsychological battery in addition to all mandatory dementia workup. Results: The mean age was 53.9 ± 9.9 years and the mean duration of illness was 2 ± 1.3 years. Sixty percent of them were <60 years. There were 9 males and 11 females. Most common heralding symptom noticed in 85% of the patients was irritability and aggression as against apathy in 100% in western studies. Memory impairment was found in only 11.1% as against 25% in western studies. Disinhibition, eating problems, stereotyped behavior, delusions, and paranoia were comparable between the study population and literature. Discussion and Conclusion: There are minor variations in the neuropsychological manifestations in our patients compared to western population. Agitation and aggression are more and memory impairment is very less making the diagnosis of FTD possible only if there is a high degree of suspicion. These symptoms are less amenable for pharmacotherapy and therefore, there is a need to explore the benefits of nonpharmacological treatment options such as yoga and meditation. PMID:27570344
Cerciello, Milena; Isella, Valeria; Proserpi, Alice; Papagno, Costanza
Alzheimer's disease (AD), vascular dementia (VaD) and frontotemporal dementia (FTD) are the most common forms of dementia. It is well known that memory deficits in AD are different from those in VaD and FTD, especially with respect to cued recall. The aim of this clinical study was to compare the memory performance in 15 AD, 10 VaD and 9 FTD patients and 20 normal controls by means of a 24-item Grober-Buschke test . The patients' groups were comparable in terms of severity of dementia. We considered free and total recall (free plus cued) both in immediate and delayed recall and computed an Index of Sensitivity to Cueing (ISC)  for immediate and delayed trials. We assessed whether cued recall predicted the subsequent free recall across our patients' groups. We found that AD patients recalled fewer items from the beginning and were less sensitive to cueing supporting the hypothesis that memory disorders in AD depend on encoding and storage deficit. In immediate recall VaD and FTD showed a similar memory performance and a stronger sensitivity to cueing than AD, suggesting that memory disorders in these patients are due to a difficulty in spontaneously implementing efficient retrieval strategies. However, we found a lower ISC in the delayed recall compared to the immediate trials in VaD than FTD due to a higher forgetting in VaD.
Kimonis, Virginia. E.; Mehta, Sarju G.; Fulchiero, Erin C.; Thomasova, Dana; Pasquali, Marzia; Boycott, Kym; Neilan, Edward G.; Kartashov, Alex; Forman, Mark S.; Tucker, Stuart; Kimonis, Katerina; Mumm, Steven; Whyte, Michael P.; Smith, Charles D.; Watts, Giles D. J.
Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9–60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy. PMID:18260132
Xu, Zihui; Poidevin, Mickael; Li, Xuekun; Li, Yujing; Shu, Liqi; Nelson, David L.; Li, He; Hales, Chadwick M.; Gearing, Marla; Wingo, Thomas S.; Jin, Peng
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. PMID:23553836
Kortte, Kathleen B; Rogalski, Emily J
Primary progressive aphasia (PPA) and behavioural-variant frontotemporal dementia (bvFTD) are clinical syndromes under the umbrella term 'frontotemporal dementia' (FTD) and are caused by a neurodegenerative disease with an onset most typically in the productive years of adulthood. The cognitive and behavioural impairments associated with FTD interfere with successful engagement in typical life roles, such as parenting, working, and maintenance of interpersonal relationships. There are currently no treatments to stop or slow the degenerative process and there are only very limited medication options for the management of the cognitive-behavioural symptoms. However, alternative, non-pharmacological interventions may offer significant benefit to the quality of life of the diagnosed individual. The goal of this paper is to provide an overview of the approaches available through neurorehabilitation and community-based services that facilitate successful engagement in life activities and promote optimal quality of life for the individuals and families living with FTD. It is hoped that as medical providers become more familiar with behavioural interventions, referrals for services will increase thereby allowing individuals with FTD and their caregivers to learn ways to adapt, adjust, and participate in life to the fullest despite the impairments from this progressive disease.
Kortte, Kathleen B.; Rogalski, Emily J.
Primary progressive aphasia (PPA) and behavioral-variant frontotemporal dementia (bvFTD) are clinical syndromes under the umbrella term “frontotemporal dementia (FTD)” and are caused by a neurodegenerative disease with an onset most typically in the productive years of adulthood. The cognitive and behavioral impairments associated with FTD interfere with the successful engagement in typical life roles, such as parenting, working, and maintenance of interpersonal relationships. There are currently no treatments to stop or slow the degenerative process and there are only very limited medication options for the management of the cognitive-behavioral symptoms. However, alternative, non-pharmacological interventions may offer significant benefit to the quality of life of the diagnosed individual. The goal of this paper is to provide an overview of the approaches available through neurorehabilitation and community-based services that facilitate successful engagement in life activities and promote optimal quality of life for the individuals and families living with FTD. It is hoped that as medical providers become more familiar with behavioral interventions, referrals for services will increase thereby allowing individuals with FTD and their caregivers to learn ways to adapt, adjust, and participate in life to the fullest despite the impairments from this progressive disease. PMID:23611353
Shinagawa, Shunichiro; Nakajima, Shinichiro; Plitman, Eric; Graff-Guerrero, Ariel; Mimura, Masaru; Nakayama, Kazuhiko; Miller, Bruce L
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by changes in behavior and language caused by focal degeneration of the frontal and anterior temporal lobes. The behavioral symptoms are distressing to patients and their caregivers. Non-pharmacological management is important as no disease-specific pharmacological treatment for FTD is currently available. The primary objective is to review the literature on non-pharmacological management for FTD and to propose directions for future research, with reference to findings. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included "frontotemporal dementia", and words related to non-pharmacological management, and it identified a total of 858 articles. Results revealed that very few randomized controlled trials exist on non-pharmacological management interventions for FTD. These interventions have been proposed by literature based on clinical experience. A small number of studies have supported behavioral management techniques that exploit disease-specific behaviors and preserved functions in patients with FTD, along with the management of caregivers' distress. These limitations warrant well-designed large-scale research to examine effects of non-pharmacological interventions on behavioral symptoms of FTD.
Thelen, Mathias; Razquin, Cristina; Hernández, Isabel; Gorostidi, Ana; Sánchez-Valle, Raquel; Ortega-Cubero, Sara; Wolfsgruber, Steffen; Drichel, Dmitriy; Fliessbach, Klaus; Duenkel, Tanja; Damian, Marinella; Heilmann, Stefanie; Slotosch, Anja; Lennarz, Martina; Seijo-Martínez, Manuel; Rene, Ramón; Kornhuber, Johannes; Peters, Oliver; Luckhaus, Christian; Jahn, Holger; Hüll, Michael; Rüther, Eckart; Wiltfang, Jens; Lorenzo, Elena; Gascon, Jordi; Lleó, Alberto; Lladó, Albert; Campdelacreu, Jaume; Moreno, Fermin; Ahmadzadehfar, Hojjat; Fortea, Juan; Indakoetxea, Begoña; Heneka, Michael T; Wetter, Axel; Pastor, Maria A; Riverol, Mario; Becker, Tim; Frölich, Lutz; Tárraga, Lluís; Boada, Mercè; Wagner, Michael; Jessen, Frank; Maier, Wolfgang; Clarimón, Jordi; López de Munain, Adolfo; Ruiz, Agustín; Pastor, Pau; Ramirez, Alfredo
Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.
Block, Nikolas R.; Sha, Sharon J.; Karydas, Anna M.; Fong, Jamie C.; De May, Mary G.; Miller, Bruce L.; Rosen, Howard J.
Objective To describe psychiatric presentations in individuals with genetic mutations causing frontotemporal dementia (FTD). Design Case descriptions from five carriers of FTD-related gene mutations with symptoms associated with non-neurodegenerative psychiatric disease. Setting A comprehensive research program investigating genetic and non-genetic FTD at the University of California, San Francisco Memory and Aging Center. Participants Three probands and two non-proband gene carriers. Measurements Medical history and neurological examination, neuropsychological testing, MR and/or PET imaging, and a genetic analysis to screen for dementia-related mutations. Genetic status was unknown at the time of initial evaluation. Results The chosen cases are illustrative of the variety of presentations of psychiatric symptoms in FTD-gene carriers. In some cases, a non-neurodegenerative psychiatric illness was diagnosed based on specific symptoms, but the diagnosis may have been inappropriate based on the overall syndrome. In other cases, symptoms closely resembling those seen in non-neurodegenerative psychiatric illness did occur, in some immediately preceding the development of dementia, and in others, developing a decade prior to dementia symptoms. Conclusions Psychiatric symptoms in FTD gene carriers can be very similar to those seen in non-neurodegenerative psychiatric illness. Psychiatric symptoms with atypical features (e.g., late-life onset, insidiously worsening course) should prompt careful assessment for neurodegenerative disease. Guidelines for such an assessment should be established. PMID:26324540
Hashimoto, Mamoru; Tanaka, Hibiki; Fujise, Noboru; Matsushita, Masateru; Miyagawa, Yusuke; Hatada, Yutaka; Fukuhara, Ryuji; Hasegawa, Noriko; Todani, Shuji; Matsukuma, Kengo; Kawano, Michiyo; Ikeda, Manabu
Malnutrition among dementia patients is an important issue. However, the biochemical markers of malnutrition have not been well studied in this population. The purpose of this study was to compare biochemical blood markers among patients with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). A total of 339 dementia outpatients and their family caregivers participated in this study. Low serum albumin was 7.2 times more prevalent among patients with DLB and 10.1 times more prevalent among those with FTLD than among those with AD, with adjustment for age. Low hemoglobin was 9.1 times more common in female DLB patients than in female AD patients, with adjustment for age. The levels of biochemical markers were not significantly correlated with cognitive function. Family caregivers of patients with low total protein, low albumin, or low hemoglobin were asked if the patients had loss of weight or appetite; 96.4% reported no loss of weight or appetite. In conclusion, nutritional status was worse in patients with DLB and FTLD than in those with AD. A multidimensional approach, including blood testing, is needed to assess malnutrition in patients with dementia. PMID:27336725
Steketee, Rebecca M.E.; Meijboom, Rozanna; Bron, Esther E.; Osse, Robert Jan; de Koning, Inge; Jiskoot, Lize C.; Klein, Stefan; de Jong, Frank Jan; van der Lugt, Aad; van Swieten, John C.; Smits, Marion
Purpose ‘Phenocopy’ frontotemporal dementia (phFTD) patients may clinically mimic the behavioral variant of FTD (bvFTD), but do not show functional decline or abnormalities upon visual inspection of routine neuroimaging. We aimed to identify abnormalities in gray matter (GM) volume and perfusion in phFTD and to assess whether phFTD belongs to the FTD spectrum. We compared phFTD patients with both healthy controls and bvFTD patients. Materials & methods Seven phFTD and 11 bvFTD patients, and 20 age-matched controls underwent structural T1-weighted magnetic resonance imaging (MRI) and 3D pseudo-continuous arterial spin labeling (pCASL) at 3T. Normalized GM (nGM) volumes and perfusion, corrected for partial volume effects, were quantified regionally as well as in the entire supratentorial cortex, and compared between groups taking into account potential confounding effects of gender and scanner. Results PhFTD patients showed cortical atrophy, most prominently in the right temporal lobe. Apart from this regional atrophy, GM volume was generally not different from either controls or from bvFTD. BvFTD however showed extensive frontotemporal atrophy. Perfusion was increased in the left prefrontal cortex compared to bvFTD and to a lesser extent to controls. Conclusion PhFTD and bvFTD show overlapping cortical structural abnormalities indicating a continuum of changes especially in the frontotemporal regions. Together with functional changes suggestive of a compensatory response to incipient pathology in the left prefrontal regions, these findings are the first to support a possible neuropathological etiology of phFTD and suggest that phFTD may be a neurodegenerative disease on the FTD spectrum. PMID:27222795
Bertoux, Maxime; de Souza, Leonardo Cruz; O'Callaghan, Claire; Greve, Andrea; Sarazin, Marie; Dubois, Bruno; Hornberger, Michael
Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.
Guinto, Jake B; Ritson, Gillian P; Taylor, J Paul; Forman, Mark S
Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions without VCP mutations. Yet, the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding protein, a feature that links this rare disease with the pathology associated with the majority of sporadic FTD as well as disease resulting from different genetic alterations. VCP, a member of the AAA-ATPase gene family, associates with a plethora of protein adaptors to perform a variety of cellular processes including Golgi assembly/disassembly and regulation of the ubiquitin-proteasome system. However, the mechanism whereby mutations in VCP lead to CNS, muscle, and bone disease is largely unknown. In this report, we review current literature on IBMPFD, focusing on the pathology of the disease and the biology of VCP with respect to IBMPFD.
Boutoleau-Bretonnière, Claire; Evrard, Christelle; Hardouin, Jean Benoît; Rocher, Laëtitia; Charriau, Tiphaine; Etcharry-Bouyx, Frédérique; Auriacombe, Sophie; Richard-Mornas, Aurélie; Lebert, Florence; Pasquier, Florence; Sauvaget, Anne; Bulteau, Samuel; Vercelletto, Martine; Derkinderen, Pascal; Bretonnière, Cédric; Thomas-Antérion, Catherine
Background The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. Objective We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. Methods Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. Results DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. Conclusion We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD. PMID:26955383
Lauterbach, Edward C; Kuppuswamy, Preetha Sharone; Greenway, Lauren L
Sequential therapeutic trials for catatonoid frontal signs in clinically-evident frontotemporal dementia (n = 2) revealed differential benefits for lorazepam, amantadine, memantine, pramipexole, aripiprazole, quetiapine, citalopram, and donepezil, although certain signs also worsened. Citalopram and donepezil were poorly tolerated. Ramelteon was without effect. While memantine appeared to improve cognition in case 1, this remains to be established by more reliable neuropsychological testing. Parkinsonism (case 2) responded to pramipexole, but not amantadine or levodopa. Possible relationships of catatonoid signs requiring future confirmation include insufficient GABA-A (multiple signs) and D2 (mutism) and excessive NMDA (immobility, rigidity), D2/D3 (mannerisms, verbal perseveration), and 5HT1a (staring) receptor stimulation. Low-dose lorazepam and quetiapine required close monitoring.
Jovičić, Ana; Paul, Joseph W; Gitler, Aaron D
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of nucleocytoplasmic transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.
Gibbons, Chris; Oken, Barry; Fried-Oken, Melanie
We describe a 57 year old, right handed, English speaking man initially diagnosed with progressive aphasia. Language assessment revealed inconsistent performance in key areas. Expressive language was reduced to a few short, perseverative phrases. Speech was severely apraxic. Primary modes of communication included gesture, pointing, gaze, physical touch and leading. Responses were 100% accurate when he was provided with written words, with random or inaccurate responses for strictly auditory/verbal input. When instructions to subsequent neuropsychological tests were written instead of spoken, performance improved markedly. A comprehensive audiology assessment revealed no hearing impairment. Neuroimaging was unremarkable. Neurobehavioral evaluation utilizing written input led to diagnoses of word deafness and frontotemporal dementia, resulting in very different management. We highlight the need for alternative modes of language input for assessment and treatment of patients with language comprehension symptoms. PMID:22425725
Gibbons, Chris; Oken, Barry; Fried-Oken, Melanie
We describe a 57 year old, right handed, English speaking man initially diagnosed with progressive aphasia. Language assessment revealed inconsistent performance in key areas. Expressive language was reduced to a few short, perseverative phrases. Speech was severely apraxic. Primary modes of communication included gesture, pointing, gaze, physical touch and leading. Responses were 100% accurate when he was provided with written words, with random or inaccurate responses for strictly auditory/verbal input. When instructions to subsequent neuropsychological tests were written instead of spoken, performance improved markedly. A comprehensive audiology assessment revealed no hearing impairment. Neuroimaging was unremarkable. Neurobehavioral evaluation utilizing written input led to diagnoses of word deafness and frontotemporal dementia, resulting in very different management. We highlight the need for alternative modes of language input for assessment and treatment of patients with language comprehension symptoms.
Guo, Christine C.; Sturm, Virginia E.; Zhou, Juan; Gennatas, Efstathios D.; Trujillo, Andrew J.; Hua, Alice Y.; Crawford, Richard; Stables, Lara; Kramer, Joel H.; Rankin, Katherine; Levenson, Robert W.; Rosen, Howard J.; Miller, Bruce L.; Seeley, William W.
The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic–sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow. PMID:27071080
Dobson-Stone, Carol; Hallupp, Marianne; Loy, Clement T; Thompson, Elizabeth M; Haan, Eric; Sue, Carolyn M; Panegyres, Peter K; Razquin, Cristina; Seijo-Martínez, Manuel; Rene, Ramon; Gascon, Jordi; Campdelacreu, Jaume; Schmoll, Birgit; Volk, Alexander E; Brooks, William S; Schofield, Peter R; Pastor, Pau; Kwok, John B J
A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in 'non-expansion' patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5-17% of patients (21-41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine 'expansion-positive' patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an 'intermediate' allele with a mean size of only ∼65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of 'non-expansion' FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ∼65 repeats may be sufficient to cause disease.
Su, J H; Nichol, K E; Sitch, T; Sheu, P; Chubb, C; Miller, B L; Tomaselli, K J; Kim, R C; Cotman, C W
Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly the frontal and anterior temporal cortex. It is associated with neuronal loss, gliosis, and microvacuolation of lamina I to III in these brain regions. In previous studies we have described neurons with DNA damage in the absence of tangle formation and suggested this may result in tangle-independent mechanisms of neurodegeneration in the AD brain. In the present study, we sought to examine DNA fragmentation and activated caspase-3 expression in FTD brain where tangle formation is largely absent. The results demonstrate that numerous nuclei were TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was detected in both neurons and astrocytes and was elevated in FTD cases as compared to control cases. A subset of activated caspase-3-positive cells were also TdT positive. In addition, the cell bodies of a subset of astrocytes showed enlarged, irregular shapes, and vacuolation and their processes appeared fragmented. These degenerating astrocytes were positive for activated caspase-3 and colocalized with robust TdT-labeled nuclei. These findings suggest that a subset of astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may contribute to neuronal cell death and astrocyte degeneration in the FTD brain. Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD (228).
Wong, Stephanie; Flanagan, Emma; Savage, Greg; Hodges, John R.; Hornberger, Michael
Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer’s disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures. PMID:24505314
Li, Pan; Zhou, Yu-Ying; Lu, Da; Wang, Yan; Zhang, Hui-Hong
Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer's disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.
Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana; Guelfi, Sebastian; Witeolar, Aree; Karch, Celeste M; Schork, Andrew J; Fan, Chun C; Brewer, James B; Schellenberg, Gerard S; Dillon, William P; Sugrue, Leo P; Hess, Christopher P; Yokoyama, Jennifer S; Bonham, Luke W; Rabinovici, Gil D; Miller, Bruce L; Andreassen, Ole A; Dale, Anders M; Hardy, John; Desikan, Rahul S
Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer’s disease (AD) and Parkinson’s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10−12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10−7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk. PMID:27899424
Gleichgerrcht, Ezequiel; Flichtentrei, Daniel; Manes, Facundo
Diagnosis of behavioral variant frontotemporal dementia (bvFTD) can be especially challenging during the early stages for several reasons, including the fact that (a) behavioral disturbances in bvFTD can mimic the symptomatic profile of psychiatric disorders; (b) neuropsychological performance may be relatively spared; and (c) changes in structural neuroimaging may go undetected. Most frequently, bvFTD is not included as part of medical or residency training outside the field of cognitive neurology. The present study aimed at examining bvFTD-related practices concerning academic and professional training, diagnosis, and treatment across Latin America. We surveyed the academic and professional aspects of clinical practice related to bvFTD of 596 physicians from different fields throughout the continent. We discuss several aspects concerning Latin American physicians' training on dementia and bvFTD, the way in which they approach the differential diagnosis of bvFTD, and their most frequent strategies for the treatment of this condition. We conclude that information about bvFTD deserves more attention in both undergraduate and postgraduate medical education in Latin America, and that understanding clinical practices related to FTD can help design more efficient training programs for physicians in this and other world regions.
Ranasinghe, Kamalini G; Rankin, Katherine P; Pressman, Peter S; Perry, David C; Lobach, Iryna V; Seeley, William W; Coppola, Giovanni; Karydas, Anna M; Grinberg, Lea T; Shany-Ur, Tal; Lee, Suzee E; Rabinovici, Gil D; Rosen, Howard J; Gorno-Tempini, Maria Luisa; Boxer, Adam L; Miller, Zachary A; Chiong, Winston; DeMay, Mary; Kramer, Joel H; Possin, Katherine L; Sturm, Virginia E; Bettcher, Brianne M; Neylan, Michael; Zackey, Diana D; Nguyen, Lauren A; Ketelle, Robin; Block, Nikolas; Wu, Teresa Q; Dallich, Alison; Russek, Natanya; Caplan, Alyssa; Geschwind, Daniel H; Vossel, Keith A; Miller, Bruce L
Importance Clearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms, and will improve clinicians’ ability to predict disease course and design targeted management strategies. Objective To identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD, using statistical classification approaches. Design, Setting and Participants In this retrospective observational study, 104 patients meeting the Frontotemporal Dementia Consortium consensus criteria for bvFTD were evaluated at the Memory and Aging Center of Department of Neurology at University of California, San Francisco. Patients underwent a multidisciplinary clinical evaluation, including clinical demographics, genetic testing, symptom evaluation, neurological exam, neuropsychological bedside testing, and socioemotional assessments. Ninety patients underwent structural Magnetic Resonance Imaging at their earliest evaluation at the memory clinic. From each patients’ structural imaging, the mean volumes of 18 regions of interest (ROI) comprising the functional networks specifically vulnerable in bvFTD, including the ‘salience network’ (SN), with key nodes in the frontoinsula and pregenual anterior cingulate, and the ‘semantic appraisal network’ (SAN) anchored in the anterior temporal lobe and subgenual cingulate, were estimated. Principal component and cluster analyses of ROI volumes were used to identify patient clusters with anatomically distinct atrophy patterns. Main Outcome Measures We evaluated brain morphology and other clinical features including presenting symptoms, neurologic exam signs, neuropsychological performance, rate of dementia progression, and socioemotional function in each patient cluster. Results We identified four subgroups of bvFTD patients with distinct anatomic patterns of
Lee, Suzee E; Tartaglia, Maria C; Yener, Görsev; Genç, Sermin; Seeley, William W; Sanchez-Juan, Pascual; Moreno, Fermin; Mendez, Mario F; Klein, Eric; Rademakers, Rosa; López de Munain, Adolfo; Combarros, Onofre; Kramer, Joel H; Kenet, Robert O; Boxer, Adam L; Geschwind, Michael D; Gorno-Tempini, Maria-Luisa; Karydas, Anna M; Rabinovici, Gil D; Coppola, Giovanni; Geschwind, Daniel H; Miller, Bruce L
Recently, Coppola and colleagues demonstrated that a rare microtubule-associated protein tau (MAPT) sequence variant, c.454G>A (p.A152T) significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer disease (AD) in a screen of 15,369 subjects. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (n=2); 2 patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathologic correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
Daianu, Madelaine; Mendez, Mario F; Baboyan, Vatche G; Jin, Yan; Melrose, Rebecca J; Jimenez, Elvira E; Thompson, Paul M
Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer's disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics - fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter - the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally
O'Connor, Claire M.; Clemson, Lindy; Hornberger, Michael; Leyton, Cristian E.; Hodges, John R.; Piguet, Olivier
Abstract Background: The relationship between behavioral changes and functional decline in frontotemporal dementia (FTD) is not well understood. Methods: Thirty-nine patients (21 behavioral variant FTD [bvFTD], 18 semantic variant primary progressive aphasia [svPPA]) were followed up longitudinally (2–4 years follow-up). Functional (Disability Assessment for Dementia) and behavioral (Cambridge Behavioural Inventory Revised) assessments were included for between-group (pairwise comparisons, mixed model analysis) and within-group analyses (bivariate correlations). Results: Functionally, patients with bvFTD were more impaired than patients with svPPA at baseline and continued to be at follow-up, despite similar disease duration. By contrast, behavioral impairments differed between patient groups at baseline and at follow-up. At baseline, patients with bvFTD exhibited higher levels of apathy and changes in eating than patients with svPPA; disinhibited and stereotypical behaviors were similar. Over the years, patients with bvFTD showed reduction in disinhibition and stereotypical behavior while apathy and eating changes increased. By contrast, all measured behaviors increased in patients with svPPA over time. Finally, only apathy made longitudinal contributions to functional disability in patients with svPPA, whereas apathy and stereotypical behavior were associated with increased disability in patients with bvFTD. Conclusions: Despite shared overlapping baseline behavioral symptoms, patients with bvFTD are more functionally impaired than patients with svPPA. Apathy has a strong role in disability for both bvFTD and svPPA, but stereotypical behaviors only contributed to functional deficits in patients with bvFTD. Our findings suggest that rigid/compulsive behaviors may in fact support activity engagement in patients with svPPA. Taken together, our results indicate that interventions to reduce disability in the FTD spectrum require an alternative rationale in
Daianu, Madelaine; Mezher, Adam; Mendez, Mario F.; Jahanshad, Neda; Jimenez, Elvira E.; Thompson, Paul M.
In network analysis, the so-called ‘rich club’ describes the core areas of the brain that are more densely interconnected among themselves than expected by chance, and has been identified as a fundamental aspect of the human brain connectome. This is the first in-depth diffusion imaging study to investigate the rich club along with other organizational changes in the brain's anatomical network in behavioral frontotemporal dementia (bvFTD), and a matched cohort with early-onset Alzheimer's disease (EOAD). Our study sheds light on how bvFTD and EOAD affect connectivity of white matter fiber pathways in the brain, revealing differences and commonalities in the connectome among the dementias. To analyze the breakdown in connectivity, we studied 3 groups: 20 bvFTD, 23 EOAD and 37 healthy elderly controls. All participants were scanned with diffusion-weighted MRI, and based on whole-brain probabilistic tractography and cortical parcellations, we analyzed the rich club of the brain's connectivity network. This revealed distinct patterns of disruption in both forms of dementia. In the connectome, we detected less disruption overall in EOAD than in bvFTD (False Discovery Rate (FDR) critical Pperm=5.7×10−3, 10,000 permutations), with more involvement of richly interconnected areas of the brain (chi-squared PΧ2=1.4×10−4) – predominantly posterior cognitive alterations. In bvFTD, we found a greater spread of disruption including the rich club (FDR critical Pperm=6×10−4), but especially more peripheral alterations (PΧ2=6.5×10−3), particularly in medial frontal areas of the brain, in line with the known behavioral socioemotional deficits seen in these patients. PMID:26678225
Miller, Laurie A.; Hsieh, Sharpley; Lah, Suncica; Savage, Sharon; Hodges, John R.; Piguet, Olivier
Patients with frontotemporal dementia (both behavioural variant [bvFTD] and semantic dementia [SD]) as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD (n = 17), SD (n = 12) or AD (n = 20) to an age- and education-matched group of healthy control subjects (n = 36) on three face emotion processing tasks (Ekman 60, Emotion Matching and Emotion Selection) and found that all three patient groups were similarly impaired. Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia. PMID:22207423
Lanata, Serggio C; Miller, Bruce L
The primary goal of this article is to critically discuss the syndromic overlap that exists between early behavioural variant frontotemporal dementia (bvFTD)—the most common clinical syndrome associated with frontotemporal lobar degeneration (FTLD)—and several primary psychiatric disorders. We begin by summarising the current state of knowledge regarding FTLD, including the recent discovery of FTLD-causative genetic mutations. Clinicopathological correlations in FTLD are subsequently discussed, while emphasising that clinical syndromes of FTD are dictated by the distribution of FTLD pathology in the brain. We then review a large number of cases with suspected and confirmed bvFTD that had previously been diagnosed with a primary psychiatric disorder. The clinical and neuroscientific implications of this overlap are discussed, focusing on the importance of early diagnosis for clinical and therapeutic reasons. We propose that largely due to the paucity of biomarkers for primary psychiatric disorders, and the limited use of FTLD-related biomarkers by psychiatrists at present, it is very difficult to separate patients with early bvFTD from those with primary psychiatric disorders based on clinical grounds. Furthermore, specific limitations of the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 criteria for bvFTD may inadvertently discourage recognition of bvFTD in mental health settings. Clinically, more research is needed to develop tools that allow early differentiation of bvFTD from primary psychiatric disease, as bvFTD therapies will likely be most effective in the earliest stages of disease. From a neuroscience perspective, we argue that bvFTD provides an excellent paradigm for investigating the neural basis of psychiatric disorders. PMID:26216940
Möller, Christiane; Pijnenburg, Yolande A L; van der Flier, Wiesje M; Versteeg, Adriaan; Tijms, Betty; de Munck, Jan C; Hafkemeijer, Anne; Rombouts, Serge A R B; van der Grond, Jeroen; van Swieten, John; Dopper, Elise; Scheltens, Philip; Barkhof, Frederik; Vrenken, Hugo; Wink, Alle Meije
Purpose To investigate the diagnostic accuracy of an image-based classifier to distinguish between Alzheimer disease (AD) and behavioral variant frontotemporal dementia (bvFTD) in individual patients by using gray matter (GM) density maps computed from standard T1-weighted structural images obtained with multiple imagers and with independent training and prediction data. Materials and Methods The local institutional review board approved the study. Eighty-four patients with AD, 51 patients with bvFTD, and 94 control subjects were divided into independent training (n = 115) and prediction (n = 114) sets with identical diagnosis and imager type distributions. Training of a support vector machine (SVM) classifier used diagnostic status and GM density maps and produced voxelwise discrimination maps. Discriminant function analysis was used to estimate suitability of the extracted weights for single-subject classification in the prediction set. Receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were calculated for image-based classifiers and neuropsychological z scores. Results Training accuracy of the SVM was 85% for patients with AD versus control subjects, 72% for patients with bvFTD versus control subjects, and 79% for patients with AD versus patients with bvFTD (P ≤ .029). Single-subject diagnosis in the prediction set when using the discrimination maps yielded accuracies of 88% for patients with AD versus control subjects, 85% for patients with bvFTD versus control subjects, and 82% for patients with AD versus patients with bvFTD, with a good to excellent AUC (range, 0.81-0.95; P ≤ .001). Machine learning-based categorization of AD versus bvFTD based on GM density maps outperforms classification based on neuropsychological test results. Conclusion The SVM can be used in single-subject discrimination and can help the clinician arrive at a diagnosis. The SVM can be used to distinguish disease-specific GM patterns in patients with AD
Khan, Baber K.; Yokoyama, Jennifer S.; Takada, Leonel T.; Sha, Sharon J.; Rutherford, Nicola. J.; Fong, Jamie C.; Karydas, Anna; Wu, Teresa; Ketelle, Robin; Baker, Matt C.; Hernandez, Mariely-Dejesus; Coppola, Giovanni; Geschwind, Daniel H.; Rademakers, Rosa; Lee, Suzee E.; Rosen, Howard J.; Rabinovici, Gil D.; Seeley, William; Rankin, Katherine P.; Boxer, Adam L.; Miller, Bruce L.
Background Some patients meeting behavioral variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy, and have thus been referred to as bvFTD “phenocopies” or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have found no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, we describe two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions. Methods Three hundred and eighty-four patients with FTD clinical spectrum and Alzheimer’s disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns assessed using voxel-based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls. Results Both patients were age 48 at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over seven years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over two years, her neuropsychological and functional scores as well as brain atrophy remained stable. Conclusions C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease. PMID:22399793
Maestri, Michelangelo; Carnicelli, Luca; Economou, Nicholas-Tiberio; Bonakis, Anastasios; Paparrigopoulos, Thomas; Papageorgiou, Sokratis T; Giorgi, Filippo Sean; Di Coscio, Elisa; Tognoni, Gloria; Ferri, Raffaele; Bonuccelli, Ubaldo; Bonanni, Enrica
Frontotemporal dementia (FTD) is increasingly becoming recognized as a major cause of early onset (<65 years) neurodegenerative dementia. Although sleep disorders significantly impair patients' and caregivers' quality of life in neurodegenerative diseases, polysomnographic data in FTD patients are scarce in literature. Aim of our study was to investigate sleep microstructure in FTD, by means of Cyclic Alternating Pattern (CAP), in a group of ten behavioral variant FTD patients (6 M, 4 F; mean age 61.2±7.3 years; disease duration: 1.4±0.7 years) and to compare them with cognitively intact healthy elderly. Sleep in FTD patients was altered at different levels, involving not only the conventional sleep stage architecture parameters (total sleep time, single stage percentage, NREM/REM cycle organization), but also microstructure. FTD subjects showed CAP disruption with decreased slow wave activity related phases (A1 index, n/h:14.5±6.8 vs 38.8±6.6; p<.001) and increased arousal-related fast CAP components (A2 index 22.9±8.2 vs 11.6±3.7; p=.006; A3 index 41.9±20.7 vs 13.0±6.5; p=.002). Several correlations between sleep variables and neuropsychological tests were found. Sleep impairment in FTD may be specifically related to the specific frontal lobe involvement in the neurodegenerative process. The pattern of alterations seems somewhat peculiar, probably due to the anatomical distribution of the neurodegenerative process with a major impact on frontal lobe generated sleep transients, and a substantial sparing of phenomena related to the posterior cortex.
Heyanka, Daniel J; Golden, Charles J; McCue, Robert B; Scarisbrick, David M; Linck, John F; Zlatkin, Nancy I
The study of olfaction in neurodegeneration has primarily focused on Alzheimer's disease. Research of olfaction in frontotemporal dementia (FTD) has generally not been empirically studied. The current study compared olfaction in FTD to major depressive disorder (MDD) using the Alberta Smell Test (AST). Independent-samples t test results suggested olfaction in FTD was impaired when compared with participants diagnosed with MDD. The AST Total score (out of 20 trials) significantly predicted the diagnostic group and accounted for 40% of the variance in diagnostic group status with an odds ratio of 20.08. Results suggested that a cutoff of ≤2/20 differentiated FTD from MDD with 94% accuracy (91% sensitivity, 97% specificity) and a cutoff of ≤1/20 differentiated the groups with a 95.5% hit rate (91% sensitivity, 100% specificity). Results confirmed olfactory identification deficits in FTD and suggested that the AST is an effective tool for the demarcation of FTD from MDD. This is especially important due to the potential for significant overlap in the behavioral/emotional phenotype and cognitive deficits between the two disorders when presented with early stages of FTD.
Papageorgiou, Sokratis G; Beratis, Ion N; Horvath, Judit; Herrmann, François R; Bouras, Constantin; Kövari, Enikö
Recent accumulated evidence indicates that episodic memory impairments could be part of the initial clinical expression of frontotemporal dementia (FTD). An early study on this issue was carried out by Constantinidis and colleagues in 1974, but it was subsequently overlooked for a long period of time. The scope of the present research was: (a) to explore the presence of early episodic memory impairments in the entire population of neuropathologically confirmed FTD patients from the Geneva brain collection; and (b) to expand the present insight on the association between the initial symptomatology and various characteristics, namely gender, age at onset, disease duration, and presence of Pick body neuropathology. A careful review of the records of 50 FTD patients hospitalized at the Department of Psychiatry of the Bel-Air Hospital, Geneva, Switzerland, from 1929 to 1999, was conducted. Further in-depth neuropathological analysis with novel immunohistological methods was carried out in 37 of the cases. The data showed that memory impairments were the first clinical symptom in several of the patients. In addition, this specific phenotypic expression of FTD was associated with the female gender, advanced age, and positive Pick body neuropathology. The current findings give the opportunity to historically vindicate the early work of Constantinidis and colleagues. In addition, the novel observations about the association of episodic memory impairments with the female gender and positive Pick body neuropathology add to the existing knowledge about this phenotypic expression of FTD.
Milan, Graziella; Napoletano, Sabrina; Pappatà, Sabina; Gentile, Maria Teresa; Colucci-D'Amato, Luca; Della Rocca, Gennaro; Maciag, Anna; Rossetti, Carmen Palermo; Fucci, Laura; Puca, Annibale; Grossi, Dario; Postiglione, Alfredo; Vitale, Emilia
Progranulin (GRN) gene mutations have been genetically associated with frontotemporal dementia (FTD) and are present in about 23% of patients with familial FTD. However, the neurobiology of this secreted glycoprotein remains unclear. Here, we report the identification of 3 pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We present evidence that all the available patients in these 3 familial cases are carrying the rare GRN gene exon 6 deletion g10325_10331delCTGCTGT (relative to nt 1 inNG_007886.1), alias Cys157LysfsX97. This mutation was previously described in 2 sporadic cases but was never associated with familial cases. Our patients demonstrate heterogeneous clinical phenotypes, such as the behavioral variant (bv-FTD) in the affected men and the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) in the affected woman. Haploinsufficiency was revealed by both quantitative real-time PCR of the gene and protein analyses. These findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability.
Grossi, Dario; De Lucia, Natascia; Milan, Graziella; Trojano, Luigi
Environmental dependency (ED) phenomena, including utilization behavior and imitation behavior, are clinical manifestations typically observed in patients with the behavioral variant of fronto-temporal dementia (bvFTD), who may also show the closing-in (CI) phenomenon. Here, we explored the neuropsychological correlates of ED and CI in bvFTD, and the association of ED with CI to clarify the mechanisms underlying these clinical manifestations. Thirty-one bvFTD patients underwent a wide cognitive assessment in addition to special tasks to detect occurrence of CI and ED phenomena. Both ED and CI phenomena were present in more than half of the sample. Logistic regression analyses revealed that both ED and CI phenomena were significantly associated with poor scores on frontal neuropsychological tests. Although ED and CI often co-occurred, 3/12 patients with CI did not show ED, and 5/18 patients with ED did not show CI. A logistic regression model showed that the presence of ED was not significantly associated to CI. CI and ED are associated to progressive derangement of frontal functions in bvFTD. However, specific frontal dysfunctions might explain the occurrence of either phenomenon in isolation.
Rahman, Shibley; Robbins, Trevor W; Hodges, John R; Mehta, Mitul A; Nestor, Peter J; Clark, Luke; Sahakian, Barbara J
The frontal variant of frontotemporal dementia is a significant neurological condition worldwide. There exist few treatments available for the cognitive and behavioural sequelae of fvFTD. Previous research has shown that these patients display risky decision-making, and numerous studies have now demonstrated pathology affecting the orbitofrontal cortex. The present study uses a within-subjects, double-blind, placebo-controlled procedure to investigate the effects of a single dose of methylphenidate (40 mg) upon a range of different cognitive processes including those assessing prefrontal cortex integrity. Methylphenidate was effective in 'normalizing' the decision-making behavior of patients, such that they became less risk taking on medication, although there were no significant effects on other aspects of cognitive function, including working memory, attentional set shifting, and reversal learning. Moreover, there was an absence of the normal subjective and autonomic responses to methylphenidate seen in elderly subjects. The results are discussed in terms of the 'somatic marker' hypothesis of impaired decision-making following orbitofrontal dysfunction.
Halliday, Glenda M; Kiernan, Matthew C; Kril, Jillian J; Mito, Remika; Masuda-Suzukake, Masami; Hasegawa, Masato; McCann, Heather; Bartley, Lauren; Dobson-Stone, Carol; Kwok, John B J; Hornberger, Michael; Hodges, John R; Tan, Rachel H
The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n=12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n=12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n=17) cohort that presented with pure bvFTD, 35% (n=6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP-43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage.
Ji, Ai-Ling; Zhang, Xia; Chen, Wei-Wei; Huang, Wen-Juan
Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future.
Yancopoulou, Despina; Crowther, R Anthony; Chakrabarti, Lisa; Gydesen, Susanne; Brown, Jeremy M; Spillantini, Maria Grazia
Recent work on frontotemporal dementia (FTD) has revealed the existence of at least 3 genetically distinct groups of inherited FTD: FTDP-17, FTD and motor neuron disease linked to chromosome 9, and FTD linked to chromosome 3 (FTD-3). Tau, on chromosome 17, is the only gene where mutations have been identified and its involvement in FTD has been firmly established. The genes on chromosome 9 and chromosome 3 associated with familial forms of FTD remain to be identified. Abnormal aggregates of tau protein characterize the brain lesions of FTDP-17 patients and ubiquitin inclusions have been found in FTD with motor neuron disease linked to chromosome 9. In this study the frontal cortices of 3 FTD-3 patients from a unique Danish family were examined for characteristic neuropathological features. In these brains tau inclusions were present in neurons and some glial cells in the absence of beta-amyloid deposits. The presence of filamentous tau protein in the frontal cortex of these patients suggests a possible link between tau and the genetic defect present on chromosome 3 and associated with FTD-3, although the limited amount of tau deposits observed makes it difficult to define this as a tauopathy.
Sutovsky, Stanislav; Smolek, Tomas; Alafuzoff, Irina; Blaho, Andrej; Parrak, Vojtech; Turcani, Peter; Palkovic, Michal; Petrovic, Robert; Novak, Michal; Zilka, Norbert
Huntington's disease is an incurable, adult-onset, autosomal dominant inherited disorder caused by an expanded trinucleotide repeat (CAG). In this study, we describe a Huntington's disease patient displaying clinical symptoms of the behavioural variant of frontotemporal dementia in the absence of tremor and ataxia. The clinical onset was at the age of 36 years and the disease progressed slowly (18 years). Genetic testing revealed expanded trinucleotide CAG repeats in the Huntingtin gene, together with a Glu318Gly polymorphism in presenilin 1. Neuropathological assessment revealed extensive amyloid β (Aβ) aggregates in all cortical regions. No inclusions displaying hyperphosphorylated tau or phosphorylated transactive response DNA-binding protein 43 (TDP43) were found. A high number of p62 (sequestosome 1) immunopositive intranuclear inclusions were seen mainly in the cortex, while subcortical areas were affected to a lesser extent. Confocal microscopy revealed that the majority of p62 intranuclear lesions co-localised with the fused-in-sarcoma protein (FUS) immunostaining. The morphology of the inclusions resembled intranuclear aggregates in Huntington's disease. The presented proband suffered from Huntington's disease showed atypical distribution of FUS positive intranuclear aggregates in the cortical areas with concomitant Alzheimer's disease pathology.
Gleichgerrcht, Ezequiel; Torralva, Teresa; Roca, María; Pose, Máriangeles; Manes, Facundo
Patients with behavioral variant frontotemporal dementia (bvFTD) exhibit a set of behavioral disturbances that have been strongly associated with involvement of the prefrontal cortex (PFC). Many such disturbances have been linked to impaired moral behavior, especially in regard to "personal" or "emotionally driven" moral dilemmatic judgment, which has been demonstrated to also depend on the integrity of the PFC. In this study, we administered a personal moral dilemma (the footbridge dilemma) and social cognition measures to patients with early bvFTD, who were also assessed with an extensive neuropsychological battery, including moral knowledge, cognitive and emotional empathy, and affective decision-making. BvFTD patients who would push a man off a footbridge (knowing this would kill him) to save the life of five workers who would have been otherwise killed by the train showed significantly lower scores on affective Theory of Mind (ToM) relative to those bvFTD patients who responded negatively. No significant differences were found on other sociodemographic, neuropsychological or social cognition variables. This study reveals that altered dilemmatic judgment may be related to impaired affective ToM, which has important clinical and theoretical implications.
Moll, Jorge; Zahn, Roland; de Oliveira-Souza, Ricardo; Bramati, Ivanei E.; Krueger, Frank; Tura, Bernardo; Cavanagh, Alyson L.; Grafman, Jordan
Poets and philosophers have long acknowledged moral sentiments as key motivators of human social behavior. Prosocial sentiments, which include guilt, pity and embarrassment, enable us to care about others and to be concerned about our mistakes. Functional imaging studies have implicated frontopolar, ventromedial frontal and basal forebrain regions in the experience of prosocial sentiments. Patients with lesions of the frontopolar and ventromedial frontal areas were observed to behave inappropriately and less prosocially, which could be attributed to a generalized emotional blunting. Direct experimental evidence for brain regions distinctively associated with moral sentiment impairments is lacking, however. We investigated this issue in patients with the behavioral variant of frontotemporal dementia, a disorder in which early and selective impairments of social conduct are consistently observed. Using a novel moral sentiment task, we show that the degree of impairment of prosocial sentiments is associated with the degree of damage to frontopolar cortex and septal area, as assessed with 18-Fluoro-Deoxy-Glucose-Positron Emission Tomography, an established measure of neurodegenerative damage. This effect was dissociable from impairment of other-critical feelings (anger and disgust), which was in turn associated with dorsomedial prefrontal and amygdala dysfunction. Our findings suggest a critical role of the frontopolar cortex and septal region in enabling prosocial sentiments, a fundamental component of moral conscience. PMID:20728544
Paternicó, Donata; Manes, Marta; Premi, Enrico; Cosseddu, Maura; Gazzina, Stefano; Alberici, Antonella; Archetti, Silvana; Bonomi, Elisa; Cotelli, Maria Sofia; Cotelli, Maria; Turla, Marinella; Micheli, Anna; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara
Variations within genes associated with dyslexia result in a language network vulnerability, and in patients with Frontotemporal Dementia (FTD), language disturbances represent a disease core feature. Here we explored whether variations within three related-dyslexia genes, namely KIAA0319, DCDC2, and CNTNAP, might affect cortical thickness measures in FTD patients. 112 FTD patients underwent clinical and neuropsychological examination, genetic analyses and brain Magnetic Resonance Imaging (MRI). KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G and CNTNAP2 rs17236239 A/G genetic variations were assessed. Cortical thickness was analysed by Freesurfer. Patients carrying KIAA0319 A*(AG or AA) carriers showed greater cortical thickness atrophy in the left fusiform and inferior temporal gyri, compared to KIAA0319 GG (p ≤ 0.001). Patients carrying CNTNAP2 G*(GA or GG) showed reduced cortical thickness in the left insula thenCNTNAP2 AA carriers (p≤0.001). When patients with both at-risk polymorphisms were considered (KIAA0319 A* and CNTNAP2 G*), greater and addictive cortical thickness atrophy of the left insula and the inferior temporal gyrus was demonstrated (p ≤ 0.001). No significant effect of DCDC2 was found. In FTD, variations of KIAA0319 and CNTNAP2 genes were related to cortical thickness abnormalities in those brain areas involved in language abilities. These findings shed light on genetic predisposition in defining phenotypic variability in FTD. PMID:27484312
Van den Stock, Jan; De Winter, François-Laurent; de Gelder, Beatrice; Rangarajan, Janaki Raman; Cypers, Gert; Maes, Frederik; Sunaert, Stefan; Goffin, Karolien; Vandenberghe, Rik; Vandenbulcke, Mathieu
Progressive deterioration of social cognition and emotion processing are core symptoms of the behavioral variant of frontotemporal dementia (bvFTD). Here we investigate whether bvFTD is also associated with impaired recognition of static (Experiment 1) and dynamic (Experiment 2) bodily expressions. In addition, we compared body expression processing with processing of static (Experiment 3) and dynamic (Experiment 4) facial expressions, as well as with face identity processing (Experiment 5). The results reveal that bvFTD is associated with impaired recognition of static and dynamic bodily and facial expressions, while identity processing was intact. No differential impairments were observed regarding motion (static vs. dynamic) or category (body vs. face). Within the bvFTD group, we observed a significant partial correlation between body and face expression recognition, when controlling for performance on the identity task. Voxel-Based Morphometry (VBM) analysis revealed that body emotion recognition was positively associated with gray matter volume in a region of the inferior frontal gyrus (pars orbitalis/triangularis). The results are in line with a supramodal emotion recognition deficit in bvFTD.
Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Nagaraju, B. C.; Philip, Mariamma
Introduction: Degenerative cortical dementias affect several million people worldwide. Early diagnosis and categorization are essential for initiating appropriate pharmacological and nonpharmacological treatment so that deterioration can be postponed, and disability adjusted life years can be saved both for the patient and for the caregiver. Therefore, an early, simple, noninvasive biomarker will serve as a boon. Patients and Methods: Patients who satisfied probable Alzheimer's disease (AD) or frontotemporal dementia (FTD) using international consensus criteria for FTD and National Institute of Neurological Disorders and Stroke-AD and Related Disorders Association criteria for AD were evaluated using single pulse transcranial magnetic stimulation with figure of eight coil and motor evoked potential from right first dorsal interossei. Resting threshold (MT), central motor conduction time (CMCT), and silent period (SP) were evaluated. Results: Resting MT and SP are reduced in patients with Alzheimer's disease whereas CMCT is prolonged in patients with FTD and SP is in the lower limit of normal in both conditions. Conclusion: The patterns of central motor conduction and MT are distinctly different in patients with early Alzheimer's disease (AD) and FTD. PMID:27011398
van Blitterswijk, Marka; Mullen, Bianca; Nicholson, Alexandra M.; Bieniek, Kevin F.; Heckman, Michael G.; Baker, Matthew C.; DeJesus-Hernandez, Mariely; Finch, NiCole A.; Brown, Patricia H.; Murray, Melissa E.; Hsiung, Ging-Yuek R.; Stewart, Heather; Karydas, Anna M.; Finger, Elizabeth; Kertesz, Andrew; Bigio, Eileen H.; Weintraub, Sandra; Mesulam, Marsel; Hatanpaa, Kimmo J.; White, Charles L.; Strong, Michael J.; Beach, Thomas G.; Wszolek, Zbigniew K.; Lippa, Carol; Caselli, Richard; Petrucelli, Leonard; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Mackenzie, Ian R.; Seeley, William W.; Grinberg, Lea T.; Miller, Bruce L.; Boylan, Kevin B.; Graff-Radford, Neill R.; Boeve, Bradley F.; Dickson, Dennis W.; Rademakers, Rosa
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions (with or without motor neuron disease [MND]; cohort 2), and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls (11.9% versus 19.1%, odds ratio (OR): 0.57, p=0.014; same direction as carriers of GRN mutations). The strongest evidence was provided by FTD patients (OR: 0.33, p=0.009) followed by FTD/MND patients (OR: 0.38, p=0.017), whereas no significant difference was observed in MND patients (OR: 0.85, p=0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR: 0.77, p=0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR: 0.26, p<0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations, and might be relevant for prognostic testing, and as a promising
Fanganiello, R D; Kimonis, V E; Côrte, C C; Nitrini, R; Passos-Bueno, M R
Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.
Baez, Sandra; Morales, Juan P; Slachevsky, Andrea; Torralva, Teresa; Matus, Cristian; Manes, Facundo; Ibanez, Agustin
Perceiving and evaluating intentional harms in an interpersonal context engages both cognitive and emotional domains. This process involves inference of intentions, moral judgment, and, crucially, empathy towards others' suffering. This latter skill is notably impaired in behavioral variant frontotemporal dementia (bvFTD). However, the relationship between regional brain atrophy in bvFTD and deficits in the above-mentioned abilities is not well understood. The present study investigated how gray matter (GM) atrophy in bvFTD patients correlates with the perception and evaluation of harmful actions (attribution of intentionality, evaluation of harmful behavior, empathic concern, and moral judgment). First, we compared the behavioral performance of 26 bvFTD patients and 23 healthy controls on an experimental task (ET) indexing intentionality, empathy, and moral cognition during evaluation of harmful actions. Second, we compared GM volume in patients and controls using voxel-based morphometry (VBM). Third, we examined brain regions where atrophy might be associated with specific impairments in the patient group. Finally, we explored whether the patients' deficits in intentionality comprehension and empathic concern could be partially explained by regional GM atrophy or impairments in other relevant factors, such as executive functions (EFs). In bvFTD patients, atrophy of limbic structures (amygdala and anterior paracingulate cortex--APC) was related to impairments in intentionality comprehension, while atrophy of the orbitofrontal cortex (OFC) was associated with empathic concern deficits. Intentionality comprehension impairments were predicted by EFs and orbitofrontal atrophy predicted deficits in empathic concern. Thus, although the perception and evaluation of harmful actions are variously compromised in bvFTD, deficits in empathic concern may be central to this syndrome as they are associated with one of the earliest atrophied region. More generally, our results
Sturm, Virginia E; Yokoyama, Jennifer S; Eckart, Janet A; Zakrzewski, Jessica; Rosen, Howard J; Miller, Bruce L; Seeley, William W; Levenson, Robert W
Positive emotions foster social relationships and motivate thought and action. Dysregulation of positive emotion may give rise to debilitating clinical symptomatology such as mania, risk-taking, and disinhibition. Neuroanatomically, there is extensive evidence that the left hemisphere of the brain, and the left frontal lobe in particular, plays an important role in positive emotion generation. Although prior studies have found that left frontal injury decreases positive emotion, it is not clear whether selective damage to left frontal emotion regulatory systems can actually increase positive emotion. We measured happiness reactivity in 96 patients with frontotemporal dementia (FTD), a neurodegenerative disease that targets emotion-relevant neural systems and causes alterations in positive emotion (i.e., euphoria and jocularity), and in 34 healthy controls. Participants watched a film clip designed to elicit happiness and a comparison film clip designed to elicit sadness while their facial behavior, physiological reactivity, and self-reported emotional experience were monitored. Whole-brain voxel-based morphometry (VBM) analyses revealed that atrophy in predominantly left hemisphere fronto-striatal emotion regulation systems including left ventrolateral prefrontal cortex, orbitofrontal cortex, anterior insula, and striatum was associated with greater happiness facial behavior during the film (pFWE < .05). Atrophy in left anterior insula and bilateral frontopolar cortex was also associated with higher cardiovascular reactivity (i.e., heart rate and blood pressure) but not self-reported positive emotional experience during the happy film (p < .005, uncorrected). No regions emerged as being associated with greater sadness reactivity, which suggests that left-lateralized fronto-striatal atrophy is selectively associated with happiness dysregulation. Whereas previous models have proposed that left frontal injury decreases positive emotional responding, we argue that
Cairns, N J; Brännström, T; Khan, M N; Rossor, M N; Lantos, P L
The neuronal density in the frontal, temporal, and parietal lobes was determined in nine cases of familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions (FTDU). The mean age at onset was 56.9 +/- 2.2 years and the duration of disease was 6.7 +/- 0.5 years. The mean age at death was 63.6 +/- 2.2 years. There was substantial loss (34%) of brain weight (877 +/- 73 g) in the familial cases in comparison with 10 normal aged controls (1326 +/- 50 g, P < 0.001). All of the familial FTDU cases showed atrophy of the frontal, temporal, and parietal lobes; neuronal loss; vacuolation in superficial laminae; reactive astrocytosis; and ubiquitin-positive, tau-negative intracytoplasmic and intranuclear inclusions and dystrophic neurites in varying sites and numbers. Neuronal loss was estimated in nine cases of familial FTDU and in 10 aged controls using a stereological probe, the optical "disector," and a computerized stereology system (CAST-Grid, Olympus, Denmark). There was a significant reduction in neuronal density in the frontal lobe (22.3 +/- 3.8 x 10(3)/mm(3)) of familial FTDU in comparison to aged controls (33.1 +/- 1.7 x 10(3) per mm(3), P < 0.05). An estimate of the relative numbers of neurons was calculated by multiplying the numerical density by the cortical thickness, which showed a striking loss of neurons of 56% in the frontal lobe, 52% loss in the temporal lobe, and a 49% loss in the parietal lobe of familial FTDU when compared to controls. This study shows that familial FTDU has profound focal neuronal loss in multiple association areas that relate to the clinical symptoms characteristic of the disease.
Morgan, Brianna; Gross, Rachel G; Clark, Robin; Dreyfuss, Michael; Boller, Ashley; Camp, Emily; Liang, Tsao-Wei; Avants, Brian; McMillan, Corey T; Grossman, Murray
Quantifiers are very common in everyday speech, but we know little about their cognitive basis or neural representation. The present study examined comprehension of three classes of quantifiers that depend on different cognitive components in patients with focal neurodegenerative diseases. Patients evaluated the truth-value of a sentence containing a quantifier relative to a picture illustrating a small number of familiar objects, and performance was related to MRI grey matter atrophy using voxel-based morphometry. We found that patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA) are significantly impaired in their comprehension of cardinal quantifiers (e.g. "At least three birds are on the branch"), due in part to their deficit in quantity knowledge. MRI analyses related this deficit to temporal-parietal atrophy found in CBS/PCA. We also found that patients with behavioral variant frontotemporal dementia (bvFTD) are significantly impaired in their comprehension of logical quantifiers (e.g. "Some of the birds are on the branch"), associated with a simple form of perceptual logic, and this correlated with their deficit on executive measures. This deficit was related to disease in rostral prefrontal cortex in bvFTD. These patients were also impaired in their comprehension of majority quantifiers (e.g. "At least half of the birds are on the branch"), and this too was correlated with their deficit on executive measures. This was related to disease in the basal ganglia interrupting a frontal-striatal loop critical for executive functioning. These findings suggest that a large-scale frontal-parietal neural network plays a crucial role in quantifier comprehension, and that comprehension of specific classes of quantifiers may be selectively impaired in patients with focal neurodegenerative conditions in these areas.
Yunusova, Yana; Graham, Naida L.; Shellikeri, Sanjana; Phuong, Kent; Kulkarni, Madhura; Rochon, Elizabeth; Tang-Wai, David F.; Chow, Tiffany W.; Black, Sandra E.; Zinman, Lorne H.; Green, Jordan R.
Objective This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. Design 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups—mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory—based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients. Results The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures. Conclusions and Relevance This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS—FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD. PMID:26789001
Lillo, Patricia; Mioshi, Eneida; Burrell, James R.; Kiernan, Matthew C.; Hodges, John R.; Hornberger, Michael
There is increasing evidence that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a clinical, pathological and genetic continuum with patients of one disease exhibiting features of the other. Nevertheless, to date, the underlying grey matter and white matter changes across the ALS-FTD disease continuum have not been explored. In this study fifty-three participants with ALS (n = 10), ALS-FTD (n = 10) and behavioural variant FTD (bvFTD; n = 15) as well as controls (n = 18), underwent detailed clinical assessment plus structural imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis of magnetic resonance brain imaging to examine grey and white matter differences and commonalities across the continuum. Importantly, patient groups were matched for age, education, gender and disease duration. VBM and DTI results showed that changes in the ALS group were confined mainly to the motor cortex and anterior cingulate as well as their underlying white matter tracts. ALS-FTD and bvFTD showed widespread grey matter and white matter changes involving frontal and temporal lobes. Extensive prefrontal cortex changes emerged as a marker for bvFTD compared to other subtypes, while ALS-FTD could be distinguished from ALS by additional temporal lobe grey and white matter changes. Finally, ALS could be mainly distinguished from the other two groups by corticospinal tract degeneration. The present study shows for the first time that FTD and ALS overlap in anterior cingulate, motor cortex and related white matter tract changes across the whole continuum. Nevertheless, frontal and temporal atrophy as well as corticospinal tract degeneration emerged as marker for subtype classification, which will inform future diagnosis and target disease management across the continuum. PMID:22952843
McMillan, Corey T.; Suh, EunRan; Powers, John; Rascovsky, Katya; Wood, Elisabeth M.; Toledo, Jon B.; Arnold, Steven E.; Lee, Virginia M.-Y.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grossman, Murray
Objective: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD). Methods: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37). Results: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p = 0.04) but not with TDP-43 proteinopathies (p > 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p < 0.01). MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p < 0.01). Conclusions: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings. PMID:24994843
Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A; Rohrer, Jonathan D; Ramasamy, Adaikalavan; Kwok, John B J; Dobson-Stone, Carol; Brooks, William S; Schofield, Peter R; Halliday, Glenda M; Hodges, John R; Piguet, Olivier; Bartley, Lauren; Thompson, Elizabeth; Haan, Eric; Hernández, Isabel; Ruiz, Agustín; Boada, Mercè; Borroni, Barbara; Padovani, Alessandro; Cruchaga, Carlos; Cairns, Nigel J; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Forloni, Gianluigi; Galimberti, Daniela; Fenoglio, Chiara; Serpente, Maria; Scarpini, Elio; Clarimón, Jordi; Lleó, Alberto; Blesa, Rafael; Waldö, Maria Landqvist; Nilsson, Karin; Nilsson, Christer; Mackenzie, Ian R A; Hsiung, Ging-Yuek R; Mann, David M A; Grafman, Jordan; Morris, Christopher M; Attems, Johannes; Griffiths, Timothy D; McKeith, Ian G; Thomas, Alan J; Pietrini, P; Huey, Edward D; Wassermann, Eric M; Baborie, Atik; Jaros, Evelyn; Tierney, Michael C; Pastor, Pau; Razquin, Cristina; Ortega-Cubero, Sara; Alonso, Elena; Perneczky, Robert; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Kurz, Alexander; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Rogaeva, Ekaterina; George-Hyslop, Peter St; Rossi, Giacomina; Tagliavini, Fabrizio; Giaccone, Giorgio; Rowe, James B; Schlachetzki, J C M; Uphill, James; Collinge, John; Mead, S; Danek, Adrian; Van Deerlin, Vivianna M; Grossman, Murray; Trojanowsk, John Q; van der Zee, Julie; Deschamps, William; Van Langenhove, Tim; Cruts, Marc; Van Broeckhoven, Christine; Cappa, Stefano F; Le Ber, Isabelle; Hannequin, Didier; Golfier, Véronique; Vercelletto, Martine; Brice, Alexis; Nacmias, Benedetta; Sorbi, Sandro; Bagnoli, Silvia; Piaceri, Irene; Nielsen, Jørgen E; Hjermind, Lena E; Riemenschneider, Matthias; Mayhaus, Manuel; Ibach, Bernd; Gasparoni, Gilles; Pichler, Sabrina; Gu, Wei; Rossor, Martin N; Fox, Nick C; Warren, Jason D; Spillantini, Maria Grazia; Morris, Huw R; Rizzu, Patrizia; Heutink, Peter; Snowden, Julie S; Rollinson, Sara; Richardson, Anna; Gerhard, Alexander; Bruni, Amalia C; Maletta, Raffaele; Frangipane, Francesca; Cupidi, Chiara; Bernardi, Livia; Anfossi, Maria; Gallo, Maura; Conidi, Maria Elena; Smirne, Nicoletta; Rademakers, Rosa; Baker, Matt; Dickson, Dennis W; Graff-Radford, Neill R; Petersen, Ronald C; Knopman, David; Josephs, Keith A; Boeve, Bradley F; Parisi, Joseph E; Seeley, William W; Miller, Bruce L; Karydas, Anna M; Rosen, Howard; van Swieten, John C; Dopper, Elise G P; Seelaar, Harro; Pijnenburg, Yolande AL; Scheltens, Philip; Logroscino, Giancarlo; Capozzo, Rosa; Novelli, Valeria; Puca, Annibale A; Franceschi, M; Postiglione, Alfredo; Milan, Graziella; Sorrentino, Paolo; Kristiansen, Mark; Chiang, Huei-Hsin; Graff, Caroline; Pasquier, Florence; Rollin, Adeline; Deramecourt, Vincent; Lebert, Florence; Kapogiannis, Dimitrios; Ferrucci, Luigi; Pickering-Brown, Stuart; Singleton, Andrew B; Hardy, John; Momeni, Parastoo
Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of
Ghetti, B; Oblak, A L; Boeve, B F; Johnson, K A; Dickerson, B C; Goedert, M
Hereditary frontotemporal dementia associated with mutations in the microtubule-associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms. PMID:25556536
Henry, Maya L; Wilson, Stephen M; Ogar, Jennifer M; Sidhu, Manu S; Rankin, Katherine P; Cattaruzza, Tatiana; Miller, Bruce L; Gorno-Tempini, Maria Luisa; Seeley, William W
We describe a patient with semantic variant of frontotemporal dementia who received longitudinal clinical evaluations and structural MRI scans and subsequently came to autopsy. She presented with early behavior changes and semantic loss for foods and people and ultimately developed a pervasive semantic impairment affecting social-emotional as well as linguistic domains. Imaging revealed predominant atrophy of the right temporal lobe, with later involvement of the left, and pathology confirmed bilateral temporal involvement. Findings support the view that left and right anterior temporal lobes serve as semantic hubs that may be affected differentially in semantic variant by early, relatively unilateral damage.
Pose, Mariangeles; Cetkovich, Marcelo; Gleichgerrcht, Ezequiel; Ibáñez, Agustin; Torralva, Teresa; Manes, Facundo
Several factors make diagnosis of a possible behavioural variant of frontotemporal dementia (bvFTD) particularly challenging, especially the overlap of certain symptomatic dimensions such as apathy, disinhibition, depression, anhedonia, stereotyped behaviour, and psychosis between bvFTD and several psychiatric disorders that appear in late adulthood. We discuss the most frequent psychiatric conditions that can simulate early bvFTD symptoms, including late onset bipolar disorder, late onset schizophrenia-like psychosis, late onset depression, and attention deficit hyperactivity disorder in middle and older age.
Farg, Manal A.; Sundaramoorthy, Vinod; Sultana, Jessica M.; Yang, Shu; Atkinson, Rachel A.K.; Levina, Vita; Halloran, Mark A.; Gleeson, Paul A.; Blair, Ian P.; Soo, Kai Y.; King, Anna E.; Atkin, Julie D.
Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking. PMID:24549040
Woollacott, Ione O.C.; Dick, Katrina M.; Brotherhood, Emilie; Gordon, Elizabeth; Fellows, Alexander; Toombs, Jamie; Druyeh, Ronald; Cardoso, M. Jorge; Ourselin, Sebastien; Nicholas, Jennifer M.; Norgren, Niklas; Mead, Simon; Andreasson, Ulf; Blennow, Kaj; Schott, Jonathan M.; Fox, Nick C.; Warren, Jason D.; Zetterberg, Henrik
Objective: To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease. Methods: Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume. Results: Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL [SD 51.3 pg/mL]) than controls (19.6 pg/mL [SD 8.2 pg/mL]; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL [SD 33.1 pg/mL]) and both the semantic and nonfluent variants of PPA (95.9 and 82.5 pg/mL [SD 33.0 and 33.8 pg/mL], respectively) compared with controls and in semantic variant PPA compared with logopenic variant PPA. Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL [SD 48.2 and 20.9 pg/mL], respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL [SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003). Conclusions: Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes. PMID:27581216
Radford, Helois; Moreno, Julie A; Verity, Nicholas; Halliday, Mark; Mallucci, Giovanna R
The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates the transient shutdown of translation in response to rising levels of misfolded proteins in the endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer's disease, the tauopathies and prion disorders. These are all characterised by the accumulation of misfolded disease-specific proteins in the brain in association with specific patterns of neuronal loss, but the role of UPR activation in their pathogenesis is unclear. In prion-diseased mice, overactivation of PERK-P/eIF2α-P signalling results in the sustained reduction in global protein synthesis, leading to synaptic failure, neuronal loss and clinical disease. Critically, restoring vital neuronal protein synthesis rates by inhibiting the PERK-eIF2α pathway, both genetically and pharmacologically, prevents prion neurodegeneration downstream of misfolded prion protein accumulation. Here we show that PERK-eIF2α-mediated translational failure is a key process leading to neuronal loss in a mouse model of frontotemporal dementia, where the misfolded protein is a form of mutant tau. rTg4510 mice, which overexpress the P301L tau mutation, show dysregulated PERK signalling and sustained repression of protein synthesis by 6 months of age, associated with onset of neurodegeneration. Treatment with the PERK inhibitor, GSK2606414, from this time point in mutant tau-expressing mice restores protein synthesis rates, protecting against further neuronal loss, reducing brain atrophy and abrogating the appearance of clinical signs. Further, we show that PERK-eIF2α activation also contributes to the pathological phosphorylation of tau in rTg4510 mice, and that levels of phospho-tau are lowered by PERK inhibitor treatment, providing a second mechanism of protection. The data support UPR-mediated translational failure as a generic pathogenic mechanism in
Banks, Sarah; Weintraub, Sandra
Lack of insight is a core diagnostic criterion for behavioral variant frontotemporal dementia (bvFTD), and is believed to be intact in the early stages of primary progressive aphasia (PPA). In other neurological conditions, symptom-specific insight has been noted, with behavioral symptoms appearing especially vulnerable to reduced insight.…
Ferrari, Raffaele; Grassi, Mario; Salvi, Erika; Borroni, Barbara; Palluzzi, Fernando; Pepe, Daniele; D'Avila, Francesca; Padovani, Alessandro; Archetti, Silvana; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Galimberti, Daniela; Scarpini, Elio; Serpente, Maria; Rossi, Giacomina; Giaccone, Giorgio; Tagliavini, Fabrizio; Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia; Bruni, Amalia C.; Maletta, Raffaele G.; Bernardi, Livia; Postiglione, Alfredo; Milan, Graziella; Franceschi, Massimo; Puca, Annibale A.; Novelli, Valeria; Barlassina, Cristina; Glorioso, Nicola; Manunta, Paolo; Singleton, Andrew; Cusi, Daniele; Hardy, John; Momeni, Parastoo
Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10−7 and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of –cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD–genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis. PMID:26154020
Kipps, Christopher M; Mioshi, Eneida; Hodges, John R
Social functioning in FTD is profoundly affected, and forms the basis for the clinical diagnosis of the behavioural variant of the disease (bv-FTD). In particular, there are deficits in emotional processing, but the inter-relationship of such deficits to other aspects of social functioning remains unclear. We studied patients with bv-FTD (n = 14) and AD (n = 14), and compared their performance on a test of emotion recognition with their scores on two carer-based assessments: the Disability Assessment for Dementia (DAD) of activities in daily living (ADL), and the Cambridge Behavioural Inventory (CBI). The bv-FTD group had significantly greater impairments in ADLs, and had higher scores on the CBI, compared to the AD group. Despite a deficit in emotion recognition, particularly involving negative emotions, in the FTD group relative to AD and controls, performance on this task did not correlate with ADL ratings which instead, correlated highly with carer-rated apathy levels on the CBI. The study highlights the multifactorial nature of social dysfunction in FTD which is important in the management of these patients and in designing effective behavioural and therapeutic interventions. The relationship of emotional processing to other aspects of social cognition in FTD is reviewed.
Wang, Jingjing; Redmond, Stephen J.; Bertoux, Maxime; Hodges, John R.; Hornberger, Michael
The clinical distinction between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) remains challenging and largely dependent on the experience of the clinician. This study investigates whether objective machine learning algorithms using supportive neuroimaging and neuropsychological clinical features can aid the distinction between both diseases. Retrospective neuroimaging and neuropsychological data of 166 participants (54 AD; 55 bvFTD; 57 healthy controls) was analyzed via a Naïve Bayes classification model. A subgroup of patients (n = 22) had pathologically-confirmed diagnoses. Results show that a combination of gray matter atrophy and neuropsychological features allowed a correct classification of 61.47% of cases at clinical presentation. More importantly, there was a clear dissociation between imaging and neuropsychological features, with the latter having the greater diagnostic accuracy (respectively 51.38 vs. 62.39%). These findings indicate that, at presentation, machine learning classification of bvFTD and AD is mostly based on cognitive and not imaging features. This clearly highlights the urgent need to develop better biomarkers for both diseases, but also emphasizes the value of machine learning in determining the predictive diagnostic features in neurodegeneration. PMID:27378905
Guven, Gamze; Lohmann, Ebba; Bras, Jose; Gibbs, J. Raphael; Gurvit, Hakan; Bilgic, Basar; Hanagasi, Hasmet; Rizzu, Patrizia; Heutink, Peter; Emre, Murat; Erginel-Unaltuna, Nihan; Just, Walter; Hardy, John; Singleton, Andrew; Guerreiro, Rita
‘Microtubule-associated protein tau’ (MAPT), ‘granulin’ (GRN) and ‘chromosome 9 open reading frame72’ (C9ORF72) gene mutations are the major known genetic causes of frontotemporal dementia (FTD). Recent studies suggest that mutations in these genes may also be associated with other forms of dementia. Therefore we investigated whether MAPT, GRN and C9ORF72 gene mutations are major contributors to dementia in a random, unselected Turkish cohort of dementia patients. A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the ‘charged multivesicular body protein 2B’ (CHMP2B), the ‘FUS RNA binding protein’ (FUS), the ‘TAR DNA binding protein’ (TARDBP), the ‘sequestosome1’ (SQSTM1), and the ‘valosin containing protein’ (VCP). We determined one pathogenic MAPT mutation (c.1906C>T, p.P636L) and one novel missense variant (c.38A>G, p.D13G). In GRN we identified a probably pathogenic TGAG deletion in the splice donor site of exon 6. Three patients were found to carry the GGGGCC expansions in the non-coding region of the C9ORF72 gene. In summary, a complete screening for mutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of pathogenic mutations in a random cohort of 93 Turkish index patients with dementia. PMID:27632209
Takeuchi, Ryoko; Toyoshima, Yasuko; Tada, Mari; Tanaka, Hidetomo; Shimizu, Hiroshi; Shiga, Atsushi; Miura, Takeshi; Aoki, Kenju; Aikawa, Akane; Ishizawa, Shin; Ikeuchi, Takeshi; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi
Amyotrophic lateral sclerosis (ALS) may be accompanied by frontotemporal dementia (FTD). We report a case of glial mixed tau and TDP-43 proteinopathies in a Japanese patient diagnosed clinically as having ALS-D. Autopsy revealed loss of lower motor neurons and degeneration of the pyramidal tracts in the spinal cord and brain stem. The brain showed frontotemporal lobar degeneration (FTLD), the most severe neuronal loss and gliosis being evident in the precentral gyrus. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. AT8 immunostaining revealed that predominant occurrence of astrocytic tau lesions termed globular astrocytic inclusions (GAIs) was a feature of the affected regions. These GAIs were Gallyas-Braak negative. Neuronal and oligodendrocytic tau lesions were comparatively scarce. pS409/410 immunostaining also revealed similar neuronal and glial TDP-43 lesions. Interestingly, occasional co-localization of tau and TDP-43 was evident in the GAIs. Immunoblot analyses revealed band patterns characteristic of a 4-repeat (4R) tauopathy, corticobasal degeneration and a TDP-43 proteinopathy, ALS/FTLD-TDP Type B. No mutations were found in the MAPT or TDP-43 genes. We consider that this patient harbored a distinct, sporadic globular glial mixed 4R tau and TDP-43 proteinopathy associated with motor neuron disease and FTD.
Kosmidis, Mary H; Aretouli, Eleni; Bozikas, Vassilis P; Giannakou, Maria; Ioannidis, Panayiotis
We investigated social cognition and theory of mind in patients with schizophrenia and in patients with frontotemporal dementia in order to elucidate the cognitive mechanisms involved in the breakdown of these skills in psychiatric and neurological patients. Our tasks included videotaped scenarios of social interactions depicting sincere, sarcastic and paradoxical remarks, as well as lies. We found impaired performance of the schizophrenia group on all theory of mind conditions despite their intact understanding of sincere statements. In contrast, the FTD group performed poorly only when they had to rely on paralinguistic cues indicating sarcasm or lies, and not on paradoxical remarks or sarcasm when given additional verbal cues. Our findings suggest that, while current deficits in social and interpersonal functioning in patients with FTD may reflect a decrement in previously acquired skills, similar deficits in patients with schizophrenia may reflect an altogether inadequately learned process.
Dinand, Claudia; Nover, Sabine Ursula; Holle, Daniela; Zischka, Matthias; Halek, Margareta
Behavioural variant frontotemporal dementia (bvFTD) is an early-onset and progressive neurodegenerative disease associated with strong changes in judgement, behaviour, personality and emotions. These changes can cause significant problems in everyday life for people with bvFTD and their families, and have implications for health and society. Currently, there are no suitable evidence-based specific interventions for people with bvFTD. This scoping review aims to identify the self-expressed needs, demands and coping strategies of people with bvFTD. Identifying these issues is the first step towards the development of need-based psycho-social interventions for people with bvFTD. A comprehensive literature research was conducted of German and English scientific articles published between January 2000 and October 2014 using the databases MEDLINE, CINAHL, PsycINFO, PSYNDEX, SocINDEX, GeroLit, the Cochrane Library, ProQuest, the German National Library and additional search strategies in terms of a scoping review. Articles were identified by combining search terms related to 'frontotemporal dementia' with terms related to 'self-expressions', 'needs/demands' and 'coping'. After excluding duplicates, two independent reviewers screened the titles and abstracts of 2317 records for eligibility. Because eligibility could not be assessed from the titles or abstracts of 28 articles, those articles were assessed using the full text. One poster abstract met our research question and a few articles were related, but no article met all of the inclusion criteria. This lack of scientifically based knowledge concerning the perspective of people with bvFTD is discussed with reference to the search strategy and the research questions, disease-related aspects such as changes in behaviour or language and emotions and the difficulties in researching this topic. Recommendations are formulated for future research considering the perspective of people with bvFTD and that will involve the
Valotassiou, V.; Papatriantafyllou, J.; Sifakis, N.; Karageorgiou, C.; Tsougos, I.; Tzavara, C.; Zerva, C.; Georgoulias, P.
Introduction. Brain perfusion studies with single-photon emission computed tomography (SPECT) have been applied in demented patients to provide better discrimination between frontotemporal dementia (FTD) and Alzheimer's disease (AD). Aim. To assess the perfusion of specific Brodmann (Br) areas of the brain cortex in FTD and AD patients, using NeuroGam processing program to provide 3D voxel-by-voxel cerebral SPECT analysis. Material and methods. We studied 34 consecutive patients. We used the established criteria for the diagnosis of dementia and the specific established criteria for the diagnosis of FTD and AD. All the patients had a neuropsychological evaluation with a battery of tests including the mini-mental state examination (MMSE).Twenty-six patients (16 males, 10 females, mean age 68.76±6.51 years, education 11.81±4.25 years, MMSE 16.69±9.89) received the diagnosis of FTD and 8 patients (all females, mean age 71.25±10.48 years, education 10±4.6 years, MMSE 12.5±3.89) the diagnosis of AD. All the patients underwent a brain SPECT. We applied the NeuroGam Software for the evaluation of brain perfusion in specific Br areas in the left (L) and right (R) hemispheres. Results. Statistically significant hypoperfusion in FTD compared to AD patients, was found in the following Br areas: 11L (p<0.0001), 11R, 20L, 20R, 32L, 38L, 38R, 44L (p<0.001), 32R, 36L, 36R, 45L, 45R, 47R (p<0.01), 9L, 21L, 39R, 44R, 46R, 47L (p<0.05). On the contrary, AD patients presented significant (p<0.05) hypoperfusion in 7R and 39R Br areas. Conclusion. NeuroGam processing program of brain perfusion SPECT could result in enhanced accuracy for the differential diagnosis between AD and FTD patients.
Arighi, Andrea; Fumagalli, Giorgio G; Jacini, Francesca; Fenoglio, Chiara; Ghezzi, Laura; Pietroboni, Anna M; De Riz, Milena; Serpente, Maria; Ridolfi, Elisa; Bonsi, Rossana; Bresolin, Nereo; Scarpini, Elio; Galimberti, Daniela
A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration with or without concomitant motor neuron disease phenotype and TDP-43 based pathology. Here, we report on three cases carrying the hexanucleotide repeat expansion with an atypical presentation consisting in the development of psychiatric symptoms. Patient #1, a 53 year old man with positive family history for dementia, presented with mood deflection, characterized by apathy, social withdraw, and irritability in the last two years. He was diagnosed with "mild cognitive impairment due to depressive syndrome" six months later and subsequently with Alzheimer's disease. Patient #2, a woman with positive family history for dementia, developed behavioral disturbances, aggressiveness, and swearing at 57 years of age. Patient #3 presented, in the absence of brain atrophy, with mystical delirium with auditory hallucinations at 44 years of age, and did not present neurological symptoms over a 7-year follow up. The description of these cases underlines that the hexanucleotide repeat expansion in chromosome 9 could be associated with early onset psychiatric presentations.
Korada, Suresh Kumar; Chandra, Sadanandavalli Retnaswami; Benegal, Vivek; Purushothaman, Meera; Philip, Mariamma
Introduction: Frontotemporal dementias (FLD) form a group of relatively young onset, male dominant dementias with significant behavioral abnormalities early in the course of the disease. Routine assessment suggested preexisting traits such as lack of empathy, self-directedness, and persistence in most of these persons even before the onset of disease. Hence, we decided the study, the siblings and children of patients for any specific traits and correlation with hexanucleotide expansion repeats if any traits were identified. Patients and Methods: A total of 35 age- and gender-matched cases and controls were included for the study as per criteria. They were screened for mental illness and cognitive dysfunction using Hindi Mental State Examination and Mini-mental State Examination. Eligible persons were given temperament and character inventory (TCI) scores for the recommended parameters. Hexanucleotide expansion was also studied in the patients, cases and controls. Results: No specific personality trait was found to have an increased correlation with siblings and children of patients with FLD in this small group using TCI scores. Conclusions: 7% of cases showed Hexanucleotide expansion suggesting a possible risk. The role of self reporting bias resulting in normal personality trait needs to be addressed in future studies. PMID:28250555
van der Zee, Julie; Gijselinck, Ilse; Van Mossevelde, Sara; Perrone, Federica; Dillen, Lubina; Heeman, Bavo; Bäumer, Veerle; Engelborghs, Sebastiaan; De Bleecker, Jan; Baets, Jonathan; Gelpi, Ellen; Rojas-García, Ricardo; Clarimón, Jordi; Lleó, Alberto; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Perneczky, Robert; Synofzik, Matthis; Just, Jennifer; Schöls, Ludger; Graff, Caroline; Thonberg, Håkan; Borroni, Barbara; Padovani, Alessandro; Jordanova, Albena; Sarafov, Stayko; Tournev, Ivailo; de Mendonça, Alexandre; Miltenberger-Miltényi, Gabriel; Simões do Couto, Frederico; Ramirez, Alfredo; Jessen, Frank; Heneka, Michael T; Gómez-Tortosa, Estrella; Danek, Adrian; Cras, Patrick; Vandenberghe, Rik; De Jonghe, Peter; De Deyn, Peter P; Sleegers, Kristel; Cruts, Marc; Van Broeckhoven, Christine; Goeman, Johan; Nuytten, Dirk; Smets, Katrien; Robberecht, Wim; Damme, Philip Van; Bleecker, Jan De; Santens, Patrick; Dermaut, Bart; Versijpt, Jan; Michotte, Alex; Ivanoiu, Adrian; Deryck, Olivier; Bergmans, Bruno; Delbeck, Jean; Bruyland, Marc; Willems, Christiana; Salmon, Eric; Pastor, Pau; Ortega-Cubero, Sara; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Hernández, Isabel; Boada, Mercè; Ruiz, Agustín; Sorbi, Sandro; Nacmias, Benedetta; Bagnoli, Silvia; Sorbi, Sandro; Sanchez-Valle, Raquel; Llado, Albert; Santana, Isabel; Rosário Almeida, Maria; Frisoni, Giovanni B; Maetzler, Walter; Matej, Radoslav; Fraidakis, Matthew J; Kovacs, Gabor G; Fabrizi, Gian Maria; Testi, Silvia
We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
van der Zee, Julie; Gijselinck, Ilse; Van Mossevelde, Sara; Perrone, Federica; Dillen, Lubina; Heeman, Bavo; Bäumer, Veerle; Engelborghs, Sebastiaan; De Bleecker, Jan; Baets, Jonathan; Gelpi, Ellen; Rojas‐García, Ricardo; Clarimón, Jordi; Lleó, Alberto; Diehl‐Schmid, Janine; Alexopoulos, Panagiotis; Perneczky, Robert; Synofzik, Matthis; Just, Jennifer; Schöls, Ludger; Graff, Caroline; Thonberg, Håkan; Borroni, Barbara; Padovani, Alessandro; Jordanova, Albena; Sarafov, Stayko; Tournev, Ivailo; de Mendonça, Alexandre; Miltenberger‐Miltényi, Gabriel; Simões do Couto, Frederico; Ramirez, Alfredo; Jessen, Frank; Heneka, Michael T.; Gómez‐Tortosa, Estrella; Danek, Adrian; Cras, Patrick; Vandenberghe, Rik; De Jonghe, Peter; De Deyn, Peter P.; Sleegers, Kristel; Cruts, Marc; Goeman, Johan; Nuytten, Dirk; Smets, Katrien; Robberecht, Wim; Damme, Philip Van; Bleecker, Jan De; Santens, Patrick; Dermaut, Bart; Versijpt, Jan; Michotte, Alex; Ivanoiu, Adrian; Deryck, Olivier; Bergmans, Bruno; Delbeck, Jean; Bruyland, Marc; Willems, Christiana; Salmon, Eric; Pastor, Pau; Ortega‐Cubero, Sara; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Hernández, Isabel; Boada, Mercè; Ruiz, Agustín; Sorbi, Sandro; Nacmias, Benedetta; Bagnoli, Silvia; Sorbi, Sandro; Sanchez‐Valle, Raquel; Llado, Albert; Santana, Isabel; Rosário Almeida, Maria; Frisoni, Giovanni B; Maetzler, Walter; Matej, Radoslav; Fraidakis, Matthew J.; Kovacs, Gabor G.; Fabrizi, Gian Maria; Testi, Silvia
ABSTRACT We investigated the mutation spectrum of the TANK‐Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early‐Onset Dementia Consortium. We assessed pathogenicity of predicted protein‐truncating mutations by measuring loss of RNA expression. Functional effect of in‐frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB‐induced luciferase reporter assay and measuring phosphorylated TBK1. The protein‐truncating mutations led to the loss of transcript through nonsense‐mediated mRNA decay. For the in‐frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high‐risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD‐ALS. PMID:28008748
Pelicano Paulos, Jorge; Massano, João
Introdução: A Degenerescência Lobar Frontotemporal engloba um conjunto de situações heterogéneas que partilham sintomas cognitivos e comportamentais, bem como características patológicas macroscópicas. As bases genéticas e características histopatológicas são bastante diversas e formam a base da classificação molecular das várias doenças, sendo difícil fazer uma correlação com os achados clínicos e síndromas. A investigação científica trouxe um conjunto vasto de conhecimentos, nem sempre fáceis de acompanhar,especialmente nos últimos anos em relação à genética e histopatologia.Material e Métodos: Os autores fizeram uma pesquisa de literatura neste tema, escolheram referências relevantes, extraíram e sistematizaram os dados.Resultados e Conclusão: o texto apresenta uma revisão atualizada dos aspetos clínicos, genéticos e histopatológicos da Degenerescência Lobar Frontotemporal, com ênfase especial na Demência Frontotemporal, a doença mais comum. O tratamento é também revisto e são propostas pelos autores estratégias relativamente à escolha dos testes genéticos na prática clínica. Deveriam serpromovidos a atenção e conhecimento públicos sobre este grupo de doenças.
Cerami, Chiara; Dodich, Alessandra; Iannaccone, Sandro; Marcone, Alessandra; Lettieri, Giada; Crespi, Chiara; Gianolli, Luigi; Cappa, Stefano F.; Perani, Daniela
The behavioural variant of frontotemporal dementia (bvFTD) is a rare disease mainly affecting the social brain. FDG-PET fronto-temporal hypometabolism is a supportive feature for the diagnosis. It may also provide specific functional metabolic signatures for altered socio-emotional processing. In this study, we evaluated the emotion recognition and attribution deficits and FDG-PET cerebral metabolic patterns at the group and individual levels in a sample of sporadic bvFTD patients, exploring the cognitive-functional correlations. Seventeen probable mild bvFTD patients (10 male and 7 female; age 67.8±9.9) were administered standardized and validated version of social cognition tasks assessing the recognition of basic emotions and the attribution of emotions and intentions (i.e., Ekman 60-Faces test-Ek60F and Story-based Empathy task-SET). FDG-PET was analysed using an optimized voxel-based SPM method at the single-subject and group levels. Severe deficits of emotion recognition and processing characterized the bvFTD condition. At the group level, metabolic dysfunction in the right amygdala, temporal pole, and middle cingulate cortex was highly correlated to the emotional recognition and attribution performances. At the single-subject level, however, heterogeneous impairments of social cognition tasks emerged, and different metabolic patterns, involving limbic structures and prefrontal cortices, were also observed. The derangement of a right limbic network is associated with altered socio-emotional processing in bvFTD patients, but different hypometabolic FDG-PET patterns and heterogeneous performances on social tasks at an individual level exist. PMID:26513651
Boylan, Kevin B.; Graff-Radford, Neill R.; DeJesus-Hernandez, Mariely; Knopman, David S.; Pedraza, Otto; Vemuri, Prashanthi; Jones, David; Lowe, Val; Murray, Melissa E.; Dickson, Dennis W.; Josephs, Keith A.; Rush, Beth K.; Machulda, Mary M.; Fields, Julie A.; Ferman, Tanis J.; Baker, Matthew; Rutherford, Nicola J.; Adamson, Jennifer; Wszolek, Zbigniew K.; Adeli, Anahita; Savica, Rodolfo; Boot, Brendon; Kuntz, Karen M.; Gavrilova, Ralitza; Reeves, Andrew; Whitwell, Jennifer; Kantarci, Kejal; Jack, Clifford R.; Parisi, Joseph E.; Lucas, John A.; Petersen, Ronald C.; Rademakers, Rosa
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral
Shih, Ying-Jyun; Wang, Ya-Hui; Yang, Yung-Jen
This report introduces the nursing caring experience with a male patient with frontotemporal dementia (FTD) who was hospitalized in an acute psychiatric ward from March 5th to April 30th, 2012 due to the clinical manifestations of verbally expressive impairment, aggression, and subsequent caregiver burden. The patient was assessed according to the guidelines of clinical competencies for mental health nursing assessments developed by the Psychiatric Mental Health Nurses Association. Three clinical diagnoses were identified after this assessment, including (1) impaired verbal communication, (2) chronic confusion, and (3) caregiver role strain. The current report focuses only on the clinical issue of impaired verbal communication. We adopted a props-integrated communicative approach by integrating props and physical motions with communicative strategies. This approach enabled us to formulate a patient-centered communicating model and prompt for active expression and adequate communication, which ultimately resolved the patient's aggression problem. In addition, we provided psychoeducation to the family members in order to teach them the relevant knowledge, skills, and approaches that caregivers may use to enhance their caring capabilities and reduce the burden of caregiving. This successful experience may be used as a reference in caring for FTD patients with communicative impairments. Our proposed approach integrates props with simple language and develops an appropriate communicating model to provide high quality care for patients.
Itzcovich, Tatiana; Xi, Zhengrui; Martinetto, Horacio; Chrem-Méndez, Patricio; Russo, María Julieta; de Ambrosi, Bruno; Uchitel, Osvaldo D; Nogués, Martín; Silva, Emanuel; Rojas, Galeno; Bagnatti, Pablo; Amengual, Alejandra; Campos, Jorge; Rogaeva, Ekaterina; St George-Hyslop, Peter; Allegri, Ricardo; Sevlever, Gustavo; Surace, Ezequiel I
Pathologic expansion of the G4C2 repeat in C9orf72 is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To evaluate the frequency of the G4C2 expansion in a Latin American cohort of FTD and ALS patients, we used a 2-step genotyping strategy. For FTD, we observed an overall expansion frequency of 18.2% (6 of 33 unrelated cases). Moreover, the C9orf72 expansion accounted for 37.5% of all familial FTD cases (6 of 16 families). The expansion frequency in sporadic ALS cases was 2% (1 of 47 unrelated patients), whereas we observed the expansion in 1 of 3 families with a positive history for ALS. Overall, the expansion frequency in our FTD group was similar to that reported for patients in Europe and North America, whereas the frequency in our sporadic ALS group was significantly lower. To our knowledge, this is the first report on the frequency of the C9orf72 expansion in a Latin American population.
Surampalli, Abhilasha; Khare, Manaswitha; Kubrussi, Georgette; Wencel, Marie; Tanaja, Jasmin; Donkervoort, Sandra; Osann, Kathryn; Simon, Mariella; Wallace, Douglas; Smith, Charles; M McInerney-Leo, Aideen; Kimonis, Virginia
Inclusion Body Myopathy associated with Paget's disease of bone and Fronto-temporal Dementia, also known as multisystem proteinopathy is an autosomal dominant, late onset neurodegenerative disorder caused by mutations in Valosin containing protein (VCP) gene. This study aimed to assess uptake and decision making for predictive genetic testing and the impact on psychological well-being. Individuals who had participated in the gene discovery study with a 50 % a priori risk of inheriting VCP disease were sent a letter of invitation offering genetic counseling and testing and were also invited to participate in this psychosocial study. A total of 102 individuals received an invitation and 33 individuals participated in genetic counseling and testing (32.3 %) with 29 completing baseline questionnaires. Twenty completed the follow-up post-test Hospital Anxiety and Depression Scale questionnaire including 13 of the 18 who had tested positive. Mean risk perception at baseline was 50.1 %. Reasons for testing included planning for the future, relieving uncertainty, informing children and satisfying curiosity. At baseline, one quarter of the participants had high levels of anxiety. However, scores were normal one year following testing. In this small cohort, one third of individuals at 50 % risk chose pre-symptomatic testing. Although one quarter of those choosing testing had high anxiety at baseline, this was not evident at follow-up.
Warmus, Brian A.; Sekar, Dheepa R.; McCutchen, Eve; Schellenberg, Gerard D.; Roberts, Rosalinda C.; McMahon, Lori L.
Frontotemporal dementia (FTD) is a neurodegenerative behavioral disorder that selectively affects the salience network, including the ventral striatum and insula. Tau mutations cause FTD, but how mutant tau impairs the salience network is unknown. Here, we address this question using a mouse model expressing the entire human tau gene with an FTD-associated mutation (V337M). Mutant, but not wild-type, human tau transgenic mice had aging-dependent repetitive and disinhibited behaviors, with synaptic deficits selectively in the ventral striatum and insula. There, mutant tau depleted PSD-95, resulting in smaller postsynaptic densities and impaired synaptic localization of NMDA receptors (NMDARs). In the ventral striatum, decreased NMDAR-mediated transmission reduced striatal neuron firing. Pharmacologically enhancing NMDAR function with the NMDAR co-agonist cycloserine reversed electrophysiological and behavioral deficits. These results indicate that NMDAR hypofunction critically contributes to FTD-associated behavioral and electrophysiological alterations and that this process can be therapeutically targeted by a Food and Drug Administration–approved drug. PMID:25471585
Vernay, Aurélia; Sellal, François; René, Frédérique
The behavioral variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease affecting people in their early sixties, characterized by dramatic changes in individual and social behavior. Despite the heterogeneity in the presentation of the clinical symptoms of bvFTD, some characteristic changes can be highlighted. Social disinhibition, changes in food preferences as well as loss of empathy and apathy are commonly described. This is accompanied by a characteristic and dramatic atrophy of the prefrontal cortex with the accumulation of protein aggregates in the neurons in this area. Several causative mutations in different genes have been discovered, allowing the development of transgenic animal models, especially mouse models. In mice, attention has been focused on the histopathological aspects of the pathology, but now studies are taking interest in assessing the behavioral phenotype of FTD models. Finding the right test corresponding to human symptoms is quite challenging, especially since the frontal cortex is much less developed in mice than in humans. Although challenging, the ability to detect relevant prefrontal cortex impairments in mice is crucial for therapeutic approaches. In this review, we aim to present the approaches that have been used to model the behavioral symptoms of FTD and to explore other relevant approaches to assess behavior involving the prefrontal cortex, as well as the deficits associated with FTD.
Ju, Jeong-Sun; Weihl, Conrad C
Inclusion body myopathy associated with Paget's disease of the bone and fronto-temporal dementia (IBMPFD) is a progressive autosomal dominant disorder caused by mutations in p97/VCP (valosin-containing protein). p97/VCP is a member of the AAA+ (ATPase associated with a variety of activities) protein family and participates in multiple cellular processes. One particularly important role for p97/VCP is facilitating intracellular protein degradation. p97/VCP has traditionally been thought to mediate the ubiquitin-proteasome degradation of proteins; however, recent studies challenge this dogma. p97/VCP clearly participates in the degradation of aggregate-prone proteins, a process principally mediated by autophagy. In addition, IBMPFD mutations in p97/VCP lead to accumulation of autophagic structures in patient and transgenic animal tissue. This is likely due to a defect in p97/VCP-mediated autophagosome maturation. The following review will discuss the evidence for p97/VCP in autophagy and how a disruption in this process contributes to IBMPFD pathogenesis.
Rahman, Shibley; Robbins, Trevor W; Hodges, John R; Mehta, Mitul A; Nestor, Peter J; Clark, Luke; Sahakian, Barbara J
The frontal variant of frontotemporal dementia is a significant neurological condition worldwide. There exist few treatments available for the cognitive and behavioural sequelae of fvFTD. Previous research has shown that these patients display risky decision-making, and numerous studies have now demonstrated pathology affecting the orbitofrontal cortex. The present study uses a within-subjects, double-blind, placebo-controlled procedure to investigate the effects of a single dose of methylphenidate (40 mg) upon a range of different cognitive processes including those assessing prefrontal cortex integrity. Methylphenidate was effective in ‘normalizing’ the decision-making behavior of patients, such that they became less risk taking on medication, although there were no significant effects on other aspects of cognitive function, including working memory, attentional set shifting, and reversal learning. Moreover, there was an absence of the normal subjective and autonomic responses to methylphenidate seen in elderly subjects. The results are discussed in terms of the ‘somatic marker’ hypothesis of impaired decision-making following orbitofrontal dysfunction. PMID:16160709
Hallmann, Anna-Lena; Araúzo-Bravo, Marcos J.; Mavrommatis, Lampros; Ehrlich, Marc; Röpke, Albrecht; Brockhaus, Johannes; Missler, Markus; Sterneckert, Jared; Schöler, Hans R.; Kuhlmann, Tanja; Zaehres, Holm; Hargus, Gunnar
Astroglial pathology is seen in various neurodegenerative diseases including frontotemporal dementia (FTD), which can be caused by mutations in the gene encoding the microtubule-associated protein TAU (MAPT). Here, we applied a stem cell model of FTD to examine if FTD astrocytes carry an intrinsic propensity to degeneration and to determine if they can induce non-cell-autonomous effects in neighboring neurons. We utilized CRISPR/Cas9 genome editing in human induced pluripotent stem (iPS) cell-derived neural progenitor cells (NPCs) to repair the FTD-associated N279K MAPT mutation. While astrocytic differentiation was not impaired in FTD NPCs derived from one patient carrying the N279K MAPT mutation, FTD astrocytes appeared larger, expressed increased levels of 4R-TAU isoforms, demonstrated increased vulnerability to oxidative stress and elevated protein ubiquitination and exhibited disease-associated changes in transcriptome profiles when compared to astrocytes derived from one control individual and to the isogenic control. Interestingly, co-culture experiments with FTD astrocytes revealed increased oxidative stress and robust changes in whole genome expression in previously healthy neurons. Our study highlights the utility of iPS cell-derived NPCs to elucidate the role of astrocytes in the pathogenesis of FTD. PMID:28256506
Zhou, Yueqin; Liu, Songyan; Oztürk, Arzu; Hicks, Geoffrey G
Cytoplasmic inclusion of RNA binding protein FUS/TLS in neurons and glial cells is a characteristic pathology of a subgroup of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulation of RNA metabolism caused by FUS cytoplasmic inclusion emerges to be a key event in FUS-associated ALS/FTD pathogenesis. Our recent discovery of a FUS autoregulatory mechanism and its dysregulation in ALS-FUS mutants demonstrated that dysregulated alternative splicing can directly exacerbate the pathological FUS accumulation. We show here that FUS targets RNA for pre-mRNA alternative splicing and for the processing of long intron-containing transcripts, and that these targets are enriched for genes in neurogenesis and gene expression regulation. We also identify that FUS RNA targets are enriched for genes in the DNA damage response pathway. Together, the data support a model in which dysregulated RNA metabolism and DNA damage repair together may render neurons more vulnerable and accelerate neurodegeneration in ALS and FTD.
Oliver, Lindsay D; Virani, Karim; Finger, Elizabeth C; Mitchell, Derek G V
Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder characterized by severely impaired social and emotional behaviour, including emotion recognition deficits. Though fear recognition impairments seen in particular neurological and developmental disorders can be ameliorated by reallocating attention to critical facial features, the possibility that similar benefits can be conferred to patients with FTD has yet to be explored. In the current study, we examined the impact of presenting distinct regions of the face (whole face, eyes-only, and eyes-removed) on the ability to recognize expressions of anger, fear, disgust, and happiness in 24 patients with FTD and 24 healthy controls. A recognition deficit was demonstrated across emotions by patients with FTD relative to controls. Crucially, removal of diagnostic facial features resulted in an appropriate decline in performance for both groups; furthermore, patients with FTD demonstrated a lack of disproportionate improvement in emotion recognition accuracy as a result of isolating critical facial features relative to controls. Thus, unlike some neurological and developmental disorders featuring amygdala dysfunction, the emotion recognition deficit observed in FTD is not likely driven by selective inattention to critical facial features. Patients with FTD also mislabelled negative facial expressions as happy more often than controls, providing further evidence for abnormalities in the representation of positive affect in FTD. This work suggests that the emotional expression recognition deficit associated with FTD is unlikely to be rectified by adjusting selective attention to diagnostic features, as has proven useful in other select disorders.
Snowden, Julie S; Adams, Jennifer; Harris, Jennifer; Thompson, Jennifer C; Rollinson, Sara; Richardson, Anna; Jones, Matthew; Neary, David; Mann, David M; Pickering-Brown, Stuart
Our objective was to compare the clinical and pathological characteristics of frontotemporal dementia patients with MAPT, GRN and C9orf72 gene mutations. We carried out a cross-sectional comparative study of 74 gene-positive patients (15 MAPT, 17 GRN and 42 C9orf72). Thirty had post mortem pathological data permitting clinico-pathological correlation. MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. GRN patients were older at death and more likely to present with non-fluent aphasia. C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. They showed less dietary change than other groups. C9orf72 patients with and without ALS differed only in frequency of psychosis. Greater clinical overlap was observed between GRN and C9orf72 compared to MAPT cases. MAPT cases had tau and GRN and C9orf72, with one exception, TDP-43 pathology. Non-fluent aphasia was linked to TDP subtype A in both GRN and C9orf72 cases and ALS with subtype B. In conclusion, the findings reinforce clinical heterogeneity in FTD and strengthen evidence that genotype influences clinical presentation. Clinical features may inform targeted genetic testing.
Floris, Gianluca; Borghero, Giuseppe; Cannas, Antonino; Di Stefano, Francesca; Ruiu, Elisa; Murru, Maria R; Corongiu, Daniela; Cuccu, Stefania; Tranquilli, Stefania; Sardu, Claudia; Marrosu, Maria G; Chiò, Adriano; Marrosu, Francesco
In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non-mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation.
Couto, Blas; Manes, Facundo; Montañés, Patricia; Matallana, Diana; Reyes, Pablo; Velasquez, Marcela; Yoris, Adrián; Baez, Sandra; Ibáñez, Agustin
Social cognition impairments are pervasive in the frontotemporal dementias (FTD). These deficits would be triggered by (a) basic emotion and face recognition processes as well as by (b) higher level social cognition (e.g., theory of mind, ToM). Both emotional processing and social cognition impairments have been previously reported in the behavioral variant of FTD (bvFTD) and also in other versions of FTDs, including primary progressive aphasia. However, no neuroanatomic comparison between different FTD variants has been performed. We report selective behavioral impairments of face recognition, emotion recognition, and ToM in patients with bvFTD and progressive non-fluent aphasia (PNFA) when compared to controls. Voxel-based morphometry (VBM) shows a classical impairment of mainly orbitofrontal (OFC), anterior cingulate (ACC), insula and lateral temporal cortices in patients. Comparative analysis of regional gray matter related to social cognition deficits (VBM) reveals a differential pattern of fronto-insulo-temporal atrophy in bvFTD and an insulo-temporal involvement in PNFA group. Results suggest that in spite of similar social cognition impairments reported in bvFTD and PNFA, the former represents an inherent ToM affectation whereas in the PNFA these deficits could be related to more basic processes of face and emotion recognition. These results are interpreted in the frame of the fronto-insulo-temporal social context network model (SCNM). PMID:23966929
Stagi, Massimiliano; Klein, Zoe A; Gould, Travis J; Bewersdorf, Joerg; Strittmatter, Stephen M
Fronto-temporal lobar degeneration with TDP-43 (FTLD-TDP) is a fatal neurodegeneration. TMEM106B variants are linked to FTLD-TDP risk, and TMEM106B is lysosomal. Here, we focus on neuronal TMEM106B, and demonstrate co-localization and traffic with lysosomal LAMP-1. pH-sensitive reporters demonstrate that the TMEM106B C-terminus is lumenal. The TMEM106B N-terminus interacts with endosomal adaptors and other TMEM106 proteins. TMEM106B knockdown reduces neuronal lysosomal number and diameter by STED microscopy, and overexpression enlarges LAMP-positive structures. Reduction of TMEM106B increases axonally transported lysosomes, while TMEM106B elevation inhibits transport and yields large lysosomes in the soma. TMEM106B overexpression alters lysosomal stress signaling, causing a translocation of the mTOR-sensitive transcription factor, TFEB, to neuronal nuclei. TMEM106B loss-of-function delays TFEB translocation after Torin-1-induced stress. Enlarged TMEM106B-overexpressing lysosomes maintain organelle integrity longer after lysosomal photodamage than do control lysosomes, while small TMEM106B-knockdown lysosomes are more sensitive to illumination. Thus, neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress, highlighting the possible role of lysosomal biology in FTLD-TDP.
Kipps, C M; Nestor, P J; Acosta-Cabronero, J; Arnold, R; Hodges, J R
Social interaction is profoundly affected in the behavioural form of frontotemporal dementia (bvFTD) yet there are few means of objectively assessing this. Diagnosis of bvFTD is based on informant report, however a number of individuals with a clinical profile consistent with the disease have no imaging abnormality and seem to remain stable, with doubt about the presence of underlying neurodegenerative pathology. We aimed to quantify aspects of the behavioural disorder and link it to the underlying level of atrophy in socially relevant brain regions. We tested individuals with either bvFTD (N = 26) or Alzheimer's disease (N = 9) and 16 controls using The Awareness of Social Inference Test (TASIT) to assess their ability to identify emotion and sarcasm in video vignettes. A subset of bvFTD patients (N = 21) and controls (N = 12) were scanned using MRI within 6 months of assessment. There was marked impairment in the ability of bvFTD patients whose scans showed abnormalities to recognize sarcastic, but not sincere statements. Their capacity to interpret negative emotion was also impaired, and this appeared to be a major factor underlying the deficit in sarcasm recognition. Clinically diagnosed bvFTD patients whose scans were normal, Alzheimer's disease patients and controls had no difficulty in appreciating both types of statement. In a multivariate imaging analysis it was shown that the sarcasm (and emotion recognition) deficit was dependent on a circuit involving the lateral orbitofrontal cortex, insula, amygdala and temporal pole, particularly on the right. Performance on a more global test of cognitive function, the Addenbrooke's Cognitive Examination did not have a unique association with these regions. The TASIT is an objective test of social dysfunction in bvFTD which indexes the frontotemporal volume loss in bvFTD patients and provides an objective measure for separating behavioural patients who are likely to decline from those who may remain stable. These
Lindberg, Olof; Walterfang, Mark; Looi, Jeffrey C.L.; Malykhin, Nikolai; Östberg, Per; Zandbelt, Bram; Styner, Martin; Velakoulis, Dennis; Örndahl, Eva; Cavallin, Lena; Wahlund, Lars-Olof
Hippocampal pathology is central to Alzheimer’s disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients (13 frontotemporal dementia [FTD], 13 semantic dementia [SD] and 9 progressive nonfluent aphasia [PNFA]) and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. AD finally displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with pathological studies most deformation was found in CA1 and subiculum areas in FTLD and AD. PMID:22414571
Lindberg, Olof; Walterfang, Mark; Looi, Jeffrey C L; Malykhin, Nikolai; Ostberg, Per; Zandbelt, Bram; Styner, Martin; Paniagua, Beatriz; Velakoulis, Dennis; Orndahl, Eva; Wahlund, Lars-Olof
Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.
Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response. PMID:23800361
Busch, Johanna I; Unger, Travis L; Jain, Nimansha; Tyler Skrinak, R; Charan, Rakshita A; Chen-Plotkin, Alice S
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is an important cause of dementia in individuals under age 65. Common variants in the TMEM106B gene were previously discovered by genome-wide association to confer genetic risk for FTLD-TDP (p = 1 × 10(-)(11), OR = 1.6). Furthermore, TMEM106B may act as a genetic modifier affecting age at onset and age at death in the Mendelian subgoup of FTLD-TDP due to expansions of the C9orf72 gene. Evidence suggests that TMEM106B variants increase risk for developing FTLD-TDP by increasing expression of Transmembrane Protein 106B (TMEM106B), a lysosomal protein. To further understand the functional role of TMEM106B in disease pathogenesis, we investigated the cell biological effects of increased TMEM106B expression. Here, we report that increased TMEM106B expression results in the appearance of a vacuolar phenotype in multiple cell types, including neurons. Concomitant with the development of this vacuolar phenotype, cells over-expressing TMEM106B exhibit impaired lysosomal acidification and degradative function, as well as increased cytotoxicity. We further identify a potential lysosomal sorting motif for TMEM106B and demonstrate that abrogation of sorting to lysosomes rescues TMEM106B-induced defects. Finally, we show that TMEM106B-induced defects are dependent on the presence of C9orf72, as knockdown of C9orf72 also rescues these defects. In sum, our results suggest that TMEM106B exerts its effects on FTLD-TDP disease risk through alterations in lysosomal pathways. Furthermore, TMEM106B and C9orf72 may interact in FTLD-TDP pathophysiology.
Baez, Sandra; Pinasco, Clara; Roca, María; Ferrari, Jesica; Couto, Blas; García-Cordero, Indira; Ibañez, Agustín; Cruz, Francy; Reyes, Pablo; Matallana, Diana; Manes, Facundo; Cetcovich, Marcelo; Torralva, Teresa
An early stage of behavioral variant frontotemporal dementia (bvFTD) often displays a mix of behavioral disturbances and personality changes hindering a differential diagnosis from elderly bipolar disorder (BD), making this process a big challenge. However, no studies have compared these pathologies from neuropsychological and neuroanatomical perspectives. The aim of the present study was to compare the executive functions (EF) and social cognition profiles as well as the structural neuroimaging of bvFTD and elderly patients with BD. First, we compared the executive and social cognition performances of 16 bvFTD patients, 13 BD patients and 22 healthy controls. Second, we compared grey matter volumes in both groups of patients and controls using voxel-based morphometry. Lastly, we examined the brain regions where atrophy might be associated with specific impairments in bvFTD and BD patients. Compared to controls, bvFTD patients showed deficits in working memory, abstraction capacity, inhibitory control, cognitive flexibility, verbal fluency and theory of mind (ToM). Patients with BD showed lower performance than controls in terms of abstraction capacity and verbal inhibitory control. In bvFTD patients, atrophy of frontal, temporal and insular cortices was related to EF deficits. Atrophy of the amygdala, the hippocampus, the parahippocampal gyrus, the putamen, the insula, the precuneus, the right temporo-parietal junction and superior temporal pole was associated to ToM impairments. No significant associations between atrophy and EF performance were observed in BD patients. BvFTD patients showed greater EF and ToM deficits than BD patients. Moreover, compared to BD, bvFTD patients exhibited a significant decrease in GM volume in frontal, temporal and parietal regions. Our results provide the first comparison of EF, social cognition and neuroanatomical profiles of bvFTD and elderly BD patients. These findings shed light on differential diagnosis of these disorders and
Bae, Jong Seok; Ferguson, Michele; Tan, Rachel; Mioshi, Eneida; Simon, Neil; Burrell, James; Vucic, Steve; Hodges, John R.; Kiernan, Matthew C
Background and Purpose This study investigated the structural and functional changes in the motor system in amyotrophic lateral sclerosis (ALS; n=25) and behavioral-variant fronto-temporal dementia (bvFTD; n=17) relative to healthy controls (n=37). Methods Structural changes were examined using a region-of-interest approach, applying voxel-based morphometry for gray-matter changes and diffusion tensor imaging for white-matter changes. Functional changes in the motor system were elucidated using threshold-tracking transcranial magnetic stimulation (TMS) measurements of upper motor-neuron excitability. Results The structural analyses showed that in ALS there were more white-matter changes in the corticospinal and motor-cortex regions and more gray-matter changes in the cerebellum in comparison to controls. bvFTD showed substantial gray- and white-matter changes across virtually all motor-system regions compared to controls, although the brainstem was affected less than the other regions. Direct comparisons across patient groups showed that the gray- and white-matter motor-system changes inclusive of the motor cortex were greater in bvFTD than in ALS. By contrast, the functional integrity of the motor system was more adversely affected in ALS than in bvFTD, with both patient groups showing increased excitability of upper motor neurons compared to controls. Conclusions Cross-correlation of structural and functional data further revealed a neural dissociation of different motor-system regions and tracts covarying with the TMS excitability across both patient groups. The structural and functional motor-system integrities appear to be dissociated between ALS and bvFTD, which represents useful information for the diagnosis of motor-system changes in these two disorders. PMID:26932257
Walterfang, Mark; Vestberg, Susanna; Velakoulis, Dennis; Wilkes, Fiona A.; Nilsson, Christer; van Westen, Danielle; Looi, Jeffrey C. L.; Santillo, Alexander Frizell
Introduction Behavioural variant frontotemporal dementia (bvFTD) is associated with changes in dorsal striatal parts of the basal ganglia (caudate nucleus and putamen), related to dysfunction in the cortico-striato-thalamic circuits which help mediate executive and motor functions. We aimed to determine whether the size and shape of striatal structures correlated with diagnosis of bvFTD, and measures of clinical severity, behaviour and cognition. Materials and Methods Magnetic resonance imaging scans from 28 patients with bvFTD and 26 healthy controls were manually traced using image analysis software (ITK-SNAP). The resulting 3-D objects underwent volumetric analysis and shape analysis, through spherical harmonic description with point distribution models (SPHARM-PDM). Correlations with size and shape were sought with clinical measures in the bvTFD group, including Frontal Behavioural Inventory, Clinical Dementia Rating for bvFTD, Color Word Interference, Hayling part B and Brixton tests, and Trail-Making Test. Results Caudate nuclei and putamina were significantly smaller in the bvFTD group compared to controls (left caudate 16% smaller, partial eta squared 0.173, p=0.003; right caudate 11% smaller, partial eta squared 0.103, p=0.023; left putamen 18% smaller, partial eta squared 0.179, p=0.002; right putamen 12% smaller, partial eta squared 0.081, p=0.045), with global shape deflation in the caudate bilaterally but no localised shape change in putamen. In the bvFTD group, shape deflations on the left, corresponding to afferent connections from dorsolateral prefrontal mediofrontal/anterior cingulate and orbitofrontal cortex, correlated with worsening disease severity. Global shape deflation in the putamen correlated with Frontal Behavioural Inventory scores—higher scoring on negative symptoms was associated with the left putamen, while positive symptoms were associated with the right. Other cognitive tests had poor completion rates. Conclusion Behavioural
Galimberti, D; Bonsi, R; Fenoglio, C; Serpente, M; Cioffi, S M G; Fumagalli, G; Arighi, A; Ghezzi, L; Arcaro, M; Mercurio, M; Rotondo, E; Scarpini, E
Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean±SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27±151.5 versus 159.7±49pg/ml; P⩽0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17±240.0 versus 436.61±202.5pg/ml; P=0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18±1.41 versus 35.68±30.5pg/ml; P=0.013 and 9.34±5.54 versus 19.15±10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63±3.30 and 2.58±20 versus 87.57±70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.
Størmer, Fredrik C
When cryptochrome in the retina is exposed to blue light, it undergo series of complicated chemical reactions. One of these intermediates has magnetic properties. It could be a link between the magnetic stage of cryptochrome in the retina and magnetite in the brain. A disturbance in this system could be involved in the development of frontotemporal dementia and other mental disturbances like Alzheimer's disease. There could also be a link between circadian rhythms and memory dysfunction connected to schizophrenia, type 2 diabetes, and blue light.
Gascon, Eduardo; Gao, Fen-Biao
Increasing evidence suggests that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share some clinical, pathological, and molecular features as part of a common neurodegenerative spectrum disorder. In recent years, enormous progress has been made in identifying both pathological proteins and genetic mutations associated with FTD-ALS. However, the molecular pathogenic mechanisms of disease onset and progression remain largely unknown. Recent studies have uncovered unexpected links between FTD-ALS and multiple aspects of RNA metabolism, setting the stage for further understanding of the disorder. Here, the authors will focus on microRNAs and review the emerging roles of these small RNAs in several aspects of FTD-ALS pathogenesis.
Sitek, Emilia J.; Narożańska, Ewa; Barczak, Anna; Jasińska-Myga, Barbara; Harciarek, Michał; Chodakowska-Żebrowska, Małgorzata; Kubiak, Małgorzata; Wieczorek, Dariusz; Konieczna, Seweryna; Rademakers, Rosa; Baker, Matt; Berdyński, Mariusz; Brockhuis, Bogna; Barcikowska, Maria; Żekanowski, Cezary; Heilman, Kenneth M.; Wszołek, Zbigniew K.; Sławek, Jarosław
Objectives Patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) may be agraphic. The study aimed at characterizing agraphia in individuals with a P301L MAPT mutation. Methods Two pairs of siblings with FTDP-17 were longitudinally examined for agraphia in relation to language and cognitive deficits. Results All patients presented with dysexecutive agraphia. In addition, in the first pair of siblings one sibling demonstrated spatial agraphia with less pronounced allographic agraphia and the other sibling had aphasic agraphia. Aphasic agraphia was also present in one sibling from the second pair. Conclusion Agraphia associated with FTDP-17 is very heterogeneous. PMID:23121543
Cardiovascular risk factors (CRF) were widely described as related to dementia. There are very few studies regarding this association in FTD. The objective of the study was to compare the frequency of CRF in our population with FTD and controls. 100 consecutive subjects with FTD diagnosis according to Lund-Manchester clinical criteria and 200 controls matched by age and sex were included between January 2003 to February 2007 at the Cognitive and Behavior Unit of Hospital Italiano de Buenos Aires. Clinical evaluation, laboratory tests, brain images (CT/MRI), neuropsychological and neuropsychiatric assessment were performed. Multiple regression analysis was performed to analyze the association in CRF between FTD patients vs. controls. The mean age in FTD was 69.7 ± 0.9 vs. 70.1 ± 0.8 in controls (p 0.12). No difference in gender was observed between cases and controls. No differences were identified between patients and controls regarding hypertension (HTA) (65% vs. 67,3% p 0.44); dyslipidemia (57% vs. 54.7% p 0.74); obesity (39% vs. 27.6% p 0.14) and hypothyroidism (26% vs. 17.1% p 0.1). A significant difference was observed for Diabetes Mellitus (39% vs. 22.6% p 0.001). In our population, Diabetes Mellitus was associated as an independent risk factor for FTD. To our knowledge this is the first report in which CRF were evaluated prospectively in FTD patients. More studies are needed to confirm this finding in larger populations. PMID:24995127
Igari, Ryousuke; Wada, Manabu; Sato, Hiroyasu; K Hayashi, Yukiko; Nishino, Ichizo; Kato, Takeo
Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. Varied clinical features caused by VCP mutations have been reported: these clinical phenotypes include distal myopathy, frontotemporal dementia and amyotrophic lateral sclerosis. We report a 49-year-old woman with 3-year history of progressive proximal limb muscle weakness. Family history was notable for her father with motor neuron disease and an elder brother with a myopathy involving tibialis anterior and quadriceps. Neurological examinations showed proximal muscle atrophy, especially severe atrophy of paravertebral muscles, right-dominant scapular winging, bilateral pyramidal signs and hyperreflexia. Serum CK level was normal and EMG showed chronic neurogenic changes. Muscle imaging (CT) showed adipose tissue replacement of paravertebral muscles and right serratus anterior, and marked atrophy of bilateral trapezius and vastus intermedius muscles. Her lumbar spine X-ray showed an osteosclerotic change in the vertebral body, where an increased uptake of Tc99m was also observed in bone scintigraphy. Although brain MRI was normal, neuropsychological examination showed a mild attention deficit with cognitive impairment. A muscle biopsy specimen revealed scattered fibers with rimmed vacuoles. These findings prompted us to analyze a mutation in the VCP gene. Genomic sequencing of all exons of the gene showed a heterozygous missense mutation in exon 5 (c.1315G>C; p.Ala439Pro).
Gislason, T; Sjogren, M; Larsson, L; Skoog, I
Objectives: To investigate the prevalence of the frontal lobe syndrome (FLS) and the frontal variant of frontotemporal dementia (fvFTD) in a population based sample of 85 year olds. Methods: A representative sample of 85 year olds (n = 451) in Gothenburg, Sweden was examined with a neuropsychiatric examination and a key informant interview performed by an experienced psychiatrist. A subsample underwent computed tomography (CT) of the head. The Lund-Manchester research criteria were used as a basis for a symptom algorithm to identify individuals with FLS and fvFTD. These were diagnosed blindly to the diagnosis of dementia according to DSM-III-R. Results: A total of 86 individuals (19%) fulfilled the criteria for FLS, and 14 of them fulfilled criteria for fvFTD. There were no differences between men and women. Among those with FLS, 75 (87%) fulfilled DSM-III-R criteria for other types of dementia, mainly Alzheimer's disease and vascular dementia. Among the 14 fvFTD cases, only five were demented according to DSM-III-R. Moderate to severe frontal atrophy was found in 93% of those with FLS (and in all cases with fvFTD), but also in 49% of those without FLS. FLS was found in 35% of those with moderate to severe frontal atrophy, and in 3% of those without these changes. Conclusions: The prevalence of fvFTD was 3% in 85 year olds, which is higher than previously expected in this age group. Only a minority of those with fvFTD were detected by the DSM-III-R criteria for dementia. FLS was even more common, especially in those diagnosed with a dementia disorder. PMID:12810769
Linking white matter integrity loss to associated cortical regions using structural connectivity information in Alzheimer's disease and fronto-temporal dementia: the Loss in Connectivity (LoCo) score.
Kuceyeski, Amy; Zhang, Yu; Raj, Ashish
It is well known that gray matter changes occur in neurodegenerative diseases like Alzheimer's (AD) and fronto-temporal dementia (FTD), and several studies have investigated their respective patterns of atrophy progression. Recent work, however, has revealed that diffusion MRI that is able to detect white matter integrity changes may be an earlier or more sensitive biomarker in both diseases. However, studies that examine white matter changes only are limited in that they do not provide the functional specificity of GM region-based analysis. In this study, we develop a new metric called the Loss in Connectivity (LoCo) score that gives the amount of structural network disruption incurred by a gray matter region for a particular pattern of white matter integrity loss. Leveraging the relative strengths of WM and GM markers, this metric links areas of WM integrity loss to their connected GM regions as a first step in understanding their functional implications. The LoCo score is calculated for three groups: 18AD, 18 FTD, and 19 age-matched normal controls. We show significant correlations of the LoCo with the respective atrophy patterns in AD (R=0.51, p=2.2 × 10(-9)) and FTD (R=0.49, p=2.5 × 10(-8)) for a standard 116 region gray matter atlas. In addition, we demonstrate that the LoCo outperforms a measure of gray matter atrophy when classifying individuals into AD, FTD, and normal groups.
... modification may help control unacceptable or dangerous behaviors. Aggressive, agitated, or dangerous behaviors could require medication. Anti- ... modification may help control unacceptable or dangerous behaviors. Aggressive, agitated, or dangerous behaviors could require medication. Anti- ...
... Calendar of Events Fundraising Events Conferences Press Releases Genetics of FTD After receiving a diagnosis of FTD ... that recent advances in science have brought the genetics of FTD into much better focus. In 2012, ...
Moreno, Fermín; Alzualde, Ainhoa; Camblor, Pablo Martínez; Barandiaran, Myriam; Van Deerlin, Vivianna M; Gabilondo, Alazne; Martí Massó, José F; López de Munain, Adolfo; Indakoetxea, Begoña
Frontotemporal lobar degeneration because of mutations in the progranulin (PGRN) gene presents a high variability both in the clinical phenotype and age of onset of disease. Factors that influence this variability remain largely unknown. The aim of our study was to determine whether selected genetic variables modify age at onset of disease in our series of 21 patients with a single splicing mutation (c.709-1G>A) in the PGRN gene, all of whom were of Basque descent. In our analysis, we included the following genetic variables: PGRN rs5848 and rs9897526 polymorphisms, APOE and microtubule-associated protein tau genotypes, and PRNP codon 129 polymorphism. We found no association between PGRN polymorphisms, APOE and microtubule-associated protein tau genotypes, and age at onset of the disease; whereas we report evidence for an association between PRNP codon 129 polymorphism and age at onset of disease in frontotemporal dementia-PGRN(+) patients. MM homozygous carriers presented onset of disease on average 8.5 years earlier than patients who carried at least 1 valine on their PRNP codon 129 (MV or VV). The biological justification for this association remains speculative.
Chaussenot, Annabelle; Le Ber, Isabelle; Ait-El-Mkadem, Samira; Camuzat, Agnès; de Septenville, Anne; Bannwarth, Sylvie; Genin, Emmanuelle C; Serre, Valérie; Augé, Gaëlle; Brice, Alexis; Pouget, Jean; Paquis-Flucklinger, Véronique
Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment. CHCHD10 encodes a protein located in the mitochondrial intermembrane space and is likely involved in mitochondrial genome stability and maintenance of cristae junctions. However, the exact contribution of CHCHD10 in FTD and ALS diseases spectrum remains unknown. In this study, we evaluated the frequency of CHCHD10 mutations in 115 patients with FTD and FTD-ALS phenotypes. We identified 2 heterozygous variants in 3 unrelated probands presenting FTD and ALS, characterized by early and predominant bulbar symptoms. This study demonstrates the implication of CHCHD10 in FTD and ALS spectrum. Although the frequency of mutations is low in this series (2.6%), our work suggests that CHCHD10 mutations should be searched particularly when bulbar symptoms are present at onset.
Chan, Qun Lin; Xu, Xin; Shaik, Muhammad Amin; Chong, Steven Shih Tsze; Hui, Richard Jor Yeong; Chen, Christopher Li-Hsian; Dong, YanHong
The informant AD8 has excellent discriminant ability for dementia case finding in tertiary healthcare settings. However, its clinical utility for dementia case finding at the forefront of dementia management, primary healthcare, is unknown. Therefore, we recruited participants from two primary healthcare centers in Singapore and measured their performance on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a local formal neuropsychological battery, in addition to the AD8. Logistic regression was conducted to examine the associations between demographic factors and dementia. Area under the receiver operating characteristics (ROC) curve analysis was used to establish the optimal cut-off points for dementia case finding. Of the 309 participants recruited, 243 (78.7%) had CDR = 0, 22 (7.1%) CDR = 0.5, and 44 (14.2%) CDR ≥1. Age was strongly associated with dementia, and the optimal age for dementia case finding in primary healthcare settings was ≥75 years. In this age group, the AD8 has excellent dementia case finding capability and was superior to the MMSE and equivalent to the MoCA [AD8 AUC (95% CI): 0.95 (0.91-0.99), cut-off: ≥3, sensitivity: 0.90, specificity: 0.88, PPV: 0.79 and NPV: 0.94; MMSE AUC (95% CI): 0.87 (0.79-0.94), p = 0.04; MoCA AUC (95% CI): 0.88 (0.82-0.95), p = 0.06]. In conclusion, the AD8 is well suited for dementia case finding in primary healthcare settings.
Daianu, Madelaine; Jahanshad, Neda; Mendez, Mario F.; Bartzokis, George; Jimenez, Elvira E.; Thompson, Paul M.
Diffusion imaging and brain connectivity analyses can assess white matter deterioration in the brain, revealing the underlying patterns of how brain structure declines. Fiber tractography methods can infer neural pathways and connectivity patterns, yielding sensitive mathematical metrics of network integrity. Here, we analyzed 1.5-Tesla wholebrain diffusion-weighted images from 64 participants - 15 patients with behavioral variant frontotemporal dementia (bvFTD), 19 with early-onset Alzheimer's disease (EOAD), and 30 healthy elderly controls. Using whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We evaluated the brain's networks focusing on the most highly central and connected regions, also known as hubs, in each diagnostic group - specifically the "high-cost" structural backbone used in global and regional communication. The high-cost backbone of the brain, predicted by fiber density and minimally short pathways between brain regions, accounted for 81-92% of the overall brain communication metric in all diagnostic groups. Furthermore, we found that the set of pathways interconnecting high-cost and high-capacity regions of the brain's communication network are globally and regionally altered in bvFTD, compared to healthy participants; however, the overall organization of the high-cost and high-capacity networks were relatively preserved in EOAD participants, relative to controls. Disruption of the major central hubs that transfer information between brain regions may impair neural communication and functional integrity in characteristic ways typical of each subtype of dementia.
Pasqualetti, Giuseppe; Brooks, David J; Edison, Paul
The molecular mechanism of neuronal loss and synaptic damage in Alzheimer's disease (AD), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD) and Lewy body dementia (LBD) is poorly understood and could differ among different types of neurodegenerative processes. However, the presence of neuroinflammation is a common feature of dementia. In this setting, reactive microgliosis, oxidative damage and mitochondrial dysfunction are associated with the pathogenesis of all types of neurodegenerative dementia. Moreover, an increased body of evidence suggests that microglia may play a central role in AD progression. In this paper, we review the scientific literature on neuroinflammation related to the most common neurodegenerative dementias (AD, PDD, FTD and LBD) focussing on the possible molecular mechanisms and the available clinical evidence. Furthermore, we discuss the neuroimaging techniques that are currently used for the study of neuroinflammation in human brain.
Yokota, Osamu; Tsuchiya, Kuniaki; Itoh, Yoshinori; Ishizu, Hideki; Akiyama, Haruhiko; Ikeda, Manabu; Kuzuhara, Shigeki; Otomo, Eiichi
We report a case of a right-handed 74-year-old man who showed semantic dementia with a disease duration of 19 years. He initially presented with excessive use of pronouns and semantic paraphasia at the age of 55 years. Impairment of object recognition developed 5 years after the onset. Face recognition impairment and stereotypic behaviors developed 11 years after onset, and pyramidal signs 2 years before death. Pathological examination disclosed circumscribed severe atrophy in not only the bilateral temporal tips but also in the left precentral gyrus and pars opercularis in a motor speech field. Pyramidal tract involvement and loss of Betz cells were also evident. On the other hand, neurons in the anterior horns and hypoglossal nuclei were spared in number, although astrocytes were mildly proliferated. Ubiquitin-positive lesions were observed in the hippocampus, and frontal and temporal cortices. Neither Bunina bodies nor Pick bodies were present. These features clinically fit the international diagnostic criteria of semantic dementia and, histopathologically, frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). This case suggests that (1) the distribution of cortical lesions associated with language disturbance is not uniform in FTLD-MND. It may be that only some cases of FTLD with ubiquitin pathology develop semantic dementia despite the high incidence of language disturbance, and (2) the precentral gyrus can be severely affected in FTLD-MND. After reviewing previous cases of FTLD-MND with a clinical course of more than 10 years, we also noticed that (3) FTLD-MND cases with a long disease duration often show upper motor neuron-predominant involvement.
Simonsen, Anja Hviid; Herukka, Sanna-Kaisa; Andreasen, Niels; Baldeiras, Ines; Bjerke, Maria; Blennow, Kaj; Engelborghs, Sebastiaan; Frisoni, Giovanni B; Gabryelewicz, Tomasz; Galluzzi, Samantha; Handels, Ron; Kramberger, Milica G; Kulczyńska, Agnieszka; Molinuevo, Jose Luis; Mroczko, Barbara; Nordberg, Agneta; Oliveira, Catarina Resende; Otto, Markus; Rinne, Juha O; Rot, Uroš; Saka, Esen; Soininen, Hilkka; Struyfs, Hanne; Suardi, Silvia; Visser, Pieter Jelle; Winblad, Bengt; Zetterberg, Henrik; Waldemar, Gunhild
This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.
LI, PAN; QUAN, WEI; ZHOU, YU-YING; WANG, YAN; ZHANG, HUI-HONG; LIU, SHUAI
Previous studies have focused on the curative effects of memantine in patients with mild-to-moderate frontotemporal lobar degeneration (FTLD); however, its benefits in patients with moderate-to-severe FTLD have not been investigated. The present study explores the behavioral, cognitive and functional effects of memantine on behavioral variant frontotemporal dementia (bvFTD) in patients with mild and moderate-to-severe stage bvFTD. A total of 42 patients with bvFTD completed a 6-month treatment plan of 20 mg memantine daily in an open-label, self-controlled clinical trial. Patients were divided into two groups according to their Mini-Mental State Examination (MMSE) score: Mild (score, 21–26); and moderate-to-severe (score, 4–20). Primary endpoints included Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinic Dementia Rating (CDR) scores, and secondary endpoints comprised Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D), MMSE, Montreal Cognitive Assessment (MoCA), Activity of Daily Life (ADL) and Hamilton Depression Rating Scale (HAMD) scores. Memantine treatment had no effect on overall NPI-Q scores, with the exception of the agitation subdomain in all patients with bvFTD. However, patients with moderate-to-severe bvFTD exhibited a better performance than patients with mild bvFTD, demonstrated by improved NPI-Q total scores and subscales of agitation, depression, apathy and disinhibition. In the moderate-to-severe group, CDR and HAMD scores remained stable, but MMSE, MoCA and ADL scores were reduced after 6 months of treatment. Memantine was well-tolerated in patients. In conclusion, patients with moderate-to-severe bvFTD responded significantly better to memantine in comparison to patients with mild bvFTD with regard to their neuropsychiatric scores, while memantine did not present any cognitive or functional benefits in patients with mild bvFTD. A randomized, double-blind, placebo-controlled clinical trial with a larger number of patients is
Mild Cognitive Impairment; Dementia; Hypoxia; Hyperhomocysteinemia; Vitamin B 12 Deficiency; Iron Deficiency; Anemia; TBI; Neurodegenerative Disorders; Alzheimer's Disease; Vascular Dementia; Brain Injuries; Tauopathies; Parkinson's Disease; Lewy Body Dementia; Frontotemporal Dementia; TDP-43 Proteinopathies
Ingre, Caroline; Landers, John E; Rizik, Naji; Volk, Alexander E; Akimoto, Chizuru; Birve, Anna; Hübers, Annemarie; Keagle, Pamela J; Piotrowska, Katarzyna; Press, Rayomand; Andersen, Peter Munch; Ludolph, Albert C; Weishaupt, Jochen H
Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have very recently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, we performed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporal dementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenic relevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260 sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United States were screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. In a German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which was absent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recently described p.Gln117Gly sequence variant was found in another familial ALS patient from the United States. The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overt cognitive involvement. PFN1 mutations were absent in patients with motor neuron disease and dementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the "classic" ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proof-of-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motor neuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization by phosphorylation of profilin 1 might be necessary for motor neuron survival.
Seelen, Meinie; Visser, Anne E; Overste, Daniel J; Kim, Hong J; Palud, A; Wong, Tsz H; van Swieten, John C; Scheltens, Philip; Voermans, Nicol C; Baas, Frank; de Jong, J M B V; van der Kooi, Anneke J; de Visser, Marianne; Veldink, Jan H; Taylor, J Paul; Van Es, Michael A; van den Berg, Leonard H
Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle, brain, motor neurons, and bone with prominent TDP-43 pathology. Recently, 2 novel genes for multi system proteinopathy were discovered; heterogenous nuclear ribonucleoprotein (hnRNP) A1 and A2B1. Subsequently, a mutation in hnRNPA1 was also identified in a pedigree with autosomal dominant familial ALS. The genetic evidence for ALS and other neurodegenerative diseases is still insufficient. We therefore sequenced the prion-like domain of these genes in 135 familial ALS, 1084 sporadic ALS, 68 familial FTD, 74 sporadic FTD, and 31 sporadic IBM patients in a Dutch population. We did not identify any mutations in these genes in our cohorts. Mutations in hnRNPA1 and hnRNPA2B1 prove to be a rare cause of ALS, FTD, and IBM in the Netherlands.
FTLD; Progressive Supranuclear Palsy (PSP); Frontotemporal Dementia (FTD); Corticobasal Degeneration (CBD); PPA Syndrome; Behavioral Variant Frontotemporal Dementia (bvFTD); Semantic Variant Primary Progressive Aphasia (svPPA); Nonfluent Variant Primary Progressive Aphasia (nfvPPA); FTD With Amyotrophic Lateral Sclerosis (FTD/ALS); Amyotrophic Lateral Sclerosis (ALS); Oligosymptomatic PSP (oPSP); Corticobasal Syndrome (CBS)
Satoh, Jun-ichi; Yamamoto, Yoji; Kitano, Shouta; Takitani, Mika; Asahina, Naohiro; Kino, Yoshihiro
BACKGROUND Expanded GGGGCC hexanucleotide repeats, ranging from hundreds to thousands in number, located in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene represent the most common genetic abnormality for familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (abbreviated as C9ALS). Currently, three pathological mechanisms, such as haplo insufficiency of C9orf72, formation of nuclear RNA foci composed of sense and antisense repeats, and accumulation of unconventionally transcribed dipeptide-repeat (DPR) proteins, are proposed for C9ALS. However, at present, the central mechanism underlying neurodegeneration in C9ALS remains largely unknown. METHODS By using three distinct pathway analysis tools of bioinformatics, we studied molecular networks involved in C9ALS pathology by focusing on C9orf72 omics datasets, such as proteome of C9orf72 repeat RNA-binding proteins, transcriptome of induced pluripotent stem cells (iPSC)-derived motor neurons of patients with C9ALS, and transcriptome of purified motor neurons of patients with C9ALS. RESULTS We found that C9orf72 repeat RNA-binding proteins play a crucial role in the regulation of post-transcriptional RNA processing. The expression of a wide range of extracellular matrix proteins and matrix metalloproteinases was reduced in iPSC-derived motor neurons of patients with C9ALS. The regulation of RNA processing and cytoskeletal dynamics is disturbed in motor neurons of patients with C9ALS in vivo. CONCLUSIONS Bioinformatics data mining approach suggests a logical hypothesis that C9orf72 repeat expansions that deregulate post-transcriptional RNA processing disturb the homeostasis of cytoskeletal dynamics and remodeling of extracellular matrix, leading to degeneration of stress-vulnerable neurons in the brain and spinal cord of patients with C9ALS. PMID:25210488
Risacher, Shannon L.; Saykin, Andrew J.
Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer’s disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson’s disease with and without dementia, dementia with Lewy bodies, Huntington’s disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders. PMID:24234359
Beauchet, Olivier; Annweiler, Cédric; Callisaya, Michele L.; De Cock, Anne-Marie; Helbostad, Jorunn L.; Kressig, Reto W.; Srikanth, Velandai; Steinmetz, Jean-Paul; Blumen, Helena M.; Verghese, Joe; Allali, Gilles
Background Poor gait performance predicts risk of developing dementia. No structured critical evaluation has been conducted to study this association yet. The aim of this meta-analysis was to systematically examine the association of poor gait performance with incidence of dementia. Methods An English and French Medline search was conducted in June 2015, with no limit of date, using the medical subject headings terms “Gait” OR “Gait Disorders, Neurologic” OR “Gait Apraxia” OR “Gait Ataxia” AND “Dementia” OR “Frontotemporal Dementia” OR “Dementia, Multi-Infarct” OR “Dementia, Vascular” OR “Alzheimer Disease” OR “Lewy Body Disease” OR “Frontotemporal Dementia With Motor Neuron Disease” (Supplementary Concept). Poor gait performance was defined by standardized tests of walking, and dementia was diagnosed according to international consensus criteria. Four etiologies of dementia were identified: any dementia, Alzheimer disease (AD), vascular dementia (VaD), and non-AD (ie, pooling VaD, mixed dementias, and other dementias). Fixed effects meta-analyses were performed on the estimates in order to generate summary values. Results Of the 796 identified abstracts, 12 (1.5%) were included in this systematic review and meta-analysis. Poor gait performance predicted dementia [pooled hazard ratio (HR) combined with relative risk and odds ratio = 1.53 with P < .001 for any dementia, pooled HR = 1.79 with P < .001 for VaD, HR = 1.89 with P value < .001 for non-AD]. Findings were weaker for predicting AD (HR = 1.03 with P value = .004). Conclusions This meta-analysis provides evidence that poor gait performance predicts dementia. This association depends on the type of dementia; poor gait performance is a stronger predictor of non-AD dementias than AD. PMID:26852960
Piscopo, Paola; Grasso, Margherita; Fontana, Francesca; Crestini, Alessio; Puopolo, Maria; Del Vescovo, Valerio; Venerosi, Aldina; Calamandrei, Gemma; Vencken, Sebastian F.; Greene, Catherine M.; Confaloni, Annamaria; Denti, Michela A.
Progranulin (PGRN) is a secreted protein expressed ubiquitously throughout the body, including the brain, where it localizes in neurons and is activated microglia. Loss-of-function mutations in the GRN gene are an important cause of familial frontotemporal lobar degeneration (FTLD). PGRN has a neurotrophic and anti-inflammatory activity, and it is neuroprotective in several injury conditions, such as oxygen or glucose deprivation, oxidative injury, and hypoxic stress. Indeed, we have previously demonstrated that hypoxia induces the up-regulation of GRN transcripts. Several studies have shown microRNAs (miRNAs) involvement in hypoxia. Moreover, in FTLD patients with a genetic variant of GRN (rs5848), the reinforcement of miR-659-3p binding site has been suggested to be a risk factor. Here, we report that miR-659-3p interacts directly with GRN 3′UTR as shown by luciferase assay in HeLa cells and ELISA and Western Blot analysis in HeLa and Kelly cells. Moreover, we demonstrate the physical binding between GRN mRNA and miR-659-3p employing a miRNA capture-affinity technology in SK-N-BE and Kelly cells. In order to study miRNAs involvement in hypoxia-mediated up-regulation of GRN, we evaluated miR-659-3p levels in SK-N-BE cells after 24 h of hypoxic treatment, finding them inversely correlated to GRN transcripts. Furthermore, we analyzed an animal model of asphyxia, finding that GRN mRNA levels increased at post-natal day (pnd) 1 and pnd 4 in rat cortices subjected to asphyxia in comparison to control rats and miR-659-3p decreased at pnd 4 just when GRN reached the highest levels. Our results demonstrate the interaction between miR-659-3p and GRN transcript and the involvement of miR-659-3p in GRN up-regulation mediated by hypoxic/ischemic insults. PMID:27199656
... skills) Dementia usually first appears as forgetfulness. Mild cognitive impairment (MCI) is the stage between normal forgetfulness due to aging and the development of dementia. People with MCI have mild problems ...
Pal, Asutosh; Biswas, Atanu; Pandit, Alak; Roy, Arijit; Guin, Debsankar; Gangopadhyay, Goutam; Senapati, Asit Kumar
Objectives: To assess the visuospatial function in different types of dementia with the visual object and space perception (VOSP) battery and to relate the degree of visuospatial dysfunction with different types and stages of dementia. Materials and Methods: A sample of 53 participants with dementia and equal number of age-, sex-, and education-matched controls were recruited for the study. Participants were evaluated for visuospatial skill using VOSP test battery. The scores of dementia patients were compared with controls and within dementia cohort scores were compared based on stage of dementia. Results: The dementia group scored low in all of the subtests of the VOSP battery in comparison to controls. Alzheimer's disease (AD), dementia of Lewy bodies (DLB), and vascular dementia (VaD) patients performed more poorly than controls in all subtests examining object perception and space perception. The three semantic variants of frontotemporal dementia (FTD) patients scored low in all four subtests of object perception, whereas behavioral variant FTD (bvFTD) patients performed normally. The scores deteriorated with the advancement of dementia in all patients from the dementia groups. Conclusions: Visuospatial function is significantly impaired in dementia patients particularly in AD, DLB, and VaD patients from the beginning, and the impairment is severe in advanced disease stages. PMID:27011635
Kara, Eleanna; Kiely, Aoife P; Proukakis, Christos; Giffin, Nicola; Love, Seth; Hehir, Jason; Rantell, Khadija; Pandraud, Amelie; Hernandez, Dena G; Nacheva, Elizabeth; Pittman, Alan M; Nalls, Mike A; Singleton, Andrew B; Revesz, Tamas; Bhatia, Kailash P; Quinn, Niall; Hardy, John; Holton, Janice L; Houlden, Henry
Importance SNCA locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. Objective 1) To report a novel family carrying a heterozygous 6.4Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia (FTD) and late-onset pallidopyramidal syndromes. 2) To study phenotype-genotype correlations in SNCA locus duplications. Design, Setting, Participants and Data sources We report the clinical and neuropathologic features of a family carrying a 6.4Mb duplication of the SNCA locus. To identify candidate disease modifiers, we undertake a genetic analysis in the family and conduct statistical analysis on previously published cases carrying SNCA locus duplication using regression modelling with robust standard errors to account for clustering at the family level. Main outcome measures To assess whether length of the SNCA locus duplication influences disease penetrance and severity, and whether extra-duplication factors have a disease-modifying role. Results We identified a large 6.4Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of PD-related risk factors and the disease-predisposing H1/H1 MAPT haplotype. Statistical analysis of previously published cases suggested that there is a trend towards increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios (95% CI) from the univariate analyses were 1.17 (0.81 to 1.68) and 1.34 (0.78 to 2.31) respectively. Gender was significantly associated with both disease risk and severity; males compared to females had increased disease risk and severity and the corresponding odds ratios (95% CI) from the univariate analyses were 8.36 (1.97 to 35.42) and 5.55 (1.39 to 22.22) respectively
Matsuzono, Kosuke; Abe, Koji; Inoue, Haruhisa
Recent developments in induced pluripotent stem cell (iPSC) technology have facilitated, and have contributed to overcome the difficulty of modeling dementia caused by Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD), etc. The following models using iPSCs were reported: the pathophysiology caused by gene mutations such as presenilin or amyloid β precursor protein in AD, α-synuclein in DLB, and microtubule-associated protein tau, fused in sarcoma, progranulin, or chromosome 9 open reading frame 72 in FTLD, anti-AD drug screening, sortilin-related receptor L 1 haplotype influence in sporadic AD, and amyloid β secretion in Down syndrome. Patient-specific iPSC could be expected to reveal the disease pathology and lead to drug discoveries for dementia patients.
Ferencz, Beata; Gerritsen, Lotte
As the population steadily ages, dementia, in all its forms, remains a great societal challenge. Yet, our knowledge of their etiology remains rather limited. To this end, genetic studies can give us insight into the underlying mechanisms that lead to the development of dementia, potentially facilitating treatments in the future. In this review we cover the most recent genetic risk factors associated with the onset of the four most common dementia types today, including Alzheimer's disease (AD), Vascular Dementia (VaD), Frontotemporal Lobar Degeneration (FTLD) and Lewy Body Dementia (LBD). Moreover, we discuss the overlap in major underlying pathologies of dementia derived from their genetic associations. While all four dementia types appear to involve genes associated with tau-pathology and neuroinflammation only LBD, AD and VaD appear to involve amyloid genes while LBD and FTLD share alpha synuclein genes. Together these findings suggest that some of the dementias may exist along a spectrum and demonstrates the necessity to conduct large-scale studies pinpointing the etiology of the dementias and potential gene and environment interactions that may influence their development.
Rabinovici, Gil D.; Miller, Bruce L.
Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathologic heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD
Montine, Thomas J; Koroshetz, Walter J; Babcock, Debra; Dickson, Dennis W; Galpern, Wendy R; Glymour, M Maria; Greenberg, Steven M; Hutton, Michael L; Knopman, David S; Kuzmichev, Andrey N; Manly, Jennifer J; Marder, Karen S; Miller, Bruce L; Phelps, Creighton H; Seeley, William W; Sieber, Beth-Anne; Silverberg, Nina B; Sutherland, Margaret; Torborg, Christine L; Waddy, Salina P; Zlokovic, Berislav V; Corriveau, Roderick A
The National Alzheimer's Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimer's Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease-related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.
... aging. Many different diseases can cause dementia, including Alzheimer's disease and stroke. Drugs are available to treat some ... they may improve symptoms or slow down the disease. NIH: National Institute of Neurological Disorders and Stroke
Heidler-Gary, Jennifer; Gottesman, Rebecca; Newhart, Melissa; Chang, Shannon; Ken, Lynda; Hillis, Argye E
We hypothesized that a modified version of the Frontal Behavioral Inventory (FBI-mod), along with a few cognitive tests, would be clinically useful in distinguishing between clinically defined Alzheimer's disease (AD) and subtypes of frontotemporal lobar degeneration (FTLD): frontotemporal dementia (dysexecutive type), progressive nonfluent aphasia, and semantic dementia. We studied 80 patients who were diagnosed with AD (n = 30) or FTLD (n = 50), on the basis of a comprehensive neuropsychological battery, imaging, neurological examination, and history. We found significant between-group differences on the FBI-mod, two subtests of the Rey Auditory Verbal Learning Test (verbal learning and delayed recall), and the Trail Making Test Part B (one measure of 'executive functioning'). AD was characterized by relatively severe impairment in verbal learning, delayed recall, and executive functioning, with relatively normal scores on the FBI-mod. Frontotemporal dementia was characterized by relatively severe impairment on the FBI-mod and executive functioning in the absence of severe impairment in verbal learning and recall. Progressive nonfluent aphasia was characterized by severe impairment in executive functioning with relatively normal scores on verbal learning and recall and FBI-mod. Finally, semantic dementia was characterized by relatively severe deficits in delayed recall, but relatively normal performance on new learning, executive functioning, and on FBI-mod. Discriminant function analysis confirmed that the FBI-mod, in conjunction with the Rey Auditory Verbal Learning Test, and the Trail Making Test Part B categorized the majority of patients as subtypes of FTLD or AD in the same way as a full neuropsychological battery, neurological examination, complete history, and imaging. These tests may be useful for efficient clinical diagnosis, although progressive nonfluent aphasia and semantic dementia are likely to be best distinguished by language tests not included
... him or her.What should I do if hallucinations are a problem?If hallucinations are not making your loved one scared or ... to confront people who have dementia about their hallucinations. Arguing may just upset your loved one. However, ...
Kurz, Alexander F
A group of neurodegenerative diseases is outlined that affect cortical and subcortical areas of the brain. These diseases give rise to atypical forms of dementia and, unlike Alzheimer's disease (AD), are often associated with neurological symptoms. Clinical symptoms reflect the localization of the degenerative process rather than the nature of the underlying histopathology. Degeneration of the frontal and anterior temporal lobe presents initially with behavioral alterations, but later in the course, impairment of cognition and activities of daily living develops. Posterior cortical atrophy affects the parietal and occipital association cortices and causes complex visual disturbances. In corticobasal degeneration (CBD) the focus of pathology includes the frontoparietal cortex and several subcortical nuclei, causing symmetrical rigidity, bradykinesia, myoclonus and dystonia. Progressive supranuclear palsy (PSP) involves the frontal, temporal and parietal cortex as well as parts of the brain stem. Clinical features include a hypokinetic rigid syndrome with nuchal dystonia and vertical gaze palsy. Huntington's disease is a prototypical autosomal dominant disorder that affects the extrapyramidal system and causes choreatic movements in combination with personality changes and cognitive deterioration. Amyotrophic lateral sclerosis (ALS) with dementia is a neurodegeneration of the frontotemporal cortex and of the anterior horn of the spinal cord. Behavioral change similar to frontotemporal dementia (FTD) is paralleled or followed by the classic features of motor neuron disease.
Vieira, Renata Teles; Caixeta, Leonardo; Machado, Sergio; Silva, Adriana Cardoso; Nardi, Antonio Egidio; Arias-Carrión, Oscar; Carta, Mauro Giovanni
Presenile Dementia or Early Onset Dementia (EOD) is a public health problem, it differs from Senile Dementia, and encloses a significant number of cases; nevertheless, it is still poorly understood and underdiagnosed. This study aims to review the prevalence and etiology of EOD, comparing EOD with Senile Dementia, as well as to show the main causes of EOD and their prevalence in population and non-population based studies. The computer-supported search used the following databases: Pubmed/Medline, ISI Web of Knowledge and Scielo. The search terms were alcohol-associated dementia, Alzheimer’s disease, dementia, Creutzfeldt-jakob disease, dementia with lewy bodies, early onset dementia, frontotemporal lobar degeneration, Huntington’s disease, mixed dementia, neurodegenerative disorders, Parkinson’s disease dementia, presenile dementia, traumatic brain injury, vascular dementia. Only papers published in English and conducted from 1985 up to 2012 were preferentially reviewed. Neurodegenerative diseases are the most common etiologies seen in EOD. Among the general population, the prevalence of EOD was found to range between 0 to 700 per 100.000 habitants in groups of 25-64 years old, with an increasing incidence with age. The progression of EOD was found to range between 8.3 to 22.8 new cases per 100.000 in those aged under 65 years. Alzheimer's disease (AD) is the major etiology, followed by Vascular Dementia (VaD) and Frontotemporal Lobar Degeneration (FTLD). A larger number of epidemiological studies to elucidate how environmental issues contribute to EOD are necessary, thus, we can collaborate in the planning and prevention of services toward dementia patients. PMID:23878613
Kazui, Hiroaki; Yoshiyama, Kenji; Kanemoto, Hideki; Suzuki, Yukiko; Sato, Shunsuke; Hashimoto, Mamoru; Ikeda, Manabu; Tanaka, Hibiki; Hatada, Yutaka; Matsushita, Masateru; Nishio, Yoshiyuki; Mori, Etsuro; Tanimukai, Satoshi; Komori, Kenjiro; Yoshida, Taku; Shimizu, Hideaki; Matsumoto, Teruhisa; Mori, Takaaki; Kashibayashi, Tetsuo; Yokoyama, Kazumasa; Shimomura, Tatsuo; Kabeshita, Yasunobu; Adachi, Hiroyoshi; Tanaka, Toshihisa
Background/Aims Behavioral and psychological symptoms of dementia (BPSDs) negatively impact the prognosis of dementia patients and increase caregiver distress. The aims of this study were to clarify the differences of trajectories of 12 kinds of BPSDs by disease severity in four major dementias and to develop charts showing the frequency, severity, and associated caregiver distress (ACD) of BPSDs using the data of a Japan multicenter study (J-BIRD). Methods We gathered Neuropsychiatric Inventory (NPI) data of patients with Alzheimer’s disease (AD; n = 1091), dementia with Lewy bodies (DLB; n = 249), vascular dementia (VaD; n = 156), and frontotemporal lobar degeneration (FTLD; n = 102) collected during a 5-year period up to July 31, 2013 in seven centers for dementia in Japan. The NPI composite scores (frequency × severity) of 12 kinds of items were analyzed using a principal component analysis (PCA) in each dementia. The factor scores of the PCA were compared in each dementia by disease severity, which was determined with Clinical Dementia Rating (CDR). Results Significant increases with higher CDR scores were observed in 1) two of the three factor scores which were loaded for all items except euphoria in AD, 2) two of the four factor scores for apathy, aberrant motor behavior (AMB), sleep disturbances, agitation, irritability, disinhibition, and euphoria in DLB, and 3) one of the four factor scores for apathy, depression, anxiety, and sleep disturbances in VaD. However, no increases were observed in any of the five factor scores in FTLD. Conclusions As dementia progresses, several BPSDs become more severe, including 1) apathy and sleep disturbances in AD, DLB, and VaD, 2) all of the BPSDs except euphoria in AD, 3) AMB, agitation, irritability, disinhibition, and euphoria in DLB, and 4) depression and anxiety in VaD. Trajectories of BPSDs in FTLD were unclear. PMID:27536962
Frey, Kirk A; Lodge, Martin A; Meltzer, Carolyn Cidis; Peller, Patrick J; Wong, Terence Z; Hess, Christopher P; Petrella, Jeffrey R; Sair, Haris I; Subramaniam, Rathan M
This practice parameter is for both FDG and amyloid brain PET or PET/computed tomography (CT) for patients with cognitive decline, and has been developed collaboratively by the American College of Radiology (ACR) and the American Society for Neuroradiology (ASNR). It is estimated that the number of people with dementia, 36.5 million worldwide in 2010, will increase to 65.7 million in 2030 and to 115 million in 2050. Four primary neurodegenerative etiologies of dementia have been defined: Alzheimer disease (AD), vascular dementia, frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Alzheimer disease is the most common form of dementia, accounting for approximately 60%-80% of all cases. Indications for FDG and amyloid brain PET and qualifications for personnel are discussed in this practice parameter.
Varley, James; Brooks, David J; Edison, Paul
Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia (FTD), and Huntington's disease (HD) are the main neurodegenerative causes of dementia. Causes and mechanisms of these diseases remain elusive. Neuroinflammation is increasingly emerging as an important pathological factor in their development. Positron emission tomography (PET) using [11C]PK11195 represents a method of visualizing the microglial component of neuroinflammation via the translocator protein (TSPO) and we discuss the valuable insights this has yielded in neurodegenerative diseases. We discuss the limitations of this method and the development of second generation TSPO PET ligands which hope to overcome these limitations. We also discuss other methods of visualizing neuroinflammation and review the state of current dementia treatments targeted at neuroinflammation. It is our view that a multimodal investigation into neuroinflammation in AD, Parkinson's disease dementia, FTD and HD will yield valuable pathological insights which will usefully inform development of therapeutic targets and biomarkers.
C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Dafinca, Ruxandra; Scaber, Jakub; Ababneh, Nida'a; Lalic, Tatjana; Weir, Gregory; Christian, Helen; Vowles, Jane; Douglas, Andrew G.L.; Fletcher‐Jones, Alexandra; Browne, Cathy; Nakanishi, Mahito; Turner, Martin R.; Wade‐Martins, Richard
Abstract An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC‐derived motor neurons, decreased cell survival is correlated with dysfunction in Ca2+ homeostasis, reduced levels of the antiapoptotic protein Bcl‐2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC‐derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063–2078 PMID:27097283
Mendioroz Iriarte, Maite; Pulido Fontes, Laura; Méndez-López, Iván
DNA methylation is an epigenetic mechanism that controls gene expression. In Alzheimer's disease (AD), global DNA hypomethylation of neurons has been described in the human cerebral cortex. Moreover, several variants in the methylation pattern of candidate genes have been identified in brain tissue when comparing AD patients and controls. Specifically, DNA methylation changes have been observed in PSEN1 and APOE, both genes previously being involved in the pathophysiology of AD. In other degenerative dementias, methylation variants have also been described in key genes, such as hypomethylation of the SNCA gene in Parkinson's disease and dementia with Lewy bodies or hypermethylation of the GRN gene promoter in frontotemporal dementia. The finding of aberrant DNA methylation patterns shared by brain tissue and peripheral blood opens the door to use those variants as epigenetic biomarkers in the diagnosis of neurodegenerative diseases.
Prioni, S; Fetoni, V; Barocco, F; Redaelli, V; Falcone, C; Soliveri, P; Tagliavini, F; Scaglioni, A; Caffarra, P; Concari, L; Gardini, S; Girotti, F
Stereotypies are simple or complex involuntary/unvoluntary behaviors, common in fronto-temporal dementia (FTD), but not studied in other types of degenerative dementias. The aim was to investigate stereotypy frequency and type in patients with FTD, Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Parkinson's disease with dementia (PDD) in a multicenter observational study; and to investigate the relation of stereotypies to cognitive, behavioral and motor impairment. One hundred fifty-five consecutive outpatients (45 AD, 40 FTD, 35 PSP and 35 PDD) were studied in four hospitals in northern Italy. Stereotypies were examined by the five-domain Stereotypy Rating Inventory. Cognition was examined by the Mini Mental State and Frontal Assessment Battery, neuropsychiatric symptoms by the Neuropsychiatric Inventory, and motor impairment and invalidity by the Unified Parkinson's Disease Rating Scale part III, and activities of daily living. Stereotypies were present in all groups. FTD and PDD had the greatest frequency of one-domain stereotypies; FTD also had the greatest frequency of two-or-more domain stereotypies; movement stereotypies were the most common stereotypies in all groups. AD patients had fewer stereotypies than the other groups. Stereotypies are not exclusive to FTD, but are also fairly common in PSP and PDD, though less so in AD. Stereotypies may be underpinned by dysfunctional striato-frontal circuits, known to be damaged in PSP and PDD, as well as FTD.
Magerova, Hana; Vyhnalek, Martin; Laczo, Jan; Andel, Ross; Rektorova, Irena; Kadlecova, Alexandra; Bojar, Martin; Hort, Jakub
Odor identification impairment is a feature of several neurodegenerative disorders. Although neurodegenerative changes in the frontotemporal lobar degeneration (FTLD) subtypes involve areas important for olfactory processing, data on olfactory function in these patients are limited. An 18-item, multiple-choice odor identification test developed at our memory clinic, the Motol Hospital smell test, was administered to 9 patients with behavioral variant frontotemporal dementia, 13 patients with the language variants, primary nonfluent aphasia (n = 7) and semantic dementia (n = 6), and 8 patients with progressive supranuclear palsy. Compared to the control group (n = 15), all FTLD subgroups showed significant impairment of odor identification (P < .05). The differences between the FTLD subgroups were not significant. No correlation between odor identification and neuropsychological tests results was found. Our data suggest that odor identification impairment is a symptom common to FTLD syndromes, and it seems to be based on olfactory structure damage rather than cognitive decline.
Combs, Benjamin; Kneynsberg, Andrew; Kanaan, Nicholas M
Dementias are among the most common neurological disorders, and Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD remains a looming health crisis despite great efforts to learn the mechanisms surrounding the neuron dysfunction and neurodegeneration that accompanies AD primarily in the medial temporal lobe. In addition to AD, a group of diseases known as frontotemporal dementias (FTDs) are degenerative diseases involving atrophy and degeneration in the frontal and temporal lobe regions. Importantly, AD and a number of FTDs are collectively known as tauopathies due to the abundant accumulation of pathological tau inclusions in the brain. The precise role tau plays in disease pathogenesis remains an area of strong research focus. A critical component to effectively study any human disease is the availability of models that recapitulate key features of the disease. Accordingly, a number of animal models are currently being pursued to fill the current gaps in our knowledge of the causes of dementias and to develop effective therapeutics. Recent developments in gene therapy-based approaches, particularly in recombinant adeno-associated viruses (rAAVs), have provided new tools to study AD and other related neurodegenerative disorders. Additionally, gene therapy approaches have emerged as an intriguing possibility for treating these diseases in humans. This chapter explores the current state of rAAV models of AD and other dementias, discuss recent efforts to improve these models, and describe current and future possibilities in the use of rAAVs and other viruses in treatments of disease.
Alquezar, Carolina; Esteras, Noemí; de la Encarnación, Ana; Moreno, Fermín; López de Munain, Adolfo; Martín-Requero, Ángeles
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder marked by mild-life onset and progressive changes in behavior, social cognition, and language. Loss-of-function progranulin gene (GRN) mutations are the major cause of FTLD with TDP-43 protein inclusions (FTLD-TDP). Disease-modifying treatments for FTLD-TDP are not available yet. Mounting evidence indicates that cell cycle dysfunction may play a pathogenic role in neurodegenerative disorders including FTLD. Since cell cycle re-entry of posmitotic neurons seems to precede neuronal death, it was hypothesized that strategies aimed at preventing cell cycle progression would have neuroprotective effects. Recent research in our laboratory revealed cell cycle alterations in lymphoblasts from FTLD-TDP patients carrying a null GRN mutation, and in PGRN deficient SH-SY5Y neuroblastoma cells, involving overactivation of the ERK1/2 signaling pathway. In this work, we have investigated the effects of PGRN enhancers drugs and ERK1/2 inhibitors, in these cellular models of PGRN-deficient FTLD. We report here that both restoring the PGRN content, by suberoylanilide hydroxamic acid (SAHA) or chloroquine (CQ), as blocking ERK1/2 activation by selumetinib (AZD6244) or MEK162 (ARRY-162), normalized the CDK6/pRb pathway and the proliferative activity of PGRN deficient cells. Moreover, we found that SAHA and selumetinib prevented the cytosolic TDP-43 accumulation in PGRN-deficient lymphoblasts. Considering that these drugs are able to cross the blood-brain barrier, and assuming that the alterations in cell cycle and signaling observed in lymphoblasts from FTLD patients could be peripheral signs of the disease, our results suggest that these treatments may serve as novel therapeutic drugs for FTLD associated to GRN mutations.
Gong, Yuesong; Lippa, Carol F.
The most common causes of neurodegenerative dementia include Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). We believe that, in all 3, aggregates of pathogenic proteins are pathological substrates which are associated with a loss of synaptic function/plasticity. The synaptic plasticity relies on the normal integration of glutamate receptors at the postsynaptic density (PSD). The PSD organizes synaptic proteins to mediate the functional and structural plasticity of the excitatory synapse and to maintain synaptic homeostasis. Here, we will discuss the relevant disruption of the protein network at the PSD in these dementias and the accumulation of the pathological changes at the PSD years before clinical symptoms. We suggest that the functional and structural plasticity changes of the PSD may contribute to the loss of molecular homeostasis within the synapse (and contribute to early symptoms) in these dementias. PMID:20858652
Clark, Camilla N.; Nicholas, Jennifer M.; Gordon, Elizabeth; Golden, Hannah L.; Cohen, Miriam H.; Woodward, Felix J.; Macpherson, Kirsty; Slattery, Catherine F.; Mummery, Catherine J.; Schott, Jonathan M.; Rohrer, Jonathan D.; Warren, Jason D.
Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer’s disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications. PMID:26444779
Chen-Plotkin, Alice S; Unger, Travis L; Gallagher, Michael D; Bill, Emily; Kwong, Linda K; Volpicelli-Daley, Laura; Busch, Johanna I; Akle, Sebastian; Grossman, Murray; Van Deerlin, Vivianna; Trojanowski, John Q; Lee, Virginia M-Y
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene (GRN) causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of >800 microRNAs (miRs), we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with <50% normal expression levels of three members of the microRNA-132 cluster (microRNA-132, microRNA-132*, and microRNA-212) in disease. Computational analyses, corroborated empirically, demonstrate that the top mRNA target of both microRNA-132 and microRNA-212 is TMEM106B; both microRNAs repress TMEM106B expression through shared microRNA-132/212 binding sites in the TMEM106B 3'UTR. Increasing TMEM106B expression to model disease results in enlargement and poor acidification of endo-lysosomes, as well as impairment of mannose-6-phosphate-receptor trafficking. Finally, endogenous neuronal TMEM106B colocalizes with progranulin in late endo-lysosomes, and TMEM106B overexpression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant overexpression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miR-based therapies in FTLD-TDP.
Sodhi, Rupinder K; Singh, Nirmal
The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia.
Yang, Li; Yan, Jing; Jin, Xiaoqing; Jin, Yu; Yu, Wei; Xu, Shanhu; Wu, Haibin
This study was conducted to estimate screening performance of dementia screening tools including Mini-Mental State Examination (MMSE), Mini-Cog, Clock Drawing Test (CDT) and Ascertain Dementia 8 questionnaire (AD8) for older adults. 2015 participants aged 65 years or more in eastern China were enrolled. 4 screening tests were administered and scored by specifically trained psychiatrists. We used data from two-by-two tables to calculate the sensitivity, specificity, and positive and negative predictive values (PPV/NPV). Our study showed that dementia was highly prevalent among elderly in Zhejiang province. The Mini-Cog, with excellent screening characteristics and spending less time, could be considered to be used as a screening tool among communities to help to diagnose dementia early. PMID:28006822
Cary, Mark S.; Rubright, Jonathan D.; Grill, Joshua D.; Karlawish, Jason
Objectives Most Alzheimer’s disease (AD) caregivers are not spouses and yet most AD dementia trials enroll spousal study partners. This study examines the association between caregiver relationship to the patient and willingness to enroll in an AD clinical trial and how caregiver burden and research attitudes modify willingness. Design Interviews with 103 AD caregivers who met criteria for ability to serve as a study partner. Results 54% of caregivers were spouses or domestic partners and the remaining were adult children. Willingness to enroll a patient in a clinical trial was associated with being a spouse (OR = 2.53, p = 0.01), increasing age (OR = 1.39, p = 0.01), and increasing scores on the Research Attitudes Questionnaire (OR = 1.39, p < 0.001). No measures of caregiver burden or patient health were significant predictors of willingness. In multivariate models both research attitudes (OR = 1.37, p < 0.001) and being a spouse, as opposed to an adult child, (OR = 2.06, p = 0.048) were independently associated with willingness to participate. Conclusions Spousal caregivers had both a higher willingness to participate and a more positive attitude toward research. Caregiver burden had no association with willingness to participate. The strongest predictor of willingness was research attitudes. PMID:24805971
Libro, Rosaliana; Giacoppo, Sabrina; Soundara Rajan, Thangavelu; Bramanti, Placido; Mazzon, Emanuela
The word dementia describes a class of heterogeneous diseases which etiopathogenetic mechanisms are not well understood. There are different types of dementia, among which, Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) are the more common. Currently approved pharmacological treatments for most forms of dementia seem to act only on symptoms without having profound disease-modifying effects. Thus, alternative strategies capable of preventing the progressive loss of specific neuronal populations are urgently required. In particular, the attention of researchers has been focused on phytochemical compounds that have shown antioxidative, anti-amyloidogenic, anti-inflammatory and anti-apoptotic properties and that could represent important resources in the discovery of drug candidates against dementia. In this review, we summarize the neuroprotective effects of the main phytochemicals belonging to the polyphenol, isothiocyanate, alkaloid and cannabinoid families in the prevention and treatment of the most common kinds of dementia. We believe that natural phytochemicals may represent a promising sources of alternative medicine, at least in association with therapies approved to date for dementia.
Chiong, Winston; Hsu, Ming; Wudka, Danny; Miller, Bruce L; Rosen, Howard J
Financial errors by patients with dementia can have devastating personal and family consequences. We developed and evaluated a neuroeconomic conceptual framework for understanding financial errors across different dementia syndromes, using a systematic, retrospective, blinded chart review of demographically-balanced cohorts of patients with Alzheimer's disease (AD, n=100) and behavioral variant frontotemporal dementia (bvFTD, n=50). Reviewers recorded specific reports of financial errors according to a conceptual framework identifying patient cognitive and affective characteristics, and contextual influences, conferring susceptibility to each error. Specific financial errors were reported for 49% of AD and 70% of bvFTD patients (p = 0.012). AD patients were more likely than bvFTD patients to make amnestic errors (p < 0.001), while bvFTD patients were more likely to spend excessively (p = 0.004) and to exhibit other behaviors consistent with diminished sensitivity to losses and other negative outcomes (p < 0.001). Exploratory factor analysis identified a social/affective vulnerability factor associated with errors in bvFTD, and a cognitive vulnerability factor associated with errors in AD. Our findings highlight the frequency and functional importance of financial errors as symptoms of AD and bvFTD. A conceptual model derived from neuroeconomic literature identifies factors that influence vulnerability to different types of financial error in different dementia syndromes, with implications for early diagnosis and subsequent risk prevention.
Combs, Benjamin; Kneynsberg, Andrew; Kanaan, Nicholas M.
Dementias are among the most common neurological disorders, and Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD remains a looming health crisis despite great efforts to learn the mechanisms surrounding the neuron dysfunction and neurodegeneration that accompanies AD primarily in the medial temporal lobe. In addition to AD, a group of diseases known as frontotemporal dementias (FTDs) are degenerative diseases involving atrophy and degeneration in the frontal and temporal lobe regions. Importantly, AD and a number of FTDs are collectively known as tauopathies due to the abundant accumulation of pathological tau inclusions in the brain. The precise role tau plays in disease pathogenesis remains an area of strong research focus. A critical component to effectively study any human disease is the availability of models that recapitulate key features of the disease. Accordingly, a number of animal models are currently being pursued to fill the current gaps in our knowledge of the causes of dementias and to develop effective therapeutics. Recent developments in gene therapy-based approaches, particularly in recombinant adeno-associated viruses (rAAVs), have provided new tools to study AD and other related neurodegenerative disorders. Additionally, gene therapy approaches have emerged as an intriguing possibility for treating these diseases in humans. This chapter explores the current state of rAAV models of AD and other dementias, discuss recent efforts to improve these models, and describe current and future possibilities in the use of rAAVs and other viruses in treatments of disease. PMID:26611599
Sandilyan, Malarvizhi Babu; Dening, Tom
Dementia is a consequence of brain disease. This article, the second in this series on dementia, discusses normal brain function and how certain functions are localised to different areas of the brain. This is important in determining the symptoms of dementia, depending on which parts of the brain are most directly involved. The most common types of dementia - Alzheimer's disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia - affect the brain in different ways and cause different changes at the microscopic level. Dementia is affected by genetics, and recent advances in molecular techniques have improved our understanding of some of the mechanisms involved, which in turns suggests possibilities for new treatments in the future.
Alberici, A; Geroldi, C; Cotelli, M; Adorni, A; Calabria, M; Rossi, G; Borroni, B; Padovani, A; Zanetti, O; Kertesz, A
The objective was to evaluate the construct validity of the Italian version of the Frontal Behavioural Inventory (FBI) and its usefulness in the differential diagnosis of dementias. Standard criteria were used in the clinical diagnosis of dementias in 83 patients and 33 agematched healthy volunteers. The FBI scale was translated from English into Italian language and back-translated. Cronbach's alpha, inter-rater and test-retest reliability, FBI convergent validity and discriminant analysis were calculated. FBI profile was compared between patients affected by frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). The FBI showed a high internal consistency and inter-rater reliability and it distinguished normal behavioural conditions from those presented in FTLD or AD. An 86.8% diagnostic accuracy was calculated by the discriminant analysis, selecting only age at disease onset and FBI, and particularly distinguishing behavioural variants within the FTLD spectrum. FTLD patients showed a characteristic behavioural profile. The FBI might be a reliable and useful diagnostic tool for dementias in clinical practice.
Riedl, Lina; Mackenzie, Ian R; Förstl, Hans; Kurz, Alexander; Diehl-Schmid, Janine
The term frontotemporal lobar degeneration (FTLD) refers to a group of progressive brain diseases, which preferentially involve the frontal and temporal lobes. Depending on the primary site of atrophy, the clinical manifestation is dominated by behavior alterations or impairment of language. The onset of symptoms usually occurs before the age of 60 years, and the mean survival from diagnosis varies between 3 and 10 years. The prevalence is estimated at 15 per 100,000 in the population aged between 45 and 65 years, which is similar to the prevalence of Alzheimer’s disease in this age group. There are two major clinical subtypes, behavioral-variant frontotemporal dementia and primary progressive aphasia. The neuropathology underlying the clinical syndromes is also heterogeneous. A common feature is the accumulation of certain neuronal proteins. Of these, the microtubule-associated protein tau (MAPT), the transactive response DNA-binding protein, and the fused in sarcoma protein are most important. Approximately 10% to 30% of FTLD shows an autosomal dominant pattern of inheritance, with mutations in the genes for MAPT, progranulin (GRN), and in the chromosome 9 open reading frame 72 (C9orf72) accounting for more than 80% of familial cases. Although significant advances have been made in recent years regarding diagnostic criteria, clinical assessment instruments, neuropsychological tests, cerebrospinal fluid biomarkers, and brain imaging techniques, the clinical diagnosis remains a challenge. To date, there is no specific pharmacological treatment for FTLD. Some evidence has been provided for serotonin reuptake inhibitors to reduce behavioral disturbances. No large-scale or high-quality studies have been conducted to determine the efficacy of non-pharmacological treatment approaches in FTLD. In view of the limited treatment options, caregiver education and support is currently the most important component of the clinical management. PMID:24600223
Palmiero, Massimiliano; Di Giacomo, Dina; Passafiume, Domenico
In these last years, creativity was found to play an important role for dementia patients in terms of diagnosis and rehabilitation strategies. This led us to explore the relationships between dementia and creativity. At the aim, artistic creativity and divergent thinking are considered both in non-artists and artists affected by different types of dementia. In general, artistic creativity can be expressed in exceptional cases both in Alzheimer's disease and Frontotemporal dementia, whereas divergent thinking decreases in dementia. The creation of paintings or music is anyway important for expressing emotions and well-being. Yet, creativity seems to emerge when the right prefrontal cortex, posterior temporal, and parietal areas are relatively intact, whereas it declines when these areas are damaged. However, enhanced creativity in dementia is not confirmed by controlled studies conducted in non-artists, and whether artists with dementia can show creativity has to be fully addressed. Future research directions are suggested.
RASCOVSKY, KATYA; GROSSMAN, MURRAY
Frontotemporal lobar degeneration (FTLD) can manifest as a spectrum of clinical syndromes, ranging from behavioural impairment to language or motor dysfunction. Recently, revised diagnostic criteria have been proposed for the behavioural and progressive aphasia syndromes associated with frontotemporal degeneration. The present review will summarize these diagnostic guidelines and highlight some lingering controversies in the classification of FTLD clinical syndromes. We will discuss common tools and methods used to identify the insidious changes of behavioural variant frontotemporal dementia (bvFTD), the value of new, patient-based tasks of orbitofrontal function, and the issue of a benign or ‘phenocopy’ variant of bvFTD. With regard to primary progressive aphasia (PPA), we will discuss the scope of the semantic disorder in semantic-variant PPA, the nature of the speech disorder in non-fluent, agrammatic PPA, and the preliminary utility of a logopenic PPA classification. PMID:23611345
Josephs, Keith A.
Synopsis Frontotemporal lobar degeneration (FTLD) is a syndromic diagnosis that encompasses at least three different variants. Imaging modalities are clinically useful in FTLD while pathology remains the gold standard for definitive diagnosis. To date three different genes have been identified that account for FTLD. PMID:17659185
Utumi, Yushi; Iseki, Eizo; Arai, Heii
Here we report the cases of three patients with mood disorders showing catatonia and frontotemporal lobe atrophy. Catatonia is a syndrome linked to frontal dysfunction that most frequently occurs in patients with mood disorders. The diagnostic criteria of catatonia and frontotemporal dementia partly overlap. In the present patients, catatonia might be closely related to frontal dysfunction caused by frontotemporal lobe atrophy. With regard to therapeutics for catatonia, we found that administering a low dose of lorazepam alone or after electroconvulsive therapy may be useful for treating and preventing catatonia. We also found that administering glutaminate antagonists such as memantine may be useful for treating lorazepam-resistant catatonia.
Magaki, Shino; Yong, William H.; Khanlou, Negar; Tung, Spencer; Vinters, Harry V.
OBJECTIVES To examine systemic and central nervous system (CNS) comorbidities of patients with dementia evaluated during general autopsy. DESIGN Retrospective cohort study. SETTING A large tertiary academic medical center in Los Angeles, California. PARTICIPANTS A cohort of 86 participants with clinically and neuropathologically diagnosed dementia who received complete autopsies and 132 participants with dementia who received partial (brain only) autopsies. MEASUREMENTS The causes of death as well as systemic and CNS comorbidities were obtained from autopsy reports and clinical information as available from the medical records. Findings were tabulated with respect to type of dementia, semiquantitative assessment of the severity of cerebral amyloid angiopathy, semiquantitative assessment of the severity of cerebrovascular disease, and evidence of ischemic damage in the brain. RESULTS Out of a total of 218 subjects with dementia, 175 (80.3%) had Alzheimer’s disease (AD) either in isolation or in combination with other lesions that might contribute to cognitive impairment, such as cerebrovascular disease and diffuse Lewy body disease (DLBD), 14 (6.4%) had frontotemporal dementia (FTD), and 7 (3.2%) had isolated DLBD. The most common cause of death among demented patients was pneumonia (57 cases, 66.3%) followed by cardiovascular disease (14 cases, 16.3%). Eighteen subjects (20.9%) had lung disease and 16 (18.6%) had evidence of old or recent myocardial infarct. Clinically undiagnosed neoplasms included colonic adenocarcinoma, metastatic pulmonary neuroendocrine carcinoma, meningioma, and Schwannoma. CONCLUSION Significant comorbidities were discovered at autopsy in patients with dementia. Understanding the causes of death and associated comorbidities in patients with various subtypes of dementia is important in the assessment of end of life care in these subjects. PMID:25039832
Serag, Ahmed; Wenzel, Fabian; Thiele, Frank; Buchert, Ralph; Young, Stewart
FDG-PET is increasingly used for the evaluation of dementia patients, as major neurodegenerative disorders, such as Alzheimer's disease (AD), Lewy body dementia (LBD), and Frontotemporal dementia (FTD), have been shown to induce specific patterns of regional hypo-metabolism. However, the interpretation of FDG-PET images of patients with suspected dementia is not straightforward, since patients are imaged at different stages of progression of neurodegenerative disease, and the indications of reduced metabolism due to neurodegenerative disease appear slowly over time. Furthermore, different diseases can cause rather similar patterns of hypo-metabolism. Therefore, classification of FDG-PET images of patients with suspected dementia may lead to misdiagnosis. This work aims to find an optimal subset of features for automated classification, in order to improve classification accuracy of FDG-PET images in patients with suspected dementia. A novel feature selection method is proposed, and performance is compared to existing methods. The proposed approach adopts a combination of balanced class distributions and feature selection methods. This is demonstrated to provide high classification accuracy for classification of FDG-PET brain images of normal controls and dementia patients, comparable with alternative approaches, and provides a compact set of features selected.
Hsieh, Sharpley; McGrory, Sarah; Leslie, Felicity; Dawson, Kate; Ahmed, Samrah; Butler, Chris R.; Rowe, James B.; Mioshi, Eneida; Hodges, John R.
Background/Aims We developed and validated the Mini-Addenbrooke's Cognitive Examination (M-ACE) in dementia patients. Comparisons were also made with the Mini Mental State Examination (MMSE). Method The M-ACE was developed using Mokken scaling analysis in 117 dementia patients [behavioural variant frontotemporal dementia (bvFTD), n = 25; primary progressive aphasia (PPA), n = 49; Alzheimer's disease (AD), n = 34; corticobasal syndrome (CBS), n = 9] and validated in an independent sample of 164 dementia patients (bvFTD, n = 23; PPA, n = 82; AD, n = 38; CBS, n = 21) and 78 controls, who also completed the MMSE. Results The M-ACE consists of 5 items with a maximum score of 30. Two cut-offs were identified: (1) ≤25/30 has both high sensitivity and specificity, and (2) ≤21/30 is almost certainly a score to have come from a dementia patient regardless of the clinical setting. The M-ACE is more sensitive than the MMSE and is less likely to have ceiling effects. Conclusion The M-ACE is a brief and sensitive cognitive screening tool for dementia. Two cut-offs (25 or 21) are recommended. PMID:25227877
Chow, Tiffany W.; Fridhandler, Jonathan D.; Binns, Malcolm A.; Lee, Albert; Merrilees, Jennifer; Rosen, Howie J.; Ketelle, Robin; Miller, Bruce L.
Predicting the progression of dementia is a challenge for clinicians yet this information is highly valued by patients’ families. An informally observed 4-stage model of dementia can be helpful in educating caregivers and preparing them for what lies ahead. In the behavioral variant of frontotemporal dementia (bvFTD), this model describes the evolution of behavioral disturbances and is characterized by an inflection point between stage 2 (progressively severe behavioral aberration) and stage 3 (increasing apathy and remission of behavior problems). In this study we sought evidence for this model using a database of serial Neuropsychiatric Inventory (NPI) scores for 45 patients with FTD and 47 patients with Alzheimer’s disease (AD). We transformed the NPI scores into a single variable for each participant that represented the rate of change in NPI score over time (NPI slope) and used this as the dependent variable in a multivariate linear regression. Age at onset of dementia, NPI score at initial visit, and duration of illness at first NPI all contributed significantly to the regression model for NPI slope in the bvFTD group. Participants with an initial NPI acquired before 6 years of disease duration tended to have a more positive NPI slope (representing worsening behavioral disturbances) than those with an initial NPI performed after 6 years. None of the aforementioned variables were significantly associated with NPI slope in the AD group. These results support a crescendo-decrescendo trajectory of behavioral symptoms in bvFTD but do not suggest that there is a similar pattern in AD, and further longitudinal data collection is necessary. PMID:22531424
Hsu, Yuan-Yu; Du, An-Tao; Schuff, Norbert; Weiner, Michael W.
This article reviews recent studies of magnetic resonance imaging and magnetic resonance spectroscopy in dementia, including Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, idiopathic Parkinson's disease, Huntington's disease, and vascular dementia. Magnetic resonance imaging and magnetic resonance spectroscopy can detect structural alteration and biochemical abnormalities in the brain of demented subjects and may help in the differential diagnosis and early detection of affected individuals, monitoring disease progression, and evaluation of therapeutic effect. PMID:11563438
Ortega-Porcayo, Luis Alberto; Ponce-Gómez, Juan Antonio; Martínez-Moreno, Mauricio; Portocarrero-Ortíz, Lesly; Tena-Suck, Martha Lilia; Gómez-Amador, Juan Luis
Introduction Primary ectopic craniopharyngiomas have only rarely been reported. Craniopharyngiomas involve usually the sellar and suprasellar region, but can be originated from cell remnants of the obliterated craniopharyngeal duct or metaplastic change of andenohypophyseal cells. We present the first case of a primary ectopic frontotemporal craniopharyngioma. Presentation of case A 35-year old woman presented with a one-year history of headache and diplopia. MRI showed a large frontotemporal cystic lesion. Tumor resection was performed with a keyhole endoscopic frontal lateral approach. The pathological features showed an adamantinomatous craniopharyngioma with a cholesterol granuloma reaction. Discussion There have been reported different localizations for primary ectopic craniopharyngioma. Our case presented a lobulated frontotemporal cystic mass formed by a dense eosinophilic proteinaceous material dystrophic calcifications and cholesterol crystals, with epithelial remnants. No tumor regrowth was observed in the magnetic resonance image 27 months postoperatively. Conclusion Primary ectopic craniopharyngioma is a rare entity with a pathogenesis that remains uncertain. This is an unusual anatomic location associated with unique clinical findings. PMID:25725331
Garre-Olmo, Josep; Garcia-Ptacek, Sara; Calvó-Perxas, Laia; Turró-Garriga, Oriol; López-Pousa, Secundino; Eriksdotter, Maria
The aim of this study was to compare the frequency of dementia diagnoses from two dementia registries in Europe. Patients registered between 2007 and 2013 in the Swedish Dementia Registry (SveDem; Sweden) and in the Registry of Dementias of Girona (ReDeGi; North-East of Spain) were selected. We compared sociodemographic data, Mini-Mental State Examination (MMSE) scores, dementia subtype, and medication consumption of 22,384 cases from SveDem and 5,032 cases from ReDeGi. The average age (78.1 years SveDem versus 79.7 years ReDeGi) and the gender (female 58.2% SveDem versus 61.5% ReDeGi) did not greatly differ. MMSE score at diagnosis was higher for SveDem cases (22.1 versus 17.8). Alzheimer’s disease (AD) accounted for the main dementia subtype (36.6% SveDem versus 55.6% ReDeGi). The proportion of vascular dementia (VaD) and mixed dementia was higher in SveDem (18.8% versus 6.4% and 24.9 versus 13.4%), with an odds ratio (OR) and 95% confidence interval (CI) for SveDem relative to the ReDeGi of 3.41 (3.03–3.84) for VaD, and 2.15 (1.97–2.35) for mixed dementia. This was at the expense of a lower frequency of AD in SveDem (OR 0.41; 95% CI 0.39–0.44). Other dementia diagnoses such as frontotemporal dementia or dementia with Lewy bodies did not significantly differ between registries (2.3% versus 2.9%; 1.9 versus 3.1%). Large differences in medication consumption at the time of dementia diagnosis were detected (4.7 treatments SveDem versus 6.8 ReDeGi). Northern and southern European dementia cohorts differ in demographic characteristics, MMSE score at diagnosis, and drug treatment profile. PMID:27392854
Korczyn, Amos D; Vakhapova, Veronika; Grinberg, Lea T
The epidemic grow of dementia causes great concern for the society. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, followed by vascular dementia (VaD). This dichotomous view of a neurodegenerative disease as opposed to brain damage caused by extrinsic factors led to separate lines of research in these two entities. Indeed, accumulated data suggest that the two disorders have additive effects and probably interact; however it is still unknown to what degree. Furthermore, epidemiological studies have shown “vascular” risk factors to be associated with AD. Therefore, a clear distinction between AD and VaD cannot be made in most cases, and is furthermore unhelpful. In the absence of efficacious treatment for the neurodegenerative process, special attention must be given to vascular component, even in patients with presumed mixed pathology. Symptomatic treatment of VaD and AD are similar, although the former is less effective. For prevention of dementia it is important to treat aggressively all factors, even in stroke survivors who do not show evidence of cognitive decline,. In this review, we will give a clinical and pathological picture of the processes leading to VaD and discuss it interaction with AD. PMID:22575403
Carrasquillo, Minerva M.; Barber, Imelda; Lincoln, Sarah J.; Murray, Melissa E.; Camsari, Gamze Balci; Khan, Qurat ul Ain.; Nguyen, Thuy; Ma, Li; Bisceglio, Gina D.; Crook, Julia E.; Younkin, Steven G.; Dickson, Dennis W.; Boeve, Bradley F.; Graff-Radford, Neill R.; Morgan, Kevin; Ertekin-Taner, Nilüfer
Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to “posterior Alzheimer’s disease (AD)” pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n=67) or posterior AD neuropathology (n=57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~4,300 European-American population controls from the NHLBI Exome Sequencing Project (ESP). We identified two rare variants not previously reported in PCA, TREM2 Arg47His and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report two rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX. PMID:26507310
Ossenkoppele, Rik; Jansen, Willemijn J.; Rabinovici, Gil D.; Knol, Dirk L.; van der Flier, Wiesje M.; van Berckel, Bart N. M.; Scheltens, Philip; Visser, Pieter Jelle
y Dementia with Lewy bodies emsp;APOE ε4 carrier 1663 (48–80)83 (67–92) emsp;APOE ε4 noncarrier 1829 (15–50)54 (30–77) Frontotemporal dementia emsp;APOE ε4 carrier 4819 (12–28)43 (35–50) emsp;APOE ε4 noncarrier160 5 (3–8)14 (11–18) Vascular dementia emsp;APOE ε4 carrier 3025 (9–52)64 (49–77) emsp;APOE ε4 noncarrier 77 7 (3–18)29 (17–43) CONCLUSIONS AND RELEVANCE Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years. PMID:25988463
Vellas, B.; Bateman, R.; Blennow, K.; Frisoni, G.; Johnson, K.; Katz, R.; Langbaum, J.; Marson, D.; Sperling, R.; Wessels, A.; Salloway, S.; Doody, R.; Aisen, P.
For Alzheimer’s disease treatment trials that focus on the pre-dementia stage of disease, outcome measures are needed that will enable assessment of disease progression in patients who are clinically normal. The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials. Composite measures that assess changes in episodic memory, executive function, global cognition, and global function have recently been developed by a number of groups and appear to be sensitive at this stage. Functional measures that involve real-life complex tasks also appear to capture early subtle changes in pre-dementia subjects and have the advantage of representing clinically meaningful change. Patient reported outcomes and novel CSF and imaging biomarkers have also shown promise. More studies are needed to validate all of these tests in the pre-dementia population. Many of them have been incorporated as exploratory measures in ongoing or planned trials. PMID:26247004
Hu, W.T.; Wang, Z.; Lee, V.M.-Y.; Trojanowski, J.Q.; Detre, J.A.; Grossman, M.
Objective: We examined the utility of distinguishing between patients with frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) using quantitative cerebral blood flow (CBF) imaging with arterial spin labeled (ASL) perfusion MRI. Methods: Forty-two patients with FTLD and 18 patients with AD, defined by autopsy or CSF-derived biomarkers for AD, and 23 matched controls were imaged with a continuous ASL method to quantify CBF maps covering the entire brain. Results: Patients with FTLD and AD showed distinct patterns of hypoperfusion and hyperperfusion. Compared with controls, patients with FTLD showed significant hypoperfusion in regions of the frontal lobe bilaterally, and hyperperfusion in posterior cingulate and medial parietal/precuneus regions. Compared with controls, patients with AD showed significant hypoperfusion in the medial parietal/precuneus and lateral parietal cortex, and hyperperfusion in regions of the frontal lobe. Direct comparison of patient groups showed significant inferior, medial, and dorsolateral frontal hypoperfusion in FTLD, and significant hypoperfusion in bilateral lateral temporal-parietal and medial parietal/precuneus regions in AD. Conclusions: Doubly dissociated areas of hypoperfusion in FTLD and AD are consistent with areas of significant histopathologic burden in these groups. ASL is a potentially useful biomarker for distinguishing patients with these neurodegenerative diseases. GLOSSARY Aβ42 = β-amyloid1-42; AD = Alzheimer disease; ASL = arterial spin labeling; bvFTD = behavioral-variant frontotemporal dementia; cASL = continuous arterial spin labeling; CBS = corticobasal syndrome; CBF = cerebral blood flow; dACC = dorsal anterior cingulate cortex; dlPFC = dorsolateral prefrontal cortex; FDR = false detection rate; FTLD = frontotemporal lobar degeneration; GM = gray matter; iFC = inferior frontal cortex; MCI = mild cognitive impairment; MNI = Montreal Neurological Institute; mTC = middle temporal cortex; OFC
Zanardini, Roberta; Ciani, Miriam; Benussi, Luisa; Ghidoni, Roberta
The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD), which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia (SCZ), can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review, we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF) and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN) genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts. PMID:26869919
Stefani, Alessandro; Olivola, Enrica; Liguori, Claudio; Hainsworth, Atticus H.; Saviozzi, Valentina; Angileri, Giacoma; D’Angelo, Vincenza; Galati, Salvatore; Pierantozzi, Mariangela
In Alzheimer disease, the gap between excellence of diagnostics and efficacy of therapy is wide. Despite sophisticated imaging and biochemical markers, the efficacy of available therapeutic options is limited. Here we examine the possibility that assessment of endogenous catecholamine levels in cerebrospinal fluid (CSF) may fuel new therapeutic strategies. In reviewing the available literature, we consider the effects of levodopa, monoamine oxidase inhibitors, and noradrenaline (NE) modulators, showing disparate results. We present a preliminary assessment of CSF concentrations of dopamine (DA) and NE, determined by HPLC, in a small dementia cohort of either Alzheimer’s disease (AD) or frontotemporal dementia patients, compared to control subjects. Our data reveal detectable levels of DA, NE in CSF, though we found no significant alterations in the dementia population as a whole. AD patients exhibit a small impairment of the DA axis and a larger increase of NE concentration, likely to represent a compensatory mechanism. While waiting for preventive strategies, a pragmatic approach to AD may re-evaluate catecholamine modulation, possibly stratified to dementia subtypes, as part of the therapeutic armamentarium. PMID:25999852
Fletcher, Phillip D.; Downey, Laura E.; Golden, Hannah L.; Clark, Camilla N.; Slattery, Catherine F.; Paterson, Ross W.; Schott, Jonathan M.; Rohrer, Jonathan D.; Rossor, Martin N.; Warren, Jason D.
Patients with dementia may exhibit abnormally altered liking for environmental sounds and music but such altered auditory hedonic responses have not been studied systematically. Here we addressed this issue in a cohort of 73 patients representing major canonical dementia syndromes (behavioural variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA) amnestic Alzheimer's disease (AD)) using a semi-structured caregiver behavioural questionnaire and voxel-based morphometry (VBM) of patients' brain MR images. Behavioural responses signalling abnormal aversion to environmental sounds, aversion to music or heightened pleasure in music (‘musicophilia’) occurred in around half of the cohort but showed clear syndromic and genetic segregation, occurring in most patients with bvFTD but infrequently in PNFA and more commonly in association with MAPT than C9orf72 mutations. Aversion to sounds was the exclusive auditory phenotype in AD whereas more complex phenotypes including musicophilia were common in bvFTD and SD. Auditory hedonic alterations correlated with grey matter loss in a common, distributed, right-lateralised network including antero-mesial temporal lobe, insula, anterior cingulate and nucleus accumbens. Our findings suggest that abnormalities of auditory hedonic processing are a significant issue in common dementias. Sounds may constitute a novel probe of brain mechanisms for emotional salience coding that are targeted by neurodegenerative disease. PMID:25929717
Ondo, William G
Stereotypies are frequently reported in frontotemporal dementia. Their pathophysiology and optimal treatment are largely unexplored. The author reports seven cases of marked stereotype in patients with probable frontotemporal dementia who were treated with tetrabenazine, a monoamine inhibitor. All patients had near-complete resolution of stereotypy. Six patients stopped tetrabenazine at some point, with return of their stereotype within 24 hours, which again improved in the four who restarted therapy. Efficacy has not waned over time. Tetrabenazine dramatically improved stereotypies in patients with dementia. This observation could increase understanding of this interesting phenotype.
Kim, Jahae; Cho, Sang-Geon; Song, Minchul; Kang, Sae-Ryung; Kwon, Seong Young; Choi, Kang-Ho; Choi, Seong-Min; Kim, Byeong-Chae; Song, Ho-Chun
Abstract To compare diagnostic performance and confidence of a standard visual reading and combined 3-dimensional stereotactic surface projection (3D-SSP) results to discriminate between Alzheimer disease (AD)/mild cognitive impairment (MCI), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). [18F]fluorodeoxyglucose (FDG) PET brain images were obtained from 120 patients (64 AD/MCI, 38 DLB, and 18 FTD) who were clinically confirmed over 2 years follow-up. Three nuclear medicine physicians performed the diagnosis and rated diagnostic confidence twice; once by standard visual methods, and once by adding of 3D-SSP. Diagnostic performance and confidence were compared between the 2 methods. 3D-SSP showed higher sensitivity, specificity, accuracy, positive, and negative predictive values to discriminate different types of dementia compared with the visual method alone, except for AD/MCI specificity and FTD sensitivity. Correction of misdiagnosis after adding 3D-SSP images was greatest for AD/MCI (56%), followed by DLB (13%) and FTD (11%). Diagnostic confidence also increased in DLB (visual: 3.2; 3D-SSP: 4.1; P < 0.001), followed by AD/MCI (visual: 3.1; 3D-SSP: 3.8; P = 0.002) and FTD (visual: 3.5; 3D-SSP: 4.2; P = 0.022). Overall, 154/360 (43%) cases had a corrected misdiagnosis or improved diagnostic confidence for the correct diagnosis. The addition of 3D-SSP images to visual analysis helped to discriminate different types of dementia in FDG PET scans, by correcting misdiagnoses and enhancing diagnostic confidence in the correct diagnosis. Improvement of diagnostic accuracy and confidence by 3D-SSP images might help to determine the cause of dementia and appropriate treatment. PMID:27930593
Cohn-Hokke, Petra E; Elting, Mariet W; Pijnenburg, Yolande A L; van Swieten, John C
With increased frequency, clinical geneticists are asked for genetic advice on the heredity of dementia in families. Alzheimer's disease is in most cases a complex disease, but may be autosomal dominant inherited. Mutations in the PSEN1 gene are the most common genetic cause of early onset Alzheimer's disease, whereas APP and PSEN2 gene mutations are less frequent. Familial frontotemporal dementia may be associated with a mutation in the MAPT or GRN gene, or with a repeat expansion in the C9orf72 gene. All these genes show autosomal dominant inheritance with a high penetrance. Although Alzheimer's disease and frontotemporal dementia are clinically distinguishable entities, phenotypical overlap may occur. Rarely, dementia is caused by mutations in other autosomal dominant genes or by genetic defects with autosomal recessive, X-linked dominant or mitochondrial inheritance. The inherited forms of frontotemporal dementia and Alzheimer's disease show a large phenotypic variability also within families, resulting in many remaining uncertainties for mutation carriers. Therefore, genetic counseling before performing genetic testing is essential in both symptomatic individuals and healthy at risk relatives. This review provides an overview of the genetic causes of dementia and discusses all aspects relevant for genetic counseling and testing. Furthermore, based on current knowledge, we provide algorithms for genetic testing in patients with early onset Alzheimer's disease or frontotemporal dementia.
Lin, Pin-Hsuan; Chen, Hsiu-Hui; Chen, Nai-Ching; Chang, Wen-Neng; Huang, Chi-Wei; Chang, Ya-Ting; Hsu, Shih-Wei; Hsu, Che-Wei; Chang, Chiung-Chih
Purpose: Patients with dementia who have dissociations in verbal and non-verbal sound processing may offer insights into the anatomic basis for highly related auditory modes. Methods: To determine the neuronal networks on non-verbal perception, 16 patients with Alzheimer’s dementia (AD), 15 with behavior variant fronto-temporal dementia (bv-FTD), 14 with semantic dementia (SD) were evaluated and compared with 15 age-matched controls. Neuropsychological and auditory perceptive tasks were included to test the ability to compare pitch changes, scale-violated melody and for naming and associating with environmental sound. The brain 3D T1 images were acquired and voxel-based morphometry (VBM) was used to compare and correlated the volumetric measures with task scores. Results: The SD group scored the lowest among 3 groups in pitch or scale-violated melody tasks. In the environmental sound test, the SD group also showed impairment in naming and also in associating sound with pictures. The AD and bv-FTD groups, compared with the controls, showed no differences in all tests. VBM with task score correlation showed that atrophy in the right supra-marginal and superior temporal gyri was strongly related to deficits in detecting violated scales, while atrophy in the bilateral anterior temporal poles and left medial temporal structures was related to deficits in environmental sound recognition. Conclusions: Auditory perception of pitch, scale-violated melody or environmental sound reflects anatomical degeneration in dementia patients and the processing of non-verbal sounds are mediated by distinct neural circuits. PMID:27630558
Greicius, M; Geschwind, M; Miller, B
The four major degenerative dementias that often begin in presenescence: are reviewed. These are Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and Creutzfeldt–Jakob disease. Their epidemiological, genetic, and clinical features are reviewed, and controversies in taxonomy arising from recent discoveries described. Particular attention is given to the pathological role of protein aggregation, which appears to be a factor in each disease. PMID:12023408
In the past decade, positron emission tomography (PET) with carbon-11-labeled Pittsburgh Compound B (PIB) has revolutionized the neuroimaging of aging and dementia by enabling in vivo detection of amyloid plaques, a core pathologic feature of Alzheimer's disease (AD). Studies suggest that PIB-PET is sensitive for AD pathology, can distinguish AD from non-AD dementia (for example, frontotemporal lobar degeneration), and can help determine whether mild cognitive impairment is due to AD. Although the short half-life of the carbon-11 radiolabel has thus far limited the use of PIB to research, a second generation of tracers labeled with fluorine-18 has made it possible for amyloid PET to enter the clinical era. In the present review, we summarize the literature on amyloid imaging in a range of neurodegenerative conditions. We focus on potential clinical applications of amyloid PET and its role in the differential diagnosis of dementia. We suggest that amyloid imaging will be particularly useful in the evaluation of mildly affected, clinically atypical or early age-at-onset patients, and illustrate this with case vignettes from our practice. We emphasize that amyloid imaging should supplement (not replace) a detailed clinical evaluation. We caution against screening asymptomatic individuals, and discuss the limited positive predictive value in older populations. Finally, we review limitations and unresolved questions related to this exciting new technique. PMID:22071129
Johnson, Julene K; Chang, Chiung-Chih; Brambati, Simona M; Migliaccio, Raffaella; Gorno-Tempini, Maria Luisa; Miller, Bruce L; Janata, Petr
Objective To compare music recognition in patients with frontotemporal dementia, semantic dementia, Alzheimer disease, and controls and to evaluate the relationship between music recognition and brain volume. Background Recognition of familiar music depends on several levels of processing. There are few studies about how patients with dementia recognize familiar music. Methods Subjects were administered tasks that assess pitch and melody discrimination, detection of pitch errors in familiar melodies, and naming of familiar melodies. Results There were no group differences on pitch and melody discrimination tasks. However, patients with semantic dementia had considerable difficulty naming familiar melodies and also scored the lowest when asked to identify pitch errors in the same melodies. Naming familiar melodies, but not other music tasks, was strongly related to measures of semantic memory. Voxel-based morphometry analysis of brain MRI showed that difficulty in naming songs was associated with the bilateral temporal lobes and inferior frontal gyrus, whereas difficulty in identifying pitch errors in familiar melodies correlated with primarily the right temporal lobe. Conclusions The results support a view that the anterior temporal lobes play a role in familiar melody recognition, and that musical functions are affected differentially across forms of dementia. PMID:21617528
Gozes, Illana; Ivashko-Pachima, Yanina
Activity-dependent neuroprotective protein (ADNP) is deregulated in Alzheimer's disease (AD) and in schizophrenia and mutated in autism. In mice, ADNP is essential for brain formation and ADNP haploinsufficiency is associated with cognitive and social deficits and tauopathy. Tauopathy, a major pathology in AD, is also found in ~45% of frontotemporal dementias (FTDs). Tau transcript, a product of a single gene, undergoes alternative splicing. Tau splicing seems to be altered in FTD brain. In transgenic mice overexpressing a mutated tau in the cerebral cortex, significant increases in ADNP transcript expression were observed in the cerebral cortex of young transgenic mice (~disease onset) and a marked decrease with aging as compared to control littermates. ADNP is a member of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex also associated with alternative splicing, including tau transcript splicing. Further cellular interactions of ADNP include association with microtubules, with tau being a microtubule—associated protein. NAP (davundetide), a novel drug candidate derived from ADNP, increases ADNP-microtubule association and protects against tauopathy and cognitive deficiencies in mice. Although, NAP did not provide protection in progressive supranuclear palsy (PSP), a pure tauopathy, it increased cognitive scores in amnestic mild cognitively impaired patients and protected functional activity in schizophrenia patients. This mini-review focuses on ADNP in the context of FTD and tau/microtubules and proposes NAP as a novel drug target for future clinical evaluations. PMID:26578950
Borroni, B; Pilotto, A; Bianchi, M; Gilberti, N; Padovani, A
Frontotemporal Lobar Degeneration (FTLD) is a genetically and pathologically heterogeneous disorder characterized by behavioral change, executive dysfunction and language impairment associated with frontal and temporal lobe degeneration. Three major clinical subtypes have been identified so far, namely behaviour variant Frontotemporal dementia (bvFTD), Semantic Dementia (SD) and Progressive Non-Fluent Aphasia (PNFA). FTLD might also overlap with atypical parkinsonisms or motor neuron disease. Several pathogenetic mutations have been associated with specific pathological and clinical correlates. FTLD associated with either Microtuble Associated Protein Tau (MAPT) or Progranulin (PGRN) mutations is recognised as the most common form of autosomal dominant inherited disorder. However, monogenic mutations account for only about one third of all FTLD cases. Several studies have evaluated the contribution of genetic background in non-monogenic forms of FTLD, with the attempt to establish its role in increasing disease risk and in modulating clinical phenotypes. Specific MAPT and PGRN polymorphisms have been demonstrated to affect disease onset, clinical features and prognosis of FTLD, and genetic variations within other genes appear to play a role in influencing disease risk and clinical expression of FTLD. The aim of the present review is to discuss the impact and the role of genetic background in non-monogenic forms of FTLD, to highlight new potential pathogenetic and therapeutic targets.
Govaarts, Rosanne; Beeldman, Emma; Kampelmacher, Mike J; van Tol, Marie-Jose; van den Berg, Leonard H; van der Kooi, Anneke J; Wijkstra, Peter J; Zijnen-Suyker, Marianne; Cobben, Nicolle A M; Schmand, Ben A; de Haan, Rob J; de Visser, Marianne; Raaphorst, Joost
Thirty percent of ALS patients have a frontotemporal syndrome (FS), defined as behavioral changes or cognitive impairment. Despite previous studies, there are no firm conclusions on the effect of the FS on survival and the use of non-invasive ventilation (NIV) in ALS. We examined the effect of the FS on survival and the start and duration of NIV in ALS. Behavioral changes were defined as >22 points on the ALS-Frontotemporal-Dementia-Questionnaire or ≥3 points on ≥2 items of the Neuropsychiatric Inventory. Cognitive impairment was defined as below the fifth percentile on ≥2 tests of executive function, memory or language. Classic ALS was defined as ALS without the frontotemporal syndrome. We performed survival analyses from symptom onset and time from NIV initiation, respectively, to death. The impact of the explanatory variables on survival and NIV initiation were examined using Cox proportional hazards models. We included 110 ALS patients (76 men) with a mean age of 62 years. Median survival time was 4.3 years (95 % CI 3.53-5.13). Forty-seven patients (43 %) had an FS. Factors associated with shorter survival were FS, bulbar onset, older age at onset, short time to diagnosis and a C9orf72 repeat expansion. The adjusted hazard ratio (HR) for the FS was 2.29 (95 % CI 1.44-3.65, p < 0.001) in a multivariate model. Patients with an FS had a shorter survival after NIV initiation (adjusted HR 2.70, 95 % CI 1.04-4.67, p = 0.04). In conclusion, there is an association between the frontotemporal syndrome and poor survival in ALS, which remains present after initiation of NIV.
Ahmed, Samrah; Baker, Ian; Thompson, Sian; Husain, Masud; Butler, Christopher R
Introduction Existing literature suggests that the presence or absence of apraxia and associated parietal deficits may be clinically relevant in differential diagnosis of dementia syndromes. Aim This study investigated the profile of these features in Alzheimer's disease (AD) and frontotemporal dementia (FTD) spectrum disorders, at first presentation. Methods Retrospective case note analysis was undertaken in 111 patients who presented to the Oxford Cognitive Disorders Clinic, Oxford, UK, including 29 amnestic AD, 12 posterior cortical atrophy (PCA), 12 logopenic primary progressive aphasia (lvPPA), 20 behavioural variant FTD (bvFTD), 7 non-fluent variant PPA (nfvPPA), 6 semantic variant PPA (svPPA) and 25 patients with subjective cognitive impairment (SCI). The clinical features of interest were: limb apraxia, apraxia of speech (AOS), and left parietal symptoms of dyslexia, dysgraphia, and dyscalculia. Results The prevalence of limb apraxia was highest in PCA, amnestic AD, lvPPA and nfvPPA. AOS was only observed in nfvPPA. Associated parietal features were more prevalent in AD spectrum than FTD spectrum disorders. Group comparisons between key differential diagnostic challenges showed that lvPPA and nfvPPA could be significantly differentiated on the presence of left parietal features and AOS, and amnestic AD could be differentiated from bvFTD, svPPA and SCI by limb apraxia. Regression analysis showed that limb apraxia could successfully differentiate between AD and FTLD spectrum disorders with 83% accuracy. Discussion Disease-specific profiles of limb apraxia and associated deficits can be observed. FTD and AD spectrum disorders can be difficult to differentiate due to overlapping cognitive symptoms, and measures of apraxia, in particular, appear to be a promising discriminator. PMID:27251676
Cipriani, Gabriele; Lucetti, Claudio; Vedovello, Marcella; Nuti, Angelo
Diogenes syndrome (DS) is a behavioral disorder of the elderly. Symptoms include living in extreme squalor, a neglected physical state, and unhygienic conditions. This is accompanied by a self-imposed isolation, the refusal of external help, and a tendency to accumulate unusual objects. To explore the phenomenon of DS in dementia we searched for the terms: "Diogenes syndrome, self-neglect, dementia. " It has long been understood that individuals with dementia often become shut-ins, living in squalor, in the Eastern Baltimore study, dementia was present in 15% of the elderly cases with moderate and severe social breakdown syndrome; twice as many as in the general population of the same age group. Researchers have underlined the frequent presence of DS (36%) in frontotemporal dementia (FTD): different neuropsychological modifications in FTD may contribute to symptoms of DS. The initial treatment should be a behavioral program, but there is not sufficient information regarding pharmacological treatment of the syndrome.
Ismail, Zahinoor; Emeremni, Chetachi A; Houck, Patricia R.; Mazumdar, Sati; Rosen, Jules; Rajji, Tarek K.; Pollock, Bruce G.; Mulsant, Benoit H.
Objectives The aim of this study is to compare the Empirical Behavioral Rating Scale (E-BEHAVE AD), Neurobehavioral Rating Scale (NBRS), and Neuropsychiatric Interview (NPI) in detecting behavioral disturbance and psychotic symptoms in dementia and characterizing changes in response to treatment. Design 87 subjects in the randomized controlled trial “Continuation Pharmacotherapy for Agitation of Dementia” (CPAD) were included in this analysis. We compared the detection and changes over 12 weeks of both agitation and psychosis using these 3 instruments. A receiver operating characteristic (ROC) analysis was performed to compare the performance of the three instruments in detecting global improvement. Results The instruments were equally likely to detect agitation. The NBRS was most likely to detect psychosis. While the NPI best detected improvement in agitation, the instruments were equal for detecting improvement in psychosis. In the ROC analysis for overall clinical improvement in response to treatment, there were no differences in the areas under the correlated curves for the three instruments but they demonstrated different sensitivity and specificity at different cut-off points for target symptom reduction. The E-BEHAVE-AD performed best at a cutpoint of 30% target symptom reduction and the NBRS and NPI both performed best at 50%. Conclusion The E-BEHAVE-AD, NBRS, and NPI were more similar than different in characterizing symptoms but differed in detecting response to treatment. Differences in sensitivity and specificity may lead clinicians to prefer a specific instrument, depending on their goal and the expected magnitude of response to any specific intervention. PMID:23290205
Knoefel, Janice; Bhaskar, Kiran
The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer’s Disease prioritized Alzheimer’s disease-related dementias to include: Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and blood–brain barrier permeability responsible for disease etiology and progression will be discussed. PMID:26174330
Clark, Camilla N.; Nicholas, Jennifer M.; Henley, Susie M.D.; Downey, Laura E.; Woollacott, Ione O.; Golden, Hannah L.; Fletcher, Phillip D.; Mummery, Catherine J.; Schott, Jonathan M.; Rohrer, Jonathan D.; Crutch, Sebastian J.; Warren, Jason D.
Humour is a complex cognitive and emotional construct that is vulnerable in neurodegenerative diseases, notably the frontotemporal lobar degenerations. However, humour processing in these diseases has been little studied. Here we assessed humour processing in patients with behavioural variant frontotemporal dementia (n = 22, mean age 67 years, four female) and semantic dementia (n = 11, mean age 67 years, five female) relative to healthy individuals (n = 21, mean age 66 years, 11 female), using a joint cognitive and neuroanatomical approach. We created a novel neuropsychological test requiring a decision about the humorous intent of nonverbal cartoons, in which we manipulated orthogonally humour content and familiarity of depicted scenarios. Structural neuroanatomical correlates of humour detection were assessed using voxel-based morphometry. Assessing performance in a signal detection framework and after adjusting for standard measures of cognitive function, both patient groups showed impaired accuracy of humour detection in familiar and novel scenarios relative to healthy older controls (p < .001). Patient groups showed similar overall performance profiles; however the behavioural variant frontotemporal dementia group alone showed a significant advantage for detection of humour in familiar relative to novel scenarios (p = .045), suggesting that the behavioural variant syndrome may lead to particular difficulty decoding novel situations for humour, while semantic dementia produces a more general deficit of humour detection that extends to stock comedic situations. Humour detection accuracy was associated with grey matter volume in a distributed network including temporo-parietal junctional and anterior superior temporal cortices, with predominantly left-sided correlates of processing humour in familiar scenarios and right-sided correlates of processing novel humour. The findings quantify deficits of core cognitive operations underpinning humour
Clark, Camilla N; Nicholas, Jennifer M; Henley, Susie M D; Downey, Laura E; Woollacott, Ione O; Golden, Hannah L; Fletcher, Phillip D; Mummery, Catherine J; Schott, Jonathan M; Rohrer, Jonathan D; Crutch, Sebastian J; Warren, Jason D
Humour is a complex cognitive and emotional construct that is vulnerable in neurodegenerative diseases, notably the frontotemporal lobar degenerations. However, humour processing in these diseases has been little studied. Here we assessed humour processing in patients with behavioural variant frontotemporal dementia (n = 22, mean age 67 years, four female) and semantic dementia (n = 11, mean age 67 years, five female) relative to healthy individuals (n = 21, mean age 66 years, 11 female), using a joint cognitive and neuroanatomical approach. We created a novel neuropsychological test requiring a decision about the humorous intent of nonverbal cartoons, in which we manipulated orthogonally humour content and familiarity of depicted scenarios. Structural neuroanatomical correlates of humour detection were assessed using voxel-based morphometry. Assessing performance in a signal detection framework and after adjusting for standard measures of cognitive function, both patient groups showed impaired accuracy of humour detection in familiar and novel scenarios relative to healthy older controls (p < .001). Patient groups showed similar overall performance profiles; however the behavioural variant frontotemporal dementia group alone showed a significant advantage for detection of humour in familiar relative to novel scenarios (p = .045), suggesting that the behavioural variant syndrome may lead to particular difficulty decoding novel situations for humour, while semantic dementia produces a more general deficit of humour detection that extends to stock comedic situations. Humour detection accuracy was associated with grey matter volume in a distributed network including temporo-parietal junctional and anterior superior temporal cortices, with predominantly left-sided correlates of processing humour in familiar scenarios and right-sided correlates of processing novel humour. The findings quantify deficits of core cognitive operations underpinning humour
Mosconi, Lisa; Tsui, Wai H.; Herholz, Karl; Pupi, Alberto; Drzezga, Alexander; Lucignani, Giovanni; Reiman, Eric M.; Holthoff, Vjera; Kalbe, Elke; Sorbi, Sandro; Diehl-Schmid, Janine; Perneczky, Robert; Clerici, Francesca; Caselli, Richard; Beuthien-Baumann, Bettina; Kurz, Alexander; Minoshima, Satoshi; de Leon, Mony J.
This multicenter study examined 18F-FDG PET measures in the differential diagnosis of Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). Methods We examined the 18F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals (“normals” or NLs), 114 MCI, 199 AD,98FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal 18F-FDG uptake that were then applied to characterize MCI. Results Standardized disease-specific PET patterns were developed that correctly classified 95%AD, 92% DLB,94%FTD,and 94%NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. 18F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. Conclusion Standardized automated analysis of 18F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia. PMID:18287270
Suhonen, Noora-Maria; Hallikainen, Ilona; Hänninen, Tuomo; Jokelainen, Jari; Krüger, Johanna; Hall, Anette; Pikkarainen, Maria; Soininen, Hilkka; Remes, Anne M
While behavioral symptoms are both early and prevalent features of behavioral variant frontotemporal dementia (bvFTD), they can be present in other types of dementia as well, including Alzheimer's disease (AD) and even mild cognitive impairment (MCI). The Frontal Behavioral Inventory (FBI) was specifically developed to capture the behavioral and personality changes in bvFTD; it has also been modified into a self-administered caregiver questionnaire (FBI-mod). We examined the utility of the FBI-mod in differentiating bvFTD (n = 26), primary progressive aphasia (PPA) (n = 7), AD (n = 53), and MCI (n = 50) patients, and investigated how the FBI-mod may be associated with neuropsychological measures. The bvFTD patients scored significantly higher as compared to all other patient groups on the FBI-mod Total (p < 0.005), Negative (p < 0.005), and Positive (p < 0.01) scores. The cut-off point for the FBI-mod Total score that best discriminated the bvFTD and AD patients in our sample was 16, thus substantially lower than reported for the original FBI. For the bvFTD group, only mild correlations emerged between the FBI-mod and the cognitive measures. However, significant correlations between the FBI-mod and depressive symptoms as measured by the BDI-II were found for bvFTD. This suggests that while behavioral symptoms appear independent from cognitive deficits in bvFTD, they may nevertheless be interrelated with depressive symptoms. We conclude that the FBI-mod is an easily administered behavioral scale that can aid in differential diagnosis of bvFTD and should be used in clinical practice. The FBI-mod may further be considered as an outcome measure in clinical trials.
Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Abbas, Mirza Masoom
Background: Apraxia is a state of inability to carry out a learned motor act in the absence of motor, sensory or cerebellar defect on command processed through the Praxis circuit. Breakdown in default networking is one of the early dysfunction in cortical dementias and result in perplexity, awkwardness, omission, substitution errors, toying behavior and unrecognizable gestures in response to command with voluntary reflex dissociation where, when unobserved patient will carry out reflex movements normally. Awareness into the organicity of these phenomenas will help in early diagnosis, which will help in initiating appropriate treatment and slowing down the progression of the disease. Aims and Objectives: The aim was to look for the various kinds of apraxias in patients with dementia using appropriate simple tests. Patients and Methods: Three hundred patients satisfying Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia were evaluated in detail with mandatory investigations for dementia followed by testing for ideational, ideomotor, limb-kinetic, buccopharyngeal, dressing apraxia, constructional apraxia and gait apraxias in addition to recording of rare apraxias when present. Results: Alzheimer's disease showed maximum association with apraxias in all the phases of the disease ideational, ideomotor, dressing and constructional apraxias early and buccopharyngeal and gait apraxia late. Frontotemporal lobe dementia showed buccopharyngeal and gait apraxias late into the disease. Cortical basal ganglionic degeneration showed limb apraxias and diffuse Lewy body disease showed more agnosias and less apraxias common apraxias seen was Ideational and Ideomotor. Conclusion: Recognition of the apraxias help in establishing organicity, categorization, caregiver education, early strategies for treatment, avoiding anti-psychotics and introducing disease modifying pharmacotherapeutic agents and also prognosticating. PMID:25722511
Vossel, Keith A.; Miller, Bruce L
Purpose of review Treatment approaches for frontotemporal lobar degeneration (FTLD) are rapidly evolving with improved understanding of the disease. This brief review highlights recent advances. Recent findings Early-onset dementia has a devastating impact on families and rids its victims of their most productive and rewarding years. Over the past ten years, FTLD has emerged as the commonest cause of dementia under the age of 60 years, outstripping even Alzheimer’s disease in prevalence. Remarkable progress has occurred in our understanding of FTLD both as a set of distinctive clinical syndromes and as a set of disorders with unique genetic and pathological profiles. While there are no Food and Drug Administration approved medications for FTLD, new evidence of specific genetic and neurochemical defects are beginning to provide a strong rationale for pharmacological treatment. Summary Behavioral changes, which are common in behavioral variant FTD and semantic dementia, often respond to treatment with selective serotonin inhibitors. Memantine also holds promise to treat neuropsychiatric symptoms, but more prospective trials are needed. With better understanding of pathogenic molecular pathways involving microtubule associated protein tau, progranulin and TDP-43, potential disease-modifying therapies are being studied in animal models and approaching human trials. PMID:18989117
Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica
Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) represent the most frequent causes of early-onset and late-onset degenerative dementia, respectively. A correct diagnosis entails the choice of appropriate therapies. In this view the present study aimed to identify biomarkers that could improve the differential diagnosis. We recently found an overexpression of platelet amyloid precursor protein (APP) in AD; furthermore, recent studies have suggested the presence of changes in APP processing in FTLD. In this context, we analyzed the mRNA expression level of Total APP (TOT) and APP containing a Kunitz-type serine protease inhibitor domain (KPI) in platelets obtained from AD patients, subjects with FTLD, and healthy subjects. In addition, we evaluated the correlation between platelet APP mRNA expression levels and cognitive impairment. Differential gene expression measurements revealed a significant up-regulation of APP TOT and APP KPI in both AD and FTLD patients compared to the controls (being AD/Controls: 1.67 for APP TOT and 1.47 for APP KPI; FTLD/Controls: 1.62 for APP TOT and 1.51 for APP KPI; p<0.05) , although it is interesting to note that in FTLD patients this expression did not correlate with the severity of cognitive impairment. This could be related to a reduced beta-amyloid (Aβ) formation, caused by an alteration of secretase enzymatic activity, even though a post-transcriptional regulation of APP mRNAs in FTLD cannot be excluded.
Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica
Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) represent the most frequent causes of early-onset and late-onset degenerative dementia, respectively. A correct diagnosis entails the choice of appropriate therapies. In this view the present study aimed to identify biomarkers that could improve the differential diagnosis. We recently found an overexpression of platelet amyloid precursor protein (APP) in AD; furthermore, recent studies have suggested the presence of changes in APP processing in FTLD. In this context, we analyzed the mRNA expression level of Total APP (TOT) and APP containing a Kunitz-type serine protease inhibitor domain (KPI) in platelets obtained from AD patients, subjects with FTLD, and healthy subjects. In addition, we evaluated the correlation between platelet APP mRNA expression levels and cognitive impairment.Differential gene expression measurements revealed a significant up-regulation of APP TOT and APP KPI in both AD and FTLD patients compared to the controls (being AD/Controls: 1.67 for APP TOT and 1.47 for APP KPI; FTLD/Controls: 1.62 for APP TOT and 1.51 for APP KPI; p < 0.05), although it is interesting to note that in FTLD patients this expression did not correlate with the severity of cognitive impairment.This could be related to a reduced beta-amyloid (Aβ) formation, caused by an alteration of secretase enzymatic activity, even though a post-transcriptional regulation of APP mRNAs in FTLD cannot be excluded.
... the brain. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal ... Group for Tauopathies With Parkinsonism. Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options. ...
... temporal lobes . The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal ... MND. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain. 2008 Mar; ...
Thompson, Alexandra E.; Clark, Camilla N.; Hardy, Christopher J.; Fletcher, Phillip D.; Greene, John; Rohrer, Jonathan D.; Warren, Jason D.
ABSTRACT Accounts of altered eating behavior in semantic dementia generally emphasize gluttony and abnormal food preferences. Here we describe two female patients with no past history of eating disorders who developed early prominent aversion to food in the context of an otherwise typical semantic dementia syndrome. One patient (aged 57) presented features in line with anorexia nervosa while the second patient (aged 58) presented with a syndrome more suggestive of bulimia nervosa. These cases add to the growing spectrum of apparently dichotomous behavior patterns in the frontotemporal dementias and illustrate a potentially under-recognized cause of eating disorders presenting in later life. PMID:26963051
Lin, Shih-Yin; Lewis, Frances Marcus
With an aging global population, the number of dementia cases is growing exponentially. To address the upcoming dementia crisis, the World Health Organization and Alzheimer’s Disease International (2012) collaborated on an extensive report, Dementia: A Public Health Priority. In the United Kingdom, Prime Minster David Cameron initiated a national challenge on dementia, forming 3 dementia challenge champion groups aimed at improving health and care, creating dementia-friendly communities, and promoting dementia research. In the U.S., President Obama signed the National Alzheimer’s Project Act, which led to the formation of the Advisory Council on Alzheimer’s Research, Care, and Services and the launch of the first National Plan to Address Alzheimer’s Disease. The term “dementia capable” was introduced in the 2012 Recommendations of the Public Members of the Advisory Council and has since been adopted in both the recommendations and annual updates of the national plan. This paper will first compare and contrast government usage of the concepts dementia friendly and dementia capable, along with another valuable concept, dementia positive, that was added after reviewing the literature. Finally, a new vision statement for the U.S.’ national plan will be proposed and recommendations incorporating these 3 concepts in policy, research, and practice will be made. PMID:26035599
... attack) may increase your risk of developing dementia. Atherosclerosis. This condition occurs when deposits of cholesterol and ... in your arteries and narrow your blood vessels. Atherosclerosis can increase your risk of vascular dementia — and ...
Grand, Jacob HG; Caspar, Sienna; MacDonald, Stuart WS
Dementia is a clinical syndrome of widespread progressive deterioration of cognitive abilities and normal daily functioning. These cognitive and behavioral impairments pose considerable challenges to individuals with dementia, along with their family members and caregivers. Four primary dementia classifications have been defined according to clinical and research criteria: 1) Alzheimer’s disease; 2) vascular dementias; 3) frontotemporal dementias; and 4) dementia with Lewy bodies/Parkinson’s disease dementia. The cumulative efforts of multidisciplinary healthcare teams have advanced our understanding of dementia beyond basic descriptions, towards a more complete elucidation of risk factors, clinical symptoms, and neuropathological correlates. The characterization of disease subtypes has facilitated targeted management strategies, advanced treatments, and symptomatic care for individuals affected by dementia. This review briefly summarizes the current state of knowledge and directions of dementia research and clinical practice. We provide a description of the risk factors, clinical presentation, and differential diagnosis of dementia. A summary of multidisciplinary team approaches to dementia care is outlined, including management strategies for the treatment of cognitive impairments, functional deficits, and behavioral and psychological symptoms of dementia. The needs of individuals with dementia are extensive, often requiring care beyond traditional bounds of medical practice, including pharmacologic and non-pharmacologic management interventions. Finally, advanced research on the early prodromal phase of dementia is reviewed, with a focus on change-point models, trajectories of cognitive change, and threshold models of pathological burden. Future research goals are outlined, with a call to action for social policy initiatives that promote preventive lifestyle behaviors, and healthcare programs that will support the growing number of individuals affected by
de la Torre, Jack C
There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer's disease (AD) long before dyscognitive symptoms or amyloid-β accumulation in the brain appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia.
Kämpf, C; Abderhalden, C
In addition to diagnostically decisive cognitive problems, behavioural and psychological symptoms (BPSD) are frequent among people with dementia, including sexually related behavioural problems. This paper provides an overview on the state of knowledge about these problems. Research on this topic is hampered by the absence of unanimous definitions, aetiological classifications, and diagnostic instruments. The wide range of prevalence rates reported (1.8 - 18 %) originate from the heterogenity of study samples as well as in the variety of definitions and instruments employed. Regarding aetiology, dysfunctions in various cortical regions are being discussed. Sexually related behavioural problems are more prevalent in men and among patients with vascular, frontotemporal and Parkinson-associated forms of dementia, as compared with dementias of the Alzheimer type. The pharmacological and non-pharmacological treatment strategies published to date have not been sufficiently studied.
Taipa, Ricardo; Pinho, João; Melo-Pires, Manuel
Neurodegenerative dementias are a group of neurological disorders characterized by deterioration in several cognitive domains in which there is selective and progressive loss of specific populations of neurons. The precise neurobiological basis for the different neurodegenerative dementias remains unknown. It is expected that different pathologies reflect different mechanisms, at least early in the neurodegeneration process. The next decades promise treatments directed to causes and mechanisms, bringing an outstanding challenge to clinicians due to heterogeneous clinical presentations with the same molecular pathology. The purpose of this brief review is to describe the key neuropathological features of the most common neurodegenerative dementias (Alzheimer disease, dementia with Lewy bodies and Parkinson’s disease dementia, and frontotemporal lobar degeneration) and the relationship with the clinical syndromes described in clinico-pathological studies. We expect this overview contributes for the understanding of this broad topic integrating the two ends of the spectrum: clinical and pathological. PMID:22557993
Mostofi, Emily; Schievink, Wouter I; Sim, Valerie L
Frontotemporal brain sagging syndrome is a dementia associated with hypersomnolence, personality changes, and features of intracranial hypotension on magnetic resonance imaging. The literature is sparse with respect to treatment options; many patients simply worsen. We present a case in which this syndrome responded to lumbar dural reduction surgery. Postoperative magnetic resonance imaging indicated normalization of brain sagging and lumbar intrathecal pressure. Although no evidence of cerebrospinal leak was found, extremely thin dura was noted intraoperatively, suggesting that a thin and incompetent dura could result in this low-pressure syndrome. Clinicians who encounter this syndrome should consider dural reduction surgery as a treatment strategy.
[Alzheimer's disease with secondary Parkinson's syndrome. Case report of a patient with dementia and Parkinson's syndrome after long-term occupational exposure to insecticides, herbicides, and pesticides].
Laske, C; Wormstall, H; Einsiedler, K; Buchkremer, G
This case report describes long-term occupational exposure to agricultural insecticides, herbicides, and pesticides as possible environmental risk factors of Alzheimer's disease (AD) and Parkinson's syndrome in a 59-year-old man. Initially the patient complained about disturbances in concentration, mnestic deficits, and problems finding words. In the further course of the disease, he developed Parkinson's syndrome with predominant hypokinesia and rigor in addition to mild-to-moderate dementia. Low levels of beta-amyloid 1-42 were found in the CSF. Electroencephalography showed left frontotemporal theta waves. Cranial MRI revealed general brain atrophy with a maximum biparietally. In cerebral positron emission tomography, general hypometabolism was found with maxima biparietally and left frontally. The possible differential diagnosis of AD and Parkinson's syndrome is discussed.
Dick, Katrina M.; Patterson, Karalyn; Vázquez Rodríquez, Patricia; Wehmann, Eileen; Wilcox, Alicia; Lansdall, Claire J.; Dawson, Kate E.; Wiggins, Julie; Mead, Simon; Brayne, Carol; Rowe, James B.
Objectives: To estimate the lifetime risk, prevalence, incidence, and mortality of the principal clinical syndromes associated with frontotemporal lobar degeneration (FTLD) using revised diagnostic criteria and including intermediate clinical phenotypes. Methods: Multisource referral over 2 years to identify all diagnosed or suspected cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) in 2 UK counties (population 1.69 million). Diagnostic confirmation used current consensus diagnostic criteria after interview and reexamination. Results were adjusted to the 2013 European standard population. Results: The prevalence of FTD, PSP, and CBS was 10.8/100,000. The incidence and mortality were very similar, at 1.61/100,000 and 1.56/100,000 person-years, respectively. The estimated lifetime risk is 1 in 742. Survival following diagnosis varied widely: from PSP 2.9 years to semantic variant FTD 9.1 years. Age-adjusted prevalence peaked between 65 and 69 years at 42.6/100,000: the age-adjusted prevalence for persons older than 65 years is double the prevalence for those between 40 and 64 years. Fifteen percent of those screened had a relevant genetic mutation. Conclusions: Key features of this study include the revised diagnostic criteria with improved specificity and sensitivity, an unrestricted age range, and simultaneous assessment of multiple FTLD syndromes. The prevalence of FTD, PSP, and CBS increases beyond 65 years, with frequent genetic causes. The time from onset to diagnosis and from diagnosis to death varies widely among syndromes, emphasizing the challenge and importance of accurate and timely diagnosis. A high index of suspicion for FTLD syndromes is required by clinicians, even for older patients. PMID:27037234
Cohen, Miriam H.; Carton, Amelia M.; Hardy, Christopher J.; Golden, Hannah L.; Clark, Camilla N.; Fletcher, Phillip D.; Jaisin, Kankamol; Marshall, Charles R.; Henley, Susie M.D.; Rohrer, Jonathan D.; Crutch, Sebastian J.; Warren, Jason D.
Abstract art may signal emotions independently of a biological or social carrier: it might therefore constitute a test case for defining brain mechanisms of generic emotion decoding and the impact of disease states on those mechanisms. This is potentially of particular relevance to diseases in the frontotemporal lobar degeneration (FTLD) spectrum. These diseases are often led by emotional impairment despite retained or enhanced artistic interest in at least some patients. However, the processing of emotion from art has not been studied systematically in FTLD. Here we addressed this issue using a novel emotional valence matching task on abstract paintings in patients representing major syndromes of FTLD (behavioural variant frontotemporal dementia, n=11; sematic variant primary progressive aphasia (svPPA), n=7; nonfluent variant primary progressive aphasia (nfvPPA), n=6) relative to healthy older individuals (n=39). Performance on art emotion valence matching was compared between groups taking account of perceptual matching performance and assessed in relation to facial emotion matching using customised control tasks. Neuroanatomical correlates of art emotion processing were assessed using voxel-based morphometry of patients' brain MR images. All patient groups had a deficit of art emotion processing relative to healthy controls; there were no significant interactions between syndromic group and emotion modality. Poorer art emotion valence matching performance was associated with reduced grey matter volume in right lateral occopitotemporal cortex in proximity to regions previously implicated in the processing of dynamic visual signals. Our findings suggest that abstract art may be a useful model system for investigating mechanisms of generic emotion decoding and aesthetic processing in neurodegenerative diseases. PMID:26748236
Cohen, Miriam H; Carton, Amelia M; Hardy, Christopher J; Golden, Hannah L; Clark, Camilla N; Fletcher, Phillip D; Jaisin, Kankamol; Marshall, Charles R; Henley, Susie M D; Rohrer, Jonathan D; Crutch, Sebastian J; Warren, Jason D
art may signal emotions independently of a biological or social carrier: it might therefore constitute a test case for defining brain mechanisms of generic emotion decoding and the impact of disease states on those mechanisms. This is potentially of particular relevance to diseases in the frontotemporal lobar degeneration (FTLD) spectrum. These diseases are often led by emotional impairment despite retained or enhanced artistic interest in at least some patients. However, the processing of emotion from art has not been studied systematically in FTLD. Here we addressed this issue using a novel emotional valence matching task on abstract paintings in patients representing major syndromes of FTLD (behavioural variant frontotemporal dementia, n=11; sematic variant primary progressive aphasia (svPPA), n=7; nonfluent variant primary progressive aphasia (nfvPPA), n=6) relative to healthy older individuals (n=39). Performance on art emotion valence matching was compared between groups taking account of perceptual matching performance and assessed in relation to facial emotion matching using customised control tasks. Neuroanatomical correlates of art emotion processing were assessed using voxel-based morphometry of patients' brain MR images. All patient groups had a deficit of art emotion processing relative to healthy controls; there were no significant interactions between syndromic group and emotion modality. Poorer art emotion valence matching performance was associated with reduced grey matter volume in right lateral occopitotemporal cortex in proximity to regions previously implicated in the processing of dynamic visual signals. Our findings suggest that abstract art may be a useful model system for investigating mechanisms of generic emotion decoding and aesthetic processing in neurodegenerative diseases.
Meguro, Kenichi; Tanaka, Naofumi; Nakatsuka, Masahiro; Nakamura, Kei; Satoh, Masayuki
The concept and diagnosis for mixed dementia is not simple, since it is difficult to identify the type and regions of cerebrovascular disease (CVD) responsible for causing dementia. An investigation is needed to confirm the presence of mixed dementia, those who met the criteria for Alzheimer's disease (AD) and those for vascular dementia (VaD). According to the community-based stroke, dementia, and bed-confinement prevention in Kurihara, northern Japan (Kurihara Project), the prevalence of dementia and dementing diseases was surveyed in 2008-2010. Five hundred and ninety people finally agreed to participate (47.0%), and 73 (12.4%) people were diagnosed with dementia according to the DSM-IV. Using MRI, intensive evaluations on CVDs were performed for the 49 dementia patients associated with CVDs (mixed dementia, VaD, and AD with CVD). For the mixed dementia group, all had left subcortical strategic CVDs. These included the caudate head and thalamus. For the VaD group, all patients had at least cortical CVDs or subcortical strategic CVDs. The AD with CVD group had non-strategic CVDs in cortical, subcortical, or other areas in 5 or 6 patients each. Two extreme concepts regarding CVD and dementia are possible. One is that there is no concept for mixed dementia or VaD. An alternative is that the vascular factor should be considered as primary. Our data showed an importance of cortical and subcortical "strategic" areas, the latter included thalamus and caudate head.
Strong, Michael J; Abrahams, Sharon; Goldstein, Laura H; Woolley, Susan; Mclaughlin, Paula; Snowden, Julie; Mioshi, Eneida; Roberts-South, Angie; Benatar, Michael; HortobáGyi, Tibor; Rosenfeld, Jeffrey; Silani, Vincenzo; Ince, Paul G; Turner, Martin R
This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised - - including deficits in social cognition and language - but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum. These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD).
Lindquist, S G; Schwartz, M; Batbayli, M; Waldemar, G; Nielsen, J E
Autosomal dominantly transmitted Alzheimer's disease (AD) and frontotemporal dementia (FTD) are genetically heterogeneous disorders. To date, three genes have been identified in which mutations cause early-onset autosomal dominant inherited AD: APP, PSEN1, and PSEN2. Mutations in two genes on chromosome 17, the MAPT and the PGRN genes, are associated with autosomal dominant inherited FTD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in families with inherited dementia. The identification of novel mutations and/or atypical genotype-phenotype correlations contributes to further characterizing the disorders. DNA-samples from the 90 index cases from a Danish referral-based cohort representing families with presumed autosomal dominant inherited AD or FTD were screened for mutations in the known genes with sequencing, denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) techniques. Seven presumed pathogenic mutations (two PSEN1, one PSEN2, one APP, one MAPT, and two PGRN) were identified, including a novel PSEN2 mutation (V393M). No dosage aberrations were identified.
Trojano, Luigi; Gainotti, Guido
Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer's disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer's disease, from the prodromal stages of the amnesic mild cognitive impairment to the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer's disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing.
Daiello, Lori A
Diagnosis and treatment of dementia in nursing homes and assisted living facilities remains challenging since response to treatment and disease course varies for the common degenerative dementias. Four cholinesterase inhibitors and an N-methyl-D-aspartate glutamate receptor antagonist are approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Treatment with AD medications is clinically efficacious and associated with reduced caregiver burden. Some controlled trials have reported that cholinesterase inhibitors and memantine ameliorate dementia-related behavioral symptoms. Antipsychotic therapy is often used for intractable behavioral symptoms or psychosis not responding to nonpharmacologic interventions and antidementia medications; however, the risk/benefit ratio for each patient should be critically evaluated, because treatment with atypical antipsychotics has been associated with serious adverse events, including increased risk for death in older adults with dementia.
frontotemporal dementia or dementia with Lewy bodies in which memory deficits are minor or late. Presently, diagnostic strategy should be directed towards specific entities such as Alzheimer's disease which can be diagnosed accurately in mildly impaired individuals. It is proposed that the term dementia should only be used to specify a degree of severity of the disease, corresponding to the restriction of the patient's autonomy.
Möller, Christiane; Hafkemeijer, Anne; Pijnenburg, Yolande A L; Rombouts, Serge A R B; van der Grond, Jeroen; Dopper, Elise; van Swieten, John; Versteeg, Adriaan; Pouwels, Petra J W; Barkhof, Frederik; Scheltens, Philip; Vrenken, Hugo; van der Flier, Wiesje M
We investigated the ability of cortical and subcortical gray matter (GM) atrophy in combination with white matter (WM) integrity to distinguish behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) and from controls using voxel-based morphometry, subcortical structure segmentation, and tract-based spatial statistics. To determine which combination of MR markers differentiated the three groups with the highest accuracy, we conducted discriminant function analyses. Adjusted for age, sex and center, both types of dementia had more GM atrophy, lower fractional anisotropy (FA) and higher mean (MD), axial (L1) and radial diffusivity (L23) values than controls. BvFTD patients had more GM atrophy in orbitofrontal and inferior frontal areas than AD patients. In addition, caudate nucleus and nucleus accumbens were smaller in bvFTD than in AD. FA values were lower; MD, L1 and L23 values were higher, especially in frontal areas of the brain for bvFTD compared to AD patients. The combination of cortical GM, hippocampal volume and WM integrity measurements, classified 97-100% of controls, 81-100% of AD and 67-75% of bvFTD patients correctly. Our results suggest that WM integrity measures add complementary information to measures of GM atrophy, thereby improving the classification between AD and bvFTD.
Möller, Christiane; Hafkemeijer, Anne; Pijnenburg, Yolande A.L.; Rombouts, Serge A.R.B.; van der Grond, Jeroen; Dopper, Elise; van Swieten, John; Versteeg, Adriaan; Pouwels, Petra J.W.; Barkhof, Frederik; Scheltens, Philip; Vrenken, Hugo; van der Flier, Wiesje M.
We investigated the ability of cortical and subcortical gray matter (GM) atrophy in combination with white matter (WM) integrity to distinguish behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) and from controls using voxel-based morphometry, subcortical structure segmentation, and tract-based spatial statistics. To determine which combination of MR markers differentiated the three groups with the highest accuracy, we conducted discriminant function analyses. Adjusted for age, sex and center, both types of dementia had more GM atrophy, lower fractional anisotropy (FA) and higher mean (MD), axial (L1) and radial diffusivity (L23) values than controls. BvFTD patients had more GM atrophy in orbitofrontal and inferior frontal areas than AD patients. In addition, caudate nucleus and nucleus accumbens were smaller in bvFTD than in AD. FA values were lower; MD, L1 and L23 values were higher, especially in frontal areas of the brain for bvFTD compared to AD patients. The combination of cortical GM, hippocampal volume and WM integrity measurements, classified 97–100% of controls, 81–100% of AD and 67–75% of bvFTD patients correctly. Our results suggest that WM integrity measures add complementary information to measures of GM atrophy, thereby improving the classification between AD and bvFTD. PMID:26594624
Harris, Jennifer M.; Jones, Matthew; Gall, Claire; Richardson, Anna M.T.; Neary, David; du Plessis, Daniel; Pal, Piyali; Mann, David M.A.; Snowden, Julie S.; Thompson, Jennifer C.
Background/Objectives We aimed to evaluate the co-occurrence of language and behavioural impairment in patients with frontotemporal lobar degeneration (FTLD) spectrum pathology. Methods Eighty-one dementia patients with pathological confirmation of FTLD were identified. Anonymized clinical records from patients' first assessment were rated for language and behavioural features from frontotemporal dementia consensus criteria, primary progressive aphasia (PPA) criteria and 1998 FTLD criteria. Results Over 90% of patients with FTLD pathology exhibited a combination of at least one behavioural and one language feature. Changes in language, in particular, were commonly accompanied by behavioural change. Notably, the majority of patients who displayed language features characteristic of semantic variant PPA exhibited ‘early perseverative, stereotyped or compulsive/ritualistic behaviour’. Moreover, ‘executive/generation deficits with relative sparing of memory and visuospatial functions’ occurred in most patients with core features of non-fluent variant PPA. Conclusion Behavioural and language symptoms frequently co-occur in patients with FTLD pathology. Current classifications, which separate behavioural and language syndromes, do not reflect this co-occurrence. PMID:27350781
Omar, Rohani; Henley, Susie M D; Bartlett, Jonathan W; Hailstone, Julia C; Gordon, Elizabeth; Sauter, Disa A; Frost, Chris; Scott, Sophie K; Warren, Jason D
Despite growing clinical and neurobiological interest in the brain mechanisms that process emotion in music, these mechanisms remain incompletely understood. Patients with frontotemporal lobar degeneration (FTLD) frequently exhibit clinical syndromes that illustrate the effects of breakdown in emotional and social functioning. Here we investigated the neuroanatomical substrate for recognition of musical emotion in a cohort of 26 patients with FTLD (16 with behavioural variant frontotemporal dementia, bvFTD, 10 with semantic dementia, SemD) using voxel-based morphometry. On neuropsychological evaluation, patients with FTLD showed deficient recognition of canonical emotions (happiness, sadness, anger and fear) from music as well as faces and voices compared with healthy control subjects. Impaired recognition of emotions from music was specifically associated with grey matter loss in a distributed cerebral network including insula, orbitofrontal cortex, anterior cingulate and medial prefrontal cortex, anterior temporal and more posterior temporal and parietal cortices, amygdala and the subcortical mesolimbic system. This network constitutes an essential brain substrate for recognition of musical emotion that overlaps with brain regions previously implicated in coding emotional value, behavioural context, conceptual knowledge and theory of mind. Musical emotion recognition may probe the interface of these processes, delineating a profile of brain damage that is essential for the abstraction of complex social emotions.
McKeith, Ian G; Burn, David J; Ballard, Clive G; Collerton, Daniel; Jaros, Evelyn; Morris, Chris M; McLaren, Andrew; Perry, Elaine K; Perry, Robert; Piggott, Margaret A; O'Brien, John T
The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more
Sampathu, Deepak M; Neumann, Manuela; Kwong, Linda K; Chou, Thomas T; Micsenyi, Matthew; Truax, Adam; Bruce, Jennifer; Grossman, Murray; Trojanowski, John Q; Lee, Virginia M-Y
Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is a common neuropathological subtype of frontotemporal dementia. Although this subtype of frontotemporal dementia is defined by the presence of ubiquitin-positive but tau- and alpha-synuclein-negative inclusions, it is unclear whether all cases of FTLD-U have the same underlying pathogenesis. Examination of tissue sections from FTLD-U brains stained with anti-ubiquitin antibodies revealed heterogeneity in the morphological characteristics of pathological inclusions among subsets of cases. Three types of FTLD-U were delineated based on morphology and distribution of ubiquitin-positive inclusions. To address the hypothesis that FTLD-U is pathologically heterogeneous, novel monoclonal antibodies (mAbs) were generated by immunization of mice with high molecular mass (Mr > 250 kd) insoluble material prepared by biochemical fractionation of FTLD-U brains. Novel mAbs were identified that immunolabeled all of the ubiquitin-positive inclusions in one subset of FTLD-U cases, whereas other mAbs stained the ubiquitin-positive inclusions in a second subset of cases. These novel mAbs did not stain inclusions in other neurodegenerative disorders, including tauopathies and alpha-synucleinopathies. Therefore, ubiquitin immunohistochemistry and the immunostaining properties of the novel mAbs generated here suggest that FTLD-U is pathologically heterogeneous. Identification of the disease proteins recognized by these mAbs will further advance understanding of molecular substrates of FTLD-U neurodegenerative pathways.
Hoefer, M.; Allison, S. C.; Schauer, G. F.; Neuhaus, J. M.; Hall, J.; Dang, J. N.; Weiner, M. W.; Miller, B. L.; Rosen, H. J.
Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia.We studied FC in controls (n = 25), Alzheimer's disease (n =25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological–anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit.VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms. PMID:18492729
Hoefer, M; Allison, S C; Schauer, G F; Neuhaus, J M; Hall, J; Dang, J N; Weiner, M W; Miller, B L; Rosen, H J
Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia. We studied FC in controls (n = 25), Alzheimer's disease (n = 25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1 s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological-anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit. VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms.
Modrego, P J; Mojonero, J; Serrano, M; Fayed, N
Fahr's syndrome involves calcification of basal ganglia and dentate nuclei of the cerebellum. Clinically it may present with an array of movement disorders, dementia and other behavioural disturbances. Sporadic and familial cases have been reported with or without calcium/phosphorus metabolism. A rare form of frontotemporal dementia with neurofibrillary tangles and Fahr-type calcifications (DNTC) has been observed mainly in Japan. We report the singular case of a 50-year-old woman with progressive dementia but neither extrapyramidal symptoms nor a metabolic disorder. Brain CT showed Fahr-type calcifications in the basal ganglia, cerebellum and centrum semiovale as well as temporal atrophy; MRI showed diffuse atrophy predominantly in parietotemporal regions. The clinical and radiological features of our patient point to this uncommon form of dementia.
Novel diagnostic methods, such as cerebrospinal fluid-based neurochemical dementia diagnostics (CSF-NDD) and [18F] amyloid positron emission tomography (PET) are meanwhile recommended for specific indications by international guidelines for the improved early and differential diagnostics of multigenic (sporadic) Alzheimer's dementia (AD). In the case of CSF-NDD the German neuropsychiatric guidelines have already been validated on the S3 level of evidence (http://www.DGPPN.de) and the additional consideration of [18F] amyloid-PET in the current update of the guidelines is to be expected. By means of CSF-NDD and/or [18F] amyloid-PET a predictive diagnosis of incipient (preclinical) AD is also possible for patients at high risk for AD who are in prodromal stages, such as mild cognitive impairment (MCI). As accompanying (secondary) preventive therapy of AD cannot be offered a predictive molecular dementia diagnostics is not recommended by the German neuropsychiatric dementia guidelines (http://www.DGPPN.de). However, novel diagnostic approaches, which offer molecular positive diagnostics of AD have already gained high relevance in therapy research as they allow promising preventive treatment avenues to be validated directly in the clinical trial. Moreover, future blood-based dementia diagnostics by means of multiplex assays is becoming increasingly more feasible; however, so far corresponding proteomic or epigenetic assays could not be consistently validated in independent studies.
Fletcher, Phillip D; Downey, Laura E; Witoonpanich, Pirada; Warren, Jason D
Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM) on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia, and 25 did not exhibit the phenomenon. The syndrome of semantic dementia was relatively over-represented among the musicophilic subgroup. A VBM analysis revealed significantly increased regional gray matter volume in left posterior hippocampus in the musicophilic subgroup relative to the non-musicophilic group (p < 0.05 corrected for regional comparisons); at a relaxed significance threshold (p < 0.001 uncorrected across the brain volume) musicophilia was associated with additional relative sparing of regional gray matter in other temporal lobe and prefrontal areas and atrophy of gray matter in posterior parietal and orbitofrontal areas. The present findings suggest a candidate brain substrate for musicophilia as a signature of distributed network damage that may reflect a shift of hedonic processing toward more abstract (non-social) stimuli, with some specificity for particular neurodegenerative pathologies.
Fletcher, Phillip D.; Downey, Laura E.; Witoonpanich, Pirada; Warren, Jason D.
Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM) on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia, and 25 did not exhibit the phenomenon. The syndrome of semantic dementia was relatively over-represented among the musicophilic subgroup. A VBM analysis revealed significantly increased regional gray matter volume in left posterior hippocampus in the musicophilic subgroup relative to the non-musicophilic group (p < 0.05 corrected for regional comparisons); at a relaxed significance threshold (p < 0.001 uncorrected across the brain volume) musicophilia was associated with additional relative sparing of regional gray matter in other temporal lobe and prefrontal areas and atrophy of gray matter in posterior parietal and orbitofrontal areas. The present findings suggest a candidate brain substrate for musicophilia as a signature of distributed network damage that may reflect a shift of hedonic processing toward more abstract (non-social) stimuli, with some specificity for particular neurodegenerative pathologies. PMID:23801975
Flaherty, Alice W.
This paper presents a three-factor anatomical model of human idea generation and creative drive, focusing on interactions between the temporal lobes, frontal lobes, and limbic system. Evidence is drawn from functional imaging, drug studies, and lesion analysis. Temporal lobe changes, as in hypergraphia, often increase idea generation, sometimes at the expense of quality. Frontal lobe deficits may decrease idea generation, in part because of rigid judgments about an idea's worth. These phenomena are clearest in verbal creativity, and roughly parallel the pressured communication of temporal lobe epilepsy, mania, and Wernicke's aphasia--compared to the sparse speech and cognitive inflexibility of depression, Broca's aphasia, and other frontal lobe lesions. The phenomena also shape non-linguistic creativity, as in that of frontotemporal dementia. The appropriate balance between frontal and temporal activity is mediated by mutually inhibitory corticocortical interactions. Mesolimbic dopamine influences novelty seeking and creative drive. Dopamine agonists and antagonists have opposite effects on goal-directed behavior and hallucinations. Creative drive is not identical to skill—the latter depends more on neocortical association areas. However, drive correlates better with successful creative output than skill does. Traditional neuroscientific models of creativity, such as the left brain – right brain hemispheric model, emphasize skills primarily, and stress art and musical skill at the expense of language and mathematics. The three-factor model proposed here predicts findings in a broad range of normal and pathological states, and can be tested in many experimental paradigms. PMID:16254989
... with Lewy bodies , What Is Alzheimer's? NIA-Funded Memory & Aging Project Reveals Mixed Dementia Common Data from ... commonly with Alzheimer's disease. For example, in the Memory and Aging Project study involving long-term cognitive ...
... to dementia. Risk factors for VaD include: Diabetes Hardening of the arteries ( atherosclerosis ) High blood pressure ( hypertension ) ... Control conditions that increase the risk of hardening of the ... saturated fats and salt in the diet Treating related disorders
Golden, Hannah L; Clark, Camilla N; Nicholas, Jennifer M; Cohen, Miriam H; Slattery, Catherine F; Paterson, Ross W; Foulkes, Alexander J M; Schott, Jonathan M; Mummery, Catherine J; Crutch, Sebastian J; Warren, Jason D
Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimer's disease (AD, n = 16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n = 5), and progressive nonfluent aphasia (PNFA; n = 9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. Taking working memory performance into account, no specific deficits of musical temporal processing, timbre processing, musical scene analysis, or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation.
Nicholas, Jennifer M; Cohen, Miriam H; Slattery, Catherine F; Paterson, Ross W; Foulkes, Alexander J M; Schott, Jonathan M; Mummery, Catherine J; Crutch, Sebastian J; Warren, Jason D
Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimer’s disease (AD, n=16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n=5) and progressive nonfluent aphasia (PNFA; n=9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. No specific deficits of musical temporal processing, timbre processing, musical scene analysis or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation. PMID:27802226
Boutoleau-Bretonnière, Claire; Lebouvier, Thibaud; Delaroche, Odile; Lamy, Estelle; Evrard, Christelle; Charriau, Tiphaine; Bretonnière, Cédric; Damier, Philippe; Derkinderen, Pascal; Vercelletto, Martine
The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO-SPECT, and CSF levels of amyloid-β peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tau were best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis.
Ferman, Tanis J.; Boeve, Bradley F.
Synopsis The advent of new immunostains have improved our ability to detect limbic and cortical Lewy bodies, and it is now evident that Dementa with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer’s disease (AD). Distinguishing DLB from AD has important implications for treatment, in terms of substances that may worsen symptoms (i.e., anticholinergic and certain neuroleptic medications) and those that may improve them (i.e., cholinesterase inhibitors, carbidopa-levodopa). Neurocognitive patterns, psychiatric features, extrapyramidal signs and sleep disturbance are helpful in differentiating DLB from AD early in the disease course. Differences in the severity of cholinergic depletion as well as type and distribution of neuropathology contribute to these clinical differences, though DLB patients with a high density of co-occuring AD pathology are less clinical distinguishable from AD. PMID:17659188
Massano, João; Leão, Miguel; Garrett, Carolina
In the past few years several gene mutations have been identified as causative of the most frequent neurodegenerative dementias (Alzheimer disease and frontotemporal dementia). These advances, along with the complex phenotype-genotype relationships and the costs associated with genetic testing, have often made it difficult for clinicians to decide with regard to a rational plan for the investigation of the genetic etiology of the degenerative dementias. The Centro Hospitalar São João Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic etiology of Alzheimer disease and frontotemporal dementia in clinical practice, based on international consensus documents (currently containing partly outdated information) and published scientific evidence on this topic. Alzheimer disease may be caused by mutations in PSEN1, PSEN2 and APP. APOE genotyping is not recommended for the diagnostic or genetic counseling purposes in Alzheimer disease. Frontotemporal dementia may be caused by mutations in several genes such as c9orf72, PGRN, MAPT, TBK1, VCP, SQSTM1, and UBQLN2. This paper pragmatically approaches the process of genetic diagnosis in Alzheimer disease and frontotemporal dementia, with specific recommendations for both disorders.
Fachner, Jörg; Gold, Christian; Erkkilä, Jaakko
Fronto-temporal areas process shared elements of speech and music. Improvisational psychodynamic music therapy (MT) utilizes verbal and musical reflection on emotions and images arising from clinical improvisation. Music listening is shifting frontal alpha asymmetries (FAA) in depression, and increases frontal midline theta (FMT). In a two-armed randomized controlled trial (RCT) with 79 depressed clients (with comorbid anxiety), we compared standard care (SC) versus MT added to SC at intake and after 3 months. We found that MT significantly reduced depression and anxiety symptoms. The purpose of this study is to test whether or not MT has an impact on anterior fronto-temporal resting state alpha and theta oscillations. Correlations between anterior EEG, Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hospital Anxiety and Depression Scale-Anxiety Subscale (HADS-A), power spectral analysis (topography, means, asymmetry) and normative EEG database comparisons were explored. After 3 month of MT, lasting changes in resting EEG were observed, i.e., significant absolute power increases at left fronto-temporal alpha, but most distinct for theta (also at left fronto-central and right temporoparietal leads). MT differed to SC at F7-F8 (z scored FAA, p < .03) and T3-T4 (theta, p < .005) asymmetry scores, pointing towards decreased relative left-sided brain activity after MT; pre/post increased FMT and decreased HADS-A scores (r = .42, p < .05) indicate reduced anxiety after MT. Verbal reflection and improvising on emotions in MT may induce neural reorganization in fronto-temporal areas. Alpha and theta changes in fronto-temporal and temporoparietal areas indicate MT action and treatment effects on cortical activity in depression, suggesting an impact of MT on anxiety reduction.
de Jong, F.J.; Schrijvers, E.M.C.; Ikram, M.K.; Koudstaal, P.J.; de Jong, P.T.V.M.; Hofman, A.; Vingerling, J.R.
Background: Retinal vessels provide a unique opportunity to study both systemic and cerebrovascular disease. Smaller retinal arteriolar calibers are strongly related to hypertension, whereas larger retinal venular calibers are more related to inflammation, cerebral hypoperfusion, and cerebrovascular disease. Whether retinal vessel calibers are related to dementia remains unclear. Methods: We investigated whether retinal arteriolar and venular calibers are associated with risk of dementia, and its subtypes Alzheimer disease (AD) and vascular dementia, in the prospective population-based Rotterdam Study. Digitized retinal images were available in 5,553 participants aged 55 years or over and dementia-free at baseline (1990–1993). Participants were re-examined in 1993–1994, 1997–1999, and 2002–2004 and were continuously monitored for development of dementia. Results: During a mean follow-up of 11.6 years, 655 participants developed dementia. AD was diagnosed in 519 and vascular dementia in 73 participants. Larger venular calibers were associated with an increased risk of dementia, in particular vascular dementia (age- and sex-adjusted hazard ratio per SD increase: 1.31; 95% confidence interval 1.06–1.64), but not AD. The association remained significant after adjustment for stroke and cardiovascular risk factors. Smaller arteriolar calibers were also associated with an increased risk of vascular dementia, yet only when adjusted for venular calibers. Conclusions: Retinal venular widening is associated with an increased risk of vascular dementia. Our findings are in line with previous observations in stroke and cerebral small-vessel disease and suggest that the association between larger retinal venular calibers and dementia may reflect cerebral hypoperfusion and subsequent ischemia. PMID:21288987
Zee, Jarcy; Xie, Sharon X.; McMillan, Corey T.; Rascovsky, Katya; Irwin, David J.; Kolanowski, Ann; Grossman, Murray
Objective: To examine the influence of occupational attainment and education on survival in autopsy-confirmed cases of frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD). Methods: We performed a retrospective chart review of 83 demographically matched, autopsy-confirmed FTLD (n = 34) and AD (n = 49) cases. Each patient's primary occupation was classified and ranked. Level of education was recorded in years. Survival was defined as time from symptom onset until death. Linear regression was used to test for associations among occupational attainment, education, and patient survival. Results: Median survival was 81 months for FTLD and 95 months for AD. Years of education and occupational attainment were similar for both groups. We found that higher occupational attainment was associated with longer survival in FTLD but not AD. Conclusions: Our findings suggest that higher occupational attainment is associated with longer survival in autopsy-confirmed FTLD. The identification of protective factors associated with FTLD survival has important implications for estimates of prognosis and longitudinal studies such as treatment trials. PMID:25904687
Torrente, Fernando; Pose, Mariángeles; Gleichgerrcht, Ezequiel; Torralva, Teresa; López, Pablo; Cetkovich-Bakmas, Marcelo; Manes, Facundo
Previous studies about personality changes in dementia suggest that they may be due to the disruption of the biological basis of personality traits, and hence, that they are disease specific and universal. However, evidence about its specificity is still limited and scarce regarding culturally diverse populations. Accordingly, our aim was to compare personality changes in Argentinean patients with Alzheimer disease, behavioral variant of frontotemporal dementia, and primary progressive aphasia. The closest living relatives of patients diagnosed with Alzheimer disease (n=19), behavioral variant of frontotemporal dementia (n=16), and primary progressive aphasia (n=15) were asked to complete 2 versions of the personality inventory NEO Personality Inventory-Revised, one for assessing patients' premorbid personality traits, and the other for assessing current traits. All groups showed changes in several domains and facets of the NEO Personality Inventory-Revised. Globally, the observed pattern of changes was fairly consistent with previous studies based on the same model of personality. Nevertheless, our results regarding disease-specificity were less conclusive. Even if there were some indicators of specific differences between groups, most traits varied similarly across the 3 groups, revealing a pattern of generalized changes in personality expression after illness onset. More studies are needed that help to distinguish real personality changes from other affective or cognitive symptoms that accompany dementia, as well as further data from culturally diverse populations.
Pastor, Pau; Moreno, Fermín; Clarimón, Jordi; Ruiz, Agustín; Combarros, Onofre; Calero, Miguel; López de Munain, Adolfo; Bullido, Maria J; de Pancorbo, Marian M; Carro, Eva; Antonell, Anna; Coto, Eliecer; Ortega-Cubero, Sara; Hernandez, Isabel; Tárraga, Lluís; Boada, Mercè; Lleó, Alberto; Dols-Icardo, Oriol; Kulisevsky, Jaime; Vázquez-Higuera, José Luis; Infante, Jon; Rábano, Alberto; Fernández-Blázquez, Miguel Ángel; Valentí, Meritxell; Indakoetxea, Begoña; Barandiarán, Myriam; Gorostidi, Ana; Frank-García, Ana; Sastre, Isabel; Lorenzo, Elena; Pastor, María A; Elcoroaristizabal, Xabier; Lennarz, Martina; Maier, Wolfang; Rámirez, Alfredo; Serrano-Ríos, Manuel; Lee, Suzee E; Sánchez-Juan, Pascual
The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.
Skillbäck, Tobias; Farahmand, Bahman Y; Rosén, Christoffer; Mattsson, Niklas; Nägga, Katarina; Kilander, Lena; Religa, Dorota; Wimo, Anders; Winblad, Bengt; Schott, Jonathan M; Blennow, Kaj; Eriksdotter, Maria; Zetterberg, Henrik
Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-β1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-β1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-β1-42 and amyloid-β1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-β1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-β1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with
Eskelinen, Marjo H; Kivipelto, Miia
Caffeine has well-known short-term stimulating effects on central nervous system, but the long-term impacts on cognition have been less clear. Dementia and Alzheimer's disease (AD) are rapidly increasing public health problems in ageing populations and at the moment curative treatment is lacking. Thus, the putative protective effects of caffeine against dementia/AD are of great interest. Here, we discuss findings from the longitudinal epidemiological studies about caffeine/coffee/tea and dementia/AD/cognitive functioning with a special emphasis on our recent results from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. The findings of the previous studies are somewhat inconsistent, but most studies (3 out of 5) support coffee's favorable effects against cognitive decline, dementia or AD. In addition, two studies had combined coffee and tea drinking and indicated some positive effects on cognitive functioning. For tea drinking, protective effects against cognitive decline/dementia are still less evident. In the CAIDE study, coffee drinking of 3-5 cups per day at midlife was associated with a decreased risk of dementia/AD by about 65% at late-life. In conclusion, coffee drinking may be associated with a decreased risk of dementia/AD. This may be mediated by caffeine and/or other mechanisms like antioxidant capacity and increased insulin sensitivity. This finding might open possibilities for prevention or postponing the onset of dementia/AD.
Downey, Laura E; Mahoney, Colin J; Buckley, Aisling H; Golden, Hannah L; Henley, Susie M; Schmitz, Nicole; Schott, Jonathan M; Simpson, Ivor J; Ourselin, Sebastien; Fox, Nick C; Crutch, Sebastian J; Warren, Jason D
Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration. However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined. Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29) and semantic variant primary progressive aphasia (svPPA; n = 15), relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification. Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry. The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere. The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification). DTI associations of impaired social cognition were more consistent than corresponding grey matter associations. These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes. The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.
Downey, Laura E.; Mahoney, Colin J.; Buckley, Aisling H.; Golden, Hannah L.; Henley, Susie M.; Schmitz, Nicole; Schott, Jonathan M.; Simpson, Ivor J.; Ourselin, Sebastien; Fox, Nick C.; Crutch, Sebastian J.; Warren, Jason D.
Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration. However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined. Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29) and semantic variant primary progressive aphasia (svPPA; n = 15), relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification. Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry. The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere. The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification). DTI associations of impaired social cognition were more consistent than corresponding grey matter associations. These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes. The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries. PMID:26236629
Christodoulou, Georgia; Gennings, Chris; Hupf, Jonathan; Factor-Litvak, Pam; Murphy, Jennifer; Goetz, Raymond R; Mitsumoto, Hiroshi
Our objective was to establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the telephone. Thirty-one subjects were administered either in-person or by telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Equivalence testing was performed for in-person and telephone based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level compared to a revised phone version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study-Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level, respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS-Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). In conclusion, our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone based cognitive testing for ALS could become an integral resource for population based research in the future.
... What to Ask: Dementia Tools and Tips The memory loss and other changes seen in dementia can ... can ask your healthcare proffesional about dementia. Is memory loss a normal part of aging? If so, ...
Yokota, Osamu; Tsuchiya, Kuniaki; Arai, Tetsuaki; Yagishita, Saburo; Matsubara, Osamu; Mochizuki, Akihide; Tamaoka, Akira; Kawamura, Mitsuru; Yoshida, Hidetoshi; Terada, Seishi; Ishizu, Hideki; Kuroda, Shigetoshi; Akiyama, Haruhiko
Although frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions (FTLD-TDP) and Pick's disease are common pathological substrates in sporadic FTLD, clinical differentiation of these diseases is difficult. We performed a retrospective review of medical records and semiquantitative examination of neuronal loss of 20 sporadic FTLD-TDP and 19 Pick's disease cases. Semantic dementia as the first syndrome developed only in FTLD-TDP patients. Impaired speech output in the early stage was five times more frequent in Pick's disease than in FTLD-TDP. The total frequency of asymmetric motor disturbances (e.g., parkinsonism, pyramidal signs, and contracture) during the course was significantly more frequent in FTLD-TDP (78%) than in Pick's disease cases (14%). Asymmetric pyramidal signs were found in 7 of 13 FTLD-TDP cases with corticospinal tract degeneration similar to primary lateral sclerosis. Frontotemporal dementia as the first syndrome was noted in both FTLD-TDP (28%) and Pick's disease cases (64%); however, only FTLD-TDP cases subsequently developed asymmetric motor disturbances, and some of the cases further exhibited hemineglect. Concordant with these clinical findings, degeneration in the temporal cortex, caudate nucleus, putamen, globus pallidus, substantia nigra, and corticospinal tract was significantly more severe in FTLD-TDP, and degeneration in the frontal cortex tended to be more severe in Pick's disease. Given these findings, the initial impairment of semantic memory or comprehension and subsequent asymmetric motor disturbances in sporadic FTLD patients predict sporadic FTLD-TDP rather than Pick's disease, while initial behavioral symptoms or non-fluent aphasia without subsequent asymmetric motor disturbances predict Pick's disease rather than sporadic FTLD-TDP.
Femia, Elia E.; Zarit, Steven H.; Stephens, Mary Ann Parris; Greene, Rick
Purpose: This study explored whether adult day service (ADS) use was associated with reductions in behavioral and psychological symptoms of dementia (BPSD) in individuals with dementia. Design and Methods: We used a quasi-experimental design to compare a group of 133 persons with dementia (PWDs) who initially enrolled in an ADS program to a…
Liu, Jia; Wang, Lu-Ning; Tian, Jin-Zhou
A search of previous records in the literatures was done to summarize the opinions for dementia in ancient China. The earliest description of dementia was traced in the Yellow emperor's internal classic, a book written 2000 years ago. Hua Tuo (AD 140-208) in Han Dynasty first denominated "dementia" in the book, Hua Tuo Shen Yi Mi Zhuan. The pathogenesis of dementia could be generalized as the insufficiency of Qi, a flowing energy; the stagnation of phlegm, a harmful liquid substance in the body; and the blood stasis, which were also regarded as therapeutic targets. Therefore, we can conclude that dementia has been recognized and investigated in traditional Chinese medicine, which is definitely before the industrial civilization era.
Perani, Daniela; Della Rosa, Pasquale Anthony; Cerami, Chiara; Gallivanone, Francesca; Fallanca, Federico; Vanoli, Emilia Giovanna; Panzacchi, Andrea; Nobili, Flavio; Pappatà, Sabina; Marcone, Alessandra; Garibotto, Valentina; Castiglioni, Isabella; Magnani, Giuseppe; Cappa, Stefano F.; Gianolli, Luigi
Diagnostic accuracy in FDG-PET imaging highly depends on the operating procedures. In this clinical study on dementia, we compared the diagnostic accuracy at a single-subject level of a) Clinical Scenarios, b) Standard FDG Images and c) Statistical Parametrical (SPM) Maps generated via a new optimized SPM procedure. We evaluated the added value of FDG-PET, either Standard FDG Images or SPM Maps, to Clinical Scenarios. In 88 patients with neurodegenerative diseases (Alzheimer's Disease—AD, Frontotemporal Lobar Degeneration—FTLD, Dementia with Lewy bodies—DLB and Mild Cognitive Impairment—MCI), 9 neuroimaging experts made a forced diagnostic decision on the basis of the evaluation of the three types of information. There was also the possibility of a decision of normality on the FDG-PET images. The clinical diagnosis confirmed at a long-term follow-up was used as the gold standard. SPM Maps showed higher sensitivity and specificity (96% and 84%), and better diagnostic positive (6.8) and negative (0.05) likelihood ratios compared to Clinical Scenarios and Standard FDG Images. SPM Maps increased diagnostic accuracy for differential diagnosis (AD vs. FTD; beta 1.414, p = 0.019). The AUC of the ROC curve was 0.67 for SPM Maps, 0.57 for Clinical Scenarios and 0.50 for Standard FDG Images. In the MCI group, SPM Maps showed the highest predictive prognostic value (mean LOC = 2.46), by identifying either normal brain metabolism (exclusionary role) or hypometabolic patterns typical of different neurodegenerative conditions. PMID:25389519
Vascular dementia (VaD)--secondary to cerebrovascular disease (CVD)--has been traditionally distinguished from Alzheimer's disease (AD), which is a purely neurodegenerative form of dementia. However, CVDs such as lacunes and white matter lesions are common in patients with AD, whereas certain pathological changes of AD, including senile plaques and tangles, are observed in elderly patients with VaD. These findings indicate that mixed vascular-degenerative dementia (MD) is the most common cause of dementia in the elderly. In the treatment and prevention of dementia, the accurate diagnosis of each individual type of dementia is vital. However, recognizing the distinction between these diseases can be difficult in clinical practice. This article provides an overview of MD, including the incidence, diagnosis, and treatment. In particular, we emphasize that functional brain imaging, including perfusion single photon emission computed tomography and benzodiazepine receptor binding measurement, in combination with morphological imaging (such as magnetic resonance imaging) is useful for distinguishing AD, VaD and MD. In addition to antiplatelet medications, cholinesterase inhibitors and N-methyl-D-aspartic acid antagonists may be effective in treating MD. Moreover the vascular risk factors also should be treated appropriately. The article describes the need for further studies to develop a better understanding of MD.
Wiesmann, Maximilian; Kiliaan, Amanda J; Claassen, Jurgen AHR
Hypertension and stroke are highly prevalent risk factors for cognitive impairment and dementia. Alzheimer's disease (AD) and vascular dementia (VaD) are the most common forms of dementia, and both conditions are preceded by a stage of cognitive impairment. Stroke is a major risk factor for the development of vascular cognitive impairment (VCI) and VaD; however, stroke may also predispose to AD. Hypertension is a major risk factor for stroke, thus linking hypertension to VCI and VaD, but hypertension is also an important risk factor for AD. Reducing these two major, but modifiable, risk factors—hypertension and stroke—could be a successful strategy for reducing the public health burden of cognitive impairment and dementia. Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-FA) and the manipulation of factors involved in the renin–angiotensin system (e.g. angiotensin II or angiotensin-converting enzyme) have been shown to reduce the risk of developing hypertension and stroke, thereby reducing dementia risk. This paper will review the research conducted on the relationship between hypertension, stroke, and dementia and also on the impact of LC-n3-FA or antihypertensive treatments on risk factors for VCI, VaD, and AD. PMID:24022624
Su, L; Blamire, A M; Watson, R; He, J; Hayes, L; O'Brien, J T
Magnetic resonance spectroscopy has demonstrated metabolite changes in neurodegenerative disorders such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB); however, their pattern and relationship to clinical symptoms is unclear. To determine whether the spatial patterns of brain-metabolite changes in AD and DLB are regional or diffused, and to examine whether the key metabolite levels are associated with cognitive and non-cognitive symptoms, we acquired whole-brain spatially resolved 3T magnetic resonance spectroscopic imaging (MRSI) data from subjects with AD (N=36), DLB (N=35) and similarly aged controls (N=35). Voxel-wise measurement of N-acetylaspartate to creatine (NAA/Cr), choline to Cr (Cho/Cr), myo-inositol to Cr (mI/Cr) as well as glutamate and glutamine to Cr (Glx/Cr) ratios were determined using MRSI. Compared with controls, AD and DLB groups showed a significant decrease in most brain metabolites, with NAA/Cr, Cho/Cr and mI/Cr levels being reduced in posterior cingulate, thalamus, frontotemporal areas and basal ganglia. The Glx/Cr level was more widely decreased in DLB (posterior cingulate, hippocampus, temporal regions and caudate) than in AD (only in posterior cingulate). DLB was also associated with increased levels of Cho/Cr, NAA/Cr and mI/Cr in occipital regions. Changes in metabolism in the brain were correlated with cognitive and non-cognitive symptoms in the DLB but not in the AD group. The different patterns between AD and DLB may have implications for improving diagnosis, better understanding disease-specific neurobiology and targeting therapeutics. In addition, the study raised important questions about the role of occipital neuroinflammation and glial activation as well as the glutamatergic treatment in DLB. PMID:27576166
Rossor, M N; Revesz, T; Lantos, P L; Warrington, E K
Three cases are reported with dementia and ubiquitin-positive but tau-negative inclusion bodies. All patients had a semantic dementia and the clinical details of two of these have been published as the first description of a selective semantic memory impairment. The original diagnosis had been of Pick's disease based on frontotemporal atrophy, but re-examination has revealed ubiquitin-positive but tau-negative inclusions as well as neurites in the frontotemporal cortices and ubiquitin-positive, intracytoplasmic inclusions in the granule cells of the dentate fascia. These inclusions are identical to those reported in association with amyotrophic lateral sclerosis (motor neuron disease), but none were seen in brainstem or spinal cord motor neurons.
Karantzoulis, Stella; Galvin, James E
Alzheimer's disease (AD) is the most common and most studied cause of dementia. Significant advances have been made since the first set of clinical criteria for AD were put forth in 1984 that are now captured in the new criteria for AD published in 2011. Key features include recognition of a broad AD spectrum (from preclinical to mild cognitive impairment to AD dementia) and requirement of AD biomarkers for diagnosis. Correctly diagnosing dementia type is increasingly important in an era when potential disease-modifying agents are soon to be marketed. The typical AD dementia syndrome has at its core, an amnestic syndrome of the hippocampal type, followed by associated deficits in word-finding, spatial cognition, executive functions and neuropsychiatric changes. Atypical presentations of AD have also been identified that are presumed to have a different disease course. It can be difficult to distinguish between the various dementia syndromes given the overlap in many common clinical features across the dementias. The clinical difficulty in diagnosis may reflect the underlying pathology, as AD often co-occurs with other pathologies at autopsy, such as cerebrovascular disease or Lewy bodies. Neuropsychological evaluation has provided clinicians and researchers with profiles of cognitive strengths and weaknesses that help to define the dementias. There is yet no single behavioral marker that can reliably discriminate AD from the other dementias. The combined investigation of cognitive and neurobehavioral symptoms coupled with imaging markers could provide a more accurate approach for differentiating between AD and other major dementia syndromes in the future. PMID:22014137
Rami, Lorena; Loy, Clement T.; Hailstone, Julia; Warren, Jason D.
Little information is available concerning olfactory processing in frontotemporal lobar degeneration (FTLD). We undertook a case-control study of olfactory processing in three male patients fulfilling clinical criteria for FTLD. Odour identification (semantic analysis) and odour discrimination (perceptual analysis) were investigated using tests adapted from the University of Pennsylvania Smell Identification Test. General neuropsychometry and structural volumetric brain magnetic resonance imaging (MRI) were also performed. The three patients with FTLD exhibited a disorder of olfactory processing with the characteristics of a predominantly semantic (odour identification) deficit. This olfactory deficit was more prominent in patients with greater involvement of the temporal lobes on MRI. Central deficits of odour identification may be more common in FTLD than previously recognised, and these deficits may assist in clinical characterisation. PMID:17380245
Fletcher, Phillip D.; Downey, Laura E.; Golden, Hannah L.; Clark, Camilla N.; Slattery, Catherine F.; Paterson, Ross W.; Rohrer, Jonathan D.; Schott, Jonathan M.; Rossor, Martin N.
Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52–84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer’s disease (n = 20, eight female, aged 53–74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients’ brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer’s disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer’s disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical
The Japanese government has tried to establish 150 Medical Centers for Dementia (MCDs) since 2008 to overcome the dementia medical service shortage. MCDs are required to provide special medical services for dementia and connect with other community resources in order to contribute to building a comprehensive support network for demented patients. The main specific needs are as follows: 1) special medical consultation; 2) differential diagnosis and early intervention; 3) medical treatment for the acute stage of BPSD; 4) corresponding to serious physical complications of dementia; 5) education for general physicians (GPs) and other community professionals. According to the population rate, two dementia medical centers were planned in Kumamoto Prefecture. However, it seemed to be too few to cover the vast Kumamoto area. Therefore, the local government and I proposed to the Japanese government that we build up networks that consist of one core MCD in our university hospital and several regional MCDs in local mental hospitals. The local government selected seven (nine at present) centers according to the area balance and condition of equipment. The Japanese government has recommended and funded such networks between core and regional centers since 2010. The main roles of the core centers are as follows: 1) early diagnosis such as Mild cognitive impairment, very mild Alzheimer's disease, Dementia with Lewy bodies, and Frontotemporal lobar degeneration using comprehensive neuropsychological batteries and neuroimagings, such as MRI and SPECT scans; 2) education for GPs; 3) training for young consultants. The core center opens case conferences at least every one or two months for all staff of regional centers to maintain the quality of all centers and give training opportunities for standardized international assessment scales. While the main roles of the regional centers are differential diagnosis, intervention for BPSD, and management of general medical problems using
Witoonpanich, Pirada; Crutch, Sebastian J.; Warren, Jason D.; Rossor, Martin N.
Semantic dementia is a unique clinicopathological syndrome in the frontotemporal lobar degeneration spectrum. It is characterized by progressive and relatively selective impairment of semantic memory, associated with asymmetric antero-inferior temporal lobe atrophy. Although the syndrome became widely recognized only in the 1980s, descriptions of cases with typical features of semantic dementia have been on record for over a century. Here, we draw attention to a well documented historical case of a patient with features that would have fulfilled current consensus criteria for semantic dementia, as reconstructed from the notes made by her neurologist, Macdonald Critchley, in 1938. This case raises a number of issues concerning the nosology of the semantic dementia syndrome and the potential value of archived case material. PMID:24818802
Buchanan, Jeffrey A; Christenson, Angela; Houlihan, Daniel; Ostrom, Carly
With the rapidly aging population, it is expected that increases in cases of dementia will double over the next 20 years. Currently, there is no cure for diseases such as Alzheimer's disease or frontotemporal dementia (FTD) that cause progressive dementia, and only a few pharmacological interventions that slow the progression of the decline exist. Given that there is no cure available, a rehabilitation approach that emphasizes maintaining existing abilities and removing excess disability (as opposed to emphasizing cure or recovery) for as long as possible is warranted. The current paper proposes that nonpharmacological rehabilitation efforts need to target 5 broad areas/targets: memory enhancement, altering social contingencies and communication styles, improving self-care skills, the arrangement of physical environments to maintain and improve functioning, and increasing physical fitness/physical activity. The purpose of this paper is to review specific behaviorally oriented interventions that target these 5 areas and show promise for inclusion in comprehensive rehabilitation efforts for individuals with dementia.
Johnson, Julene K; Chow, Maggie L
Music is a complex acoustic signal that relies on a number of different brain and cognitive processes to create the sensation of hearing. Changes in hearing function are generally not a major focus of concern for persons with a majority of neurodegenerative diseases associated with dementia, such as Alzheimer disease (AD). However, changes in the processing of sounds may be an early, and possibly preclinical, feature of AD and other neurodegenerative diseases. The aim of this chapter is to review the current state of knowledge concerning hearing and music perception in persons who have a dementia as a result of a neurodegenerative disease. The review focuses on both peripheral and central auditory processing in common neurodegenerative diseases, with a particular focus on the processing of music and other non-verbal sounds. The chapter also reviews music interventions used for persons with neurodegenerative diseases.
Johnson, Julene K; Chow, Maggie L
Music is a complex acoustic signal that relies on a number of different brain and cognitive processes to create the sensation of hearing. Changes in hearing function are generally not a major focus of concern for persons with a majority of neurodegenerative diseases associated with dementia, such as Alzheimer disease (AD). However, changes in the processing of sounds may be an early, and possibly preclinical, feature of AD and other neurodegenerative diseases. The aim of this chapter is to review the current state of knowledge concerning hearing and music perception in persons who have a dementia as a result of a neurodegenerative disease. The review focuses on both peripheral and central auditory processing in common neurodegenerative diseases, with a particular focus on the processing of music and other non-verbal sounds. The chapter also reviews music interventions used for persons with neurodegenerative diseases. PMID:25726296
Rosenthal, Michal; Berkman, Pinhas; Shapira, Adi; Gil, Israel; Abramovitz, Jancu
Urethral masturbation and sexual disinhibition as manifestations of behavioral and psychological symptoms of dementia (BPSD) are described in a 90-year-old patient who repeatedly self-inserted foreign bodies into his urethra. A diagnosis was made of late onset sexual disinhibition and hypersexuality in a patient with Dementia of the Alzheimer Type. Significant reduction of his sexual behavior was achieved with low doses of haloperidol. Similar symptoms are noted in Pick's disease, other fronto-temporal lesions, mania and following a seizure or treatment of Parkinson's disease, and have been described as Kluver-Busy-type. Clinicians should consider this diagnosis when investigating dysuria, cystitis, haematuria and urinary tract infections even in the very old.
Sayed, Nasreen; Culver, Carlee; Dams-O'Connor, Kristen; Hammond, Flora
Abstract Traumatic brain injury (TBI) in early to mid-life is associated with an increased risk of dementia in late life. It is unclear whether TBI results in acceleration of Alzheimer's disease (AD)-like pathology or has features of another dementing condition, such as chronic traumatic encephalopathy, which is associated with more-prominent mood, behavior, and motor disturbances than AD. Data from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set was obtained over a 5-year period. Categorical data were analyzed using Fisher's exact test. Continuous parametric data were analyzed using the Student's t-test. Nonparametric data were analyzed using Mann-Whitney's test. Overall, 877 individuals with dementia who had sustained TBI were identified in the NACC database. Only TBI with chronic deficit or dysfunction was associated with increased risk of dementia. Patients with dementia after TBI (n=62) were significantly more likely to experience depression, anxiety, irritability, and motor disorders than patients with probable AD. Autopsy data were available for 20 of the 62 TBI patients. Of the patients with TBI, 62% met National Institute of Aging-Reagan Institute “high likelihood” criteria for AD. We conclude that TBI with chronic deficit or dysfunction is associated with an increased odds ratio for dementia. Clinically, patients with dementia associated with TBI were more likely to have symptoms of depression, agitation, irritability, and motor dysfunction than patients with probable AD. These findings suggest that dementia in individuals with a history of TBI may be distinct from AD. PMID:23374007
Lu, Po H.; Mendez, Mario F.; Lee, Grace J.; Leow, Alex D.; Lee, Hyun-Woo; Shapira, Jill; Jimenez, Elvira; Boeve, Bradley B.; Caselli, Richard J.; Graff-Radford, Neill R.; Jack, Clifford R.; Kramer, Joel H.; Miller, Bruce L.; Bartzokis, George; Thompson, Paul M.; Knopman, David S.
Background/Aims The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups. Methods Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects. Results Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology. Conclusion The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex. PMID:23306166
... our e-newsletter! Aging & Health A to Z Dementia Diagnosis & Tests If you or someone you care ... To determine whether an older adult might have dementia, a healthcare professional will: Ask about the person’s ...
Kumfor, Fiona; Landin-Romero, Ramon; Devenney, Emma; Hutchings, Rosalind; Grasso, Roberto; Hodges, John R; Piguet, Olivier
with right temporal pole cortical thinning. While left and right semantic dementia show distinct profiles at presentation, both phenotypes develop deficits in emotion recognition and behaviour. These findings highlight the pervasive socio-emotional deficits in frontotemporal dementia, even in patients with an initial language presentation. These changes reflect right anterior temporal and orbitofrontal cortex degeneration, underscoring the role of these regions in social cognition and behaviour.
Nozaki, Shoko; Yoshimura, Kimio; Mimura, Masaru
In this review, we present an overview of clinical studies that addressed the relationship between depression and dementia or cognitive decline. Cross-sectional studies and meta-analyses have repeatedly shown an association between late-life depression (LLD) and dementia, particularly Alzheimer's disease (AD) and vascular dementia; however, the findings of cohort studies have been inconsistent. Furthermore, studies on the association between depression with a younger age of onset and dementia have yielded inconsistent results. Regarding cognitive decline associated with LLD, several studies have reported an association between LLD and mild cognitive impairment, suggesting that depression itself can cause persistent cognitive impairment. Other studies have compared the cognitive profile between LLD and depression with a younger age of onset, but their results have been inconclusive, especially regarding the association between memory impairment and the age of onset of depression. LLD is associated with vascular change and white matter degeneration of the brain, as shown by magnetic resonance imaging (MRI). Recently, several studies reported an association between gray matter change and LLD. Studies currently in progress employ functional brain imaging methods such as single-photon emission computed tomography, functional MRI, and positron emission tomography. Clinically, it is important to understand how subtypes of depression can be defined in terms of risk of developing dementia, and to devise effective treatments. One paper explored the possibility of detecting depression associated with AD by measuring the blood Aβ40/Aβ42 levels, and other studies have suggested that symptoms of apathy and loss of interest are associated with conversion of depression to AD. Unfortunately, current antidepressants may have limited efficacy on depression with dementia; therefore, further investigation for devising methods of predicting conversion of depression to dementia and
Goldman, Jill S
The discovery of new autosomal dominant and susceptibility genes for Alzheimer's disease (AD) and frontotemporal degeneration (FTD) is revealing important new information about the neurodegenerative process and the risk for acquiring these diseases. It is becoming increasingly clear that both the mechanisms that drive these diseases and their phenotypes overlap. New technologies will assist access to genetic testing but may increase difficulty with genetic test interpretation. Thus, the process of genetic counseling and testing for these diseases is becoming more complex. This article will review current knowledge on the genetics of AD and FTD and suggest clinical guidelines for helping families to navigate through these complexities. The implications of future discoveries will be offered.
Christodoulou, Georgia; Gennings, Chris; Hupf, Jonathan; Factor-Litvak, Pam; Murphy, Jennifer; Goetz, Raymond R.; Mitsumoto, Hiroshi
Objective To establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the phone. Methods Thirty-one subjects were administered either in-person or telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Results Equivalence testing was performed for in-person and telephone-based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level when compared to a revised phone-version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study-Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS-Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). Conclusions Our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone-based cognitive testing for ALS could become an integral resource for population-based research in the future. PMID:27121545
Piscopo, Paola; Albani, Diego; Castellano, Anna E.; Forloni, Gianluigi; Confaloni, Annamaria
Frontotemporal lobar degeneration (FTLD) includes a spectrum of disorders characterized by changes of personality and social behavior and, often, a gradual and progressive language dysfunction. In the last years, several efforts have been fulfilled in identifying both genetic mutations and pathological proteins associated with FTLD. The molecular bases undergoing the onset and progression of the disease remain still unknown. Recent literature prompts an involvement of RNA metabolism in FTLD, particularly microRNAs (miRNAs). Dysregulation of miRNAs in several disorders, including neurodegenerative diseases, and increasing importance of circulating miRNAs in different pathologies has suggested to implement the study of their possible application as biological markers and new therapeutic targets; moreover, miRNA-based therapy is becoming a powerful tool to deepen the function of a gene, the mechanism of a disease, and validate therapeutic targets. Regarding FTLD, different studies showed that miRNAs are playing an important role. For example, several reports have evaluated miRNA regulation of the progranulin gene suggesting that it is under their control, as described for miR-29b, miR-107, and miR-659. More recently, it has been demonstrated that TMEM106B gene, which protein is elevated in FTLD-TDP brains, is repressed by miR-132/212 cluster; this post-transcriptional mechanism increases intracellular levels of progranulin, affecting its pathways. These findings if confirmed could suggest that these microRNAs have a role as potential targets for some related-FTLD genes. In this review, we focus on the emerging roles of the miRNAs in the pathogenesis of FTLD. PMID:26903860
Growing epidemiologic evidence has suggested that people with diabetes mellitus are at an increased risk for the development of dementia. However, the results for the subtypes of dementia are inconsistent. This review examines the risk of dementia in people with diabetes mellitus, and discusses the possible mechanism underpinning this association. Diabetes mellitus is associated with a 1.5- to 2.5-fold greater risk of dementia among community-dwelling elderly people. Notably, diabetes mellitus is a significant risk factor for not only vascular dementia, but also Alzheimer's disease. The mechanisms underpinning the association are unclear, but it may be multifactorial in nature, involving factors such as cardiovascular risk factors, glucose toxicity, changes in insulin metabolism and inflammation. The optimal management of these risk factors in early life may be important to prevent late-life dementia. Furthermore, novel therapeutic strategies will be needed to prevent or reduce the development of dementia in people with diabetes mellitus.
Kun-Rodrigues, Celia; Ross, Owen A; Orme, Tatiana; Shepherd, Claire; Parkkinen, Laura; Darwent, Lee; Hernandez, Dena; Ansorge, Olaf; Clark, Lorraine N; Honig, Lawrence S; Marder, Karen; Lemstra, Afina; Scheltens, Philippe; van der Flier, Wiesje; Louwersheimer, Eva; Holstege, Henne; Rogaeva, Ekaterina; St George-Hyslop, Peter; Londos, Elisabet; Zetterberg, Henrik; Barber, Imelda; Braae, Anne; Brown, Kristelle; Morgan, Kevin; Maetzler, Walter; Berg, Daniela; Troakes, Claire; Al-Sarraj, Safa; Lashley, Tammaryn; Holton, Janice; Compta, Yaroslau; Van Deerlin, Vivianna; Trojanowski, John Q; Serrano, Geidy E; Beach, Thomas G; Clarimon, Jordi; Lleó, Alberto; Morenas-Rodríguez, Estrella; Lesage, Suzanne; Galasko, Douglas; Masliah, Eliezer; Santana, Isabel; Diez, Monica; Pastor, Pau; Tienari, Pentti J; Myllykangas, Liisa; Oinas, Minna; Revesz, Tamas; Lees, Andrew; Boeve, Brad F; Petersen, Ronald C; Ferman, Tanis J; Escott-Price, Valentina; Graff-Radford, Neill; Cairns, Nigel J; Morris, John C; Stone, David J; Pickering-Brown, Stuart; Mann, David; Dickson, Dennis W; Halliday, Glenda M; Singleton, Andrew; Guerreiro, Rita; Bras, Jose
C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.
Kirkwood, Caitlin M; MacDonald, Matthew L; Schempf, Tadhg A; Vatsavayi, Anil V; Ikonomovic, Milos D; Koppel, Jeremy L; Ding, Ying; Sun, Mai; Kofler, Julia K; Lopez, Oscar L; Yates, Nathan A; Sweet, Robert A
Recent studies have implicated the neuronal calcium-sensing protein visinin-like 1 protein (Vilip-1) as a peripheral biomarker in Alzheimer disease (AD), but little is known about expression of Vilip-1 in the brains of patients with AD. We used targeted and quantitative mass spectrometry to measure Vilip-1 peptide levels in the entorhinal cortex (ERC) and the superior frontal gyrus (SF) from cases with early to moderate stage AD, frontotemporal lobar degeneration (FTLD), and cognitively and neuropathologically normal elderly controls. We found that Vilip-1 levels were significantly lower in the ERC, but not in SF, of AD subjects compared to normal controls. In FTLD cases, Vilip-1 levels in the SF were significantly lower than in normal controls. These findings suggest a unique role for cerebrospinal fluid Vilip-1 as a biomarker of ERC neuron loss in AD.
Kawakami, Ito; Kobayashi, Zen; Arai, Tetsuaki; Yokota, Osamu; Nonaka, Takashi; Aoki, Naoya; Niizato, Kazuhiro; Oshima, Kenichi; Higashi, Shinji; Katsuse, Omi; Hosokawa, Masato; Hasegawa, Masato; Akiyama, Haruhiko
Choreoathetoid involuntary movements are rarely reported in patients with frontotemporal lobar degeneration (FTLD), suggesting their exclusion as a supportive feature in clinical diagnostic criteria for FTLD. Here, we identified three cases of the behavioral variant of frontotemporal dementia (bvFTD) that display chorea with fused in sarcoma (FUS)-positive inclusions (FTLD-FUS) and the basophilic inclusion body disease (BIBD) subtype. We determined the behavioral and cognitive features in this group that were distinct from other FTLD-FUS cases. We also reviewed the clinical records of 72 FTLD cases, and clarified additional clinical features that are predictive of the BIBD pathology. Symptom onset in the three patients with chorea was at 44.0 years of age (±12.0 years), and occurred in the absence of a family history of dementia. The cases were consistent with a clinical form of FTD known as bvFTD, as well as reduced neurological muscle tone in addition to chorea. The three patients showed no or mild parkinsonism, which by contrast, increased substantially in the other FTLD cases until a later stage of disease. The three patients exhibited severe caudate atrophy, which has previously been reported as a histological feature distinguishing FTLD-FUS from FTLD-tau or FTLD-TAR DNA-binding protein 43. Thus, our findings suggest that the clinical feature of choreoathetosis in bvFTD might be associated with FTLD-FUS, and in particular, with the BIBD subtype.
Improved neuroimaging and molecular markers of Alzheimer disease (AD) have aided diagnosis of AD in the very early stages, and have facilitated differential diagnosis between AD and other neurodegenerative disorders with dementia. The finding that some older individuals can show amyloid-β pathology while remaining cognitively intact raises important questions regarding prevention strategies.
Baird, Amee; Samson, Séverine
There is an increasing incidence of dementia in our aging population, and consequently an urgent need to develop treatments and activities that may alleviate the symptoms of dementia. Accumulating evidence shows that persons with dementia enjoy music, and their ability to respond to music is potentially preserved even in the late or severe stages of dementia when verbal communication may have ceased. Media interest in this topic has contributed to the public perception that music abilities are an "island of preservation" in an otherwise cognitively impaired person with dementia. In this chapter, we review the current literature on music cognition in dementia and show that there has been very scarce rigorous scientific investigation of this issue, and that various types of music memory exist and are differentially impaired in the different types of dementia. Furthermore, we discuss the recent development of music activities as a nonpharmacological treatment for dementia and highlight the methodological limitations of the current literature on this topic. While it has been reported that music activities can improve behavior, (particularly agitation), mood, and cognition in persons with dementia, recent large-scale randomized control studies have questioned the specificity of the effect of music and found that it is no more beneficial than other pleasant activities. Nevertheless, music is unique in its powerful ability to elicit both memories and emotions. This can provide an important link to individual's past and a means of nonverbal communication with carers, which make it an ideal stimulus for persons with dementia.
Jha, Sanjeev; Patel, R
A study was designed to generate epidemiological and clinical data on dementia, in a teaching hospital in India. It was conducted on 124 (94 male and 30 female) elderly patients (aged more than 60 years) presenting with clinical syndrome of dementia (DSM-3). Their age range was 64-78 (mean 65.7 4.1) years. Detailed clinical, biochemical, radiological and electrophysiological evaluation was done to establish etiology. Patients with psychiatric ailments, cranial trauma and tumors were excluded. The study period was 4.2 years. Multi-infarct dementia (MID) was observed to be commonest cause of dementia and was present in 59 (47.6%) cases. There were 10 (8%) patients each of tuberculosis (TB) and neurocysticercosis (NCC). Alcohol-related dementia was present in 13 (10.5%), while malnutrition (Vitamin B12 deficiency) was present in 9 (7.2%). Alzheimer's Disease (AD) was present (NINCDS-ADRDA criteria) in 6 patients (4.8%). There were 3 (2.4%) cases 1 each of Huntington's disease, Parkinson's and Normal Pressure Hydrocephalus and 2 each of diabetes, hypothyroidism, hyperthyroidism and Creutzfeldt' Jakob Disease. We conclude that AD, which is irreversible and common in the west, is relatively uncommon in India as compared to MID, infections and malnutrition, which are potentially treatable.
Molinuevo, José L; Garcia-Gil, Vicente; Villar, Amparo
Alzheimer's disease (AD) is the most common form of dementia in occidental countries. Currently approved treatments for AD provide mainly symptomatic benefits without clear evidence of neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in several central nervous system disorders, including neuroprotective treatment in chronic neurodegenerative diseases, and symptomatic treatment in other neurologic diseases. Memantine, an NMDA antagonist, has been recently approved for the treatment of advanced AD. Due to its mechanism of action, memantine is considered a neuroprotective drug, whose utility has been demonstrated in preclinical studies. In addition, memantine is a useful symptomatic treatment for AD and vascular dementia. This paper reviews both aspects of memantine as well as some basic mechanisms mediating cognition and glutamatergic neurodegeneration.
Mantero, Vittorio; Tarlarini, Claudia; Aliprandi, Angelo; Lauria, Giuseppe; Rigamonti, Andrea; Abate, Lucia; Origone, Paola; Mandich, Paola; Penco, Silvana; Salmaggi, Andrea
Amyotrophic lateral sclerosis (ALS), frontotemporal degeneration and Parkinson's disease may be different expressions of the same neurodegenerative disease. However, association between ALS and parkinsonism-dementia complex (ALS-PDC) has only rarely been reported apart from the cluster detected in Guam. We report a patient presenting with ALS-PDC in whom pathological mutations/expansions were investigated. No other family members were reported to have any symptoms of a neurological condition. Our case demonstrates that ALS-PDC can occur as a sporadic disorder, even though the coexistence of the three clinical features in one patient suggests a single underlying genetic cause. It is known that genetic testing should be preferentially offered to patients with ALS who have affected first or second-degree relatives. However, this case illustrates the importance of genetic counseling for family members of patients with sporadic ALC-PDC in order to provide education on the low recurrence risk. Here, we dicuss the ethical, psychological and practical consequences for patients and their relatives.
Dillon, Whitney A.; Prorok, Jeanette C.; Seitz, Dallas P.
Purpose Information about dementia is important for persons with dementia (PWD) and their caregivers and the Internet has become the key source of health information. We reviewed the content and quality of information provided on Canadian websites for Alzheimer’s disease (AD). Methods We used the terms “dementia” and “Alzheimer” in Google to identify Canadian dementia websites. The contents of websites were compared to 16 guideline recommendations provided in Canadian Consensus Conference on Diagnosis and Treatment of Dementia. The quality of information provided on websites was evaluated using the DISCERN instrument. The content and quality of information provided on selected websites were then described. Results Seven websites were identified, three of which provided relatively comprehensive and high-quality information on dementia. Websites frequently provided information about diagnosis of dementia, its natural course, and types of dementia, while other topics were less commonly addressed. The quality of information provided on the websites varied, and many websites had several areas where the quality of information provided was relatively low according to the DISCERN instrument. Conclusions There is variation in the content and quality of dementia websites, although some websites provide high-quality and relatively comprehensive information which would serve as a useful resource for PWD, caregivers, and healthcare providers. Improvements in the content and quality of information provided on AD websites would provide PWD and their caregivers with access to better information. PMID:23440180
Preobrazhenskaia, I S; Mkhitarian, E A; Iakhno, N N
Basing on a neuropsychological study of 50 patients with dementia with Levy's bodies (DLB) and 50 patients with Alzheimer's disease (AD), peculiarities of cognitive impairment in these diseases are discussed. In similar severity of dementia, patients with DLB demonstrated a greater impairment of executive and visual-spatial functions as well as neurodynamic disturbances and patients with AD had more severe memory impairment.
Preobrazhenskaya, I S; Mkhitaryan, E A; Yakhno, N N
Neuropsychological studies of 50 patients with Lewy body dementia (LBD) and 50 patients with Alzheimer's disease (AD) were performed to assess the characteristics of the cognitive impairments in these diseases. In patients with dementias of similar severities, patients with LBD showed greater impairment of executive and visuospatial functions and had more marked neurodynamic dysfunction. Patients with AD showed more profound memory disorders.
Venkat, Poornima; Chopp, Michael; Chen, Jieli
Vascular Dementia (VaD) is the second leading form of dementia after Alzheimer’s disease (AD) plaguing the elderly population. VaD is a progressive disease caused by reduced blood flow to the brain, and it affects cognitive abilities especially executive functioning. VaD is poorly understood and lacks suitable animal models, which constrain the progress on understanding the basis of the disease and developing treatments. This review article discusses VaD, its risk factors, induced cognitive disability, various animal (rodent) models of VaD, pathology, and mechanisms of VaD and treatment options. PMID:25987538
Lattante, Serena; Ciura, Sorana; Rouleau, Guy A; Kabashi, Edor
Several genetic causes have been recently described for neurological diseases, increasing our knowledge of the common pathological mechanisms involved in these disorders. Mutation analysis has shown common causative factors for two major neurodegenerative disorders, ALS and FTD. Shared pathological and genetic markers as well as common neurological signs between these diseases have given rise to the notion of an ALS/FTD spectrum. This overlap among genetic factors causing ALS/FTD and the coincidence of mutated alleles (including causative, risk and modifier variants) have given rise to the notion of an oligogenic model of disease. In this review we summarize major advances in the elucidation of novel genetic factors in these diseases which have led to a better understanding of the common pathogenic factors leading to neurodegeneration.
Morgan, Brianna; Gross, Rachel G.; Clark, Robin; Dreyfuss, Michael; Boller, Ashley; Camp, Emily; Liang, Tsao-Wei; Avants, Brian; McMillan, Corey T.; Grossman, Murray
Quantifiers are very common in everyday speech, but we know little about their cognitive basis or neural representation. The present study examined comprehension of three classes of quantifiers that depend on different cognitive components in patients with focal neurodegenerative diseases. Patients evaluated the truth-value of a sentence…
... of the brain that control reasoning, personality, social skills, speech, and language. People with this condition initially may have trouble speaking, remembering words and names (dysnomia), and using numbers ( ...
Tierney, Mary C.; And Others
Thirty-eight elderly control subjects performed better than did 18 patients with moderate Alzheimer's disease (AD), 33 with severe AD, and 12 with Parkinson's dementia on all measures of the Rey Auditory Verbal Learning Test. Results indicate that the test is useful in distinguishing AD from Parkinson's dementia. (SLD)
The molecular determinants of dementia of Alzheimer's tipe (DAT) are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor is represented by the unbalanced homeostasis of two cations: calcium (Ca(2) ) and zinc (Zn(2)). The two ions serve a critical role in the physiological signalling of the central nervous system. However, Alzheimer's disease-related neurodegeneration, deregulation of brain levels of Ca(2) and Zn(2) is instrumental in promoting amyloid-β (Aβ) dysmetabolism and tau phosphorylation as well as interference with additional pathogenic factors like energy production failure, hyperexcitabilty, excitotoxicity, and oxidative stress. Hyperexcitabilty and excitotoxicity are key mechanisms in the disease development and progression as an altered glutamatergic activation can further promote both Ca(2) and Zn(2) dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further increase intracellular Ca(2) and Zn(2) rises and set the stage for a self-perpetuating injurious loop. In the talk, we will review mechanisms of AD-related Ca(2) and Zn(2) dyshomeostasis in a preclinical model of DAT and discuss opportunity for disease-modifying strategies based on interventions aimed at restoring brain metal homeostasis.
Prevention and treatment of dementia has turned into a major public health challenge. Several epidemiological studies have indicated a significant association between the presence of hypertension and the onset of dementia (vascular or Alzheimer's type) several years later. Cognitive disorder may be related to focal cerebral lesions of vascular origin (infarctus, lacunae) and/or chronic ischemia of the white matter (white matter lesions) related to arteriosclerosis and/or lipohyalinosis of small perforating arteries high blood pressure in mid-life to later cognitive decline and dementia. Moreover, disorders of cerebral microcirculation and endothelial dysfunction may be associated to blood brain barrier dysfunction and amyloid plaques formation leading to Alzheimer's process. Few randomized clinical trials have included a cognitive assessment and dementia as outcome in their design. They all raise some major criticisms: cognitive assessment was never the main outcome, too short follow-up to study dementia; incomplete assessment of cognition, lost of follow-up and a small proportion of subjects at risk for dementia at inclusion. However, the results of therapeutic trials (SYST-EUR, PROGRESS) open the way to the prevention of dementia (vascular or Alzheimer's type) or cognitive decline by antihypertensive treatments. A meta-analysis including randomized controlled studies, suggests a significant decrease in the risk of dementia with antihypertensive treatment compared to placebo.
Bruno, S. D.; Cercignani, M.; Wheeler-Kingshott, C. A. M.
Theimpact of neuroimaging on the study and understanding of dementing illnesses has been enormous. Here we review the main MR structural technical developments applied to Alzheimer's disease and fronto-temporal dementia, two forms of neurodegenerative disorders that have a number of similarities but also several differences. The possibility of detecting increasingly subtle brain changes, together with the need of handling larger and larger data sets, keeping up with the ever expanding aging population, are perhaps the main driving forces behind recent MR technique developments in the field of dementia. The measurement of atrophy is now integrated by more advanced approaches, investigating the alterations of the architecture of brain tissues beyond pure volumetric loss. Brain connectivity is now studied in vivo with techniques such as diffusion tensor imaging and tractography. Also, automated methods of subject classification open up new possibilities of rapid and cost-effective diagnosis. The inter-disciplinary efforts are changing the clinical scenario of dementia care from one of helpless defeat to one of promising innovation.
Freedman, Morris; Alladi, Suvarna; Chertkow, Howard; Bialystok, Ellen; Craik, Fergus I M; Phillips, Natalie A; Duggirala, Vasanta; Raju, Surampudi Bapi; Bak, Thomas H
There is an emerging literature suggesting that speaking two or more languages may significantly delay the onset of dementia. Although the mechanisms are unknown, it has been suggested that these may involve cognitive reserve, a concept that has been associated with factors such as higher levels of education, occupational status, social networks, and physical exercise. In the case of bilingualism, cognitive reserve may involve reorganization and strengthening of neural networks that enhance executive control. We review evidence for protective effects of bilingualism from a multicultural perspective involving studies in Toronto and Montreal, Canada, and Hyderabad, India. Reports from Toronto and Hyderabad showed a significant effect of speaking two or more languages in delaying onset of Alzheimer's disease by up to 5 years, whereas the Montreal study showed a significant protective effect of speaking at least four languages and a protective effect of speaking at least two languages in immigrants. Although there were differences in results across studies, a common theme was the significant effect of language use history as one of the factors in determining the onset of Alzheimer's disease. Moreover, the Hyderabad study extended the findings to frontotemporal dementia and vascular dementia.
Freedman, Morris; Alladi, Suvarna; Chertkow, Howard; Bialystok, Ellen; Craik, Fergus I. M.; Phillips, Natalie A.; Duggirala, Vasanta; Raju, Surampudi Bapi; Bak, Thomas H.
There is an emerging literature suggesting that speaking two or more languages may significantly delay the onset of dementia. Although the mechanisms are unknown, it has been suggested that these may involve cognitive reserve, a concept that has been associated with factors such as higher levels of education, occupational status, social networks, and physical exercise. In the case of bilingualism, cognitive reserve may involve reorganization and strengthening of neural networks that enhance executive control. We review evidence for protective effects of bilingualism from a multicultural perspective involving studies in Toronto and Montreal, Canada, and Hyderabad, India. Reports from Toronto and Hyderabad showed a significant effect of speaking two or more languages in delaying onset of Alzheimer's disease by up to 5 years, whereas the Montreal study showed a significant protective effect of speaking at least four languages and a protective effect of speaking at least two languages in immigrants. Although there were differences in results across studies, a common theme was the significant effect of language use history as one of the factors in determining the onset of Alzheimer's disease. Moreover, the Hyderabad study extended the findings to frontotemporal dementia and vascular dementia. PMID:24959001
Hardy, Chris J D; Marshall, Charles R; Golden, Hannah L; Clark, Camilla N; Mummery, Catherine J; Griffiths, Timothy D; Bamiou, Doris-Eva; Warren, Jason D
Hearing deficits associated with cognitive impairment have attracted much recent interest, motivated by emerging evidence that impaired hearing is a risk factor for cognitive decline. However, dementia and hearing impairment present immense challenges in their own right, and their intersection in the auditory brain remains poorly understood and difficult to assess. Here, we outline a clinically oriented, symptom-based approach to the assessment of hearing in dementias, informed by recent progress in the clinical auditory neuroscience of these diseases. We consider the significance and interpretation of hearing loss and symptoms that point to a disorder of auditory cognition in patients with dementia. We identify key auditory characteristics of some important dementias and conclude with a bedside approach to assessing and managing auditory dysfunction in dementia.
Ashby, Emma L; Kierzkowska, Marta; Hull, Jonathon; Kehoe, Patrick G; Hutson, Susan M; Conway, Myra E
Cytosolic and mitochondrial human branched chain aminotransferase (hBCATc and hBCATm, respectively) play an integral role in brain glutamate metabolism. Regional increased levels of hBCATc in the CA1 and CA4 region of Alzheimer's disease (AD) brain together with increased levels of hBCATm in frontal and temporal cortex of AD brains, suggest a role for these proteins in glutamate excitotoxicity. Glutamate toxicity is a key pathogenic feature of several neurological disorders including epilepsy associated dementia, AD, vascular dementia (VaD) and dementia with Lewy bodies (DLB). To further understand if these increases are specific to AD, the expression profiles of hBCATc and hBCATm were examined in other forms of dementia including DLB and VaD. Similar to AD, levels of hBCATm were significantly increased in the frontal and temporal cortex of VaD cases and in frontal cortex of DLB cases compared to controls, however there were no observed differences in hBCATc between groups in these areas. Moreover, multiple forms of hBCATm were observed that were particular to the disease state relative to matched controls. Real-time PCR revealed similar expression of hBCATm mRNA in frontal and temporal cortex for all cohort comparisons, whereas hBCATc mRNA expression was significantly increased in VaD cases compared to controls. Collectively our results suggest that hBCATm protein expression is significantly increased in the brains of DLB and VaD cases, similar to those reported in AD brain. These findings indicate a more global response to altered glutamate metabolism and suggest common metabolic responses that might reflect shared neurodegenerative mechanisms across several forms of dementia.
Chang, Hyuk; Park, HyunYoung; Lee, Hak Seung; Cheong, JinSung; Kang, HyunGu
We are approaching a period of population ageing in which the number of dementia patients will increase rapidly and become a significant social problem. There are many study guides for treatment of dementia, but there are limited numbers of studies and limited amounts of data available for evaluating the treatment used on dementia patients as related to their hospital for the first time. A study was performed using information gathered from 50 domestic hospitals to ensure that the treatment status data was representative of the actual field of clinical dementia. We observed retrospectively the medical records of 4282 patients who visited the hospital and were finally judged to have dementia from January, 2009 to December, 2010. Among the types of dementia, Alzheimer's disease (AD) had the greatest occurrence at 66.57%, with vascular dementia (VD) at 17.63%, AD with CVD at 10.18%, and Parkinson related dementia at 4.25%. The drug primarily used for initial therapy is the same drug primarily used for patients who have undergone long term dementia treatment, namely donepezil (75.22%). Among all 4282 patients, there was addition or transition of drugs used for 389 of the patients. Ineffectiveness of the initial drug treatment was the reason for the addition of drugs or transition to other drugs in almost all cases. In this study, the clinical characteristics observed for dementia treatment is compared as drugs changing, which will be helpful in the preparation of a treatment guide for dementia in the future.
Heser, Kathrin; Wagner, Michael; Wiese, Birgitt; Prokein, Jana; Ernst, Annette; König, Hans-Helmut; Brettschneider, Christian; Riedel-Heller, Steffi G.; Luppa, Melanie; Weyerer, Siegfried; Eifflaender-Gorfer, Sandra; Bickel, Horst; Mösch, Edelgard; Pentzek, Michael; Fuchs, Angela; Maier, Wolfgang; Scherer, Martin; Eisele, Marion
Background Social relations and depressive symptoms are intertwined. They both predict subsequent dementia, but only few studies on the association between social life aspects and subsequent dementia exist. Methods The risk of subsequent dementia was estimated over 2 follow-up assessments, each 18 months apart, depending on leisure activity, social support (general scale and the 3 factors emotional support, practical support, and social integration), and depressive symptoms, using proportional hazard models in a cohort of elderly patients (n = 2,300, with a mean age of 82.45 years) recruited for the study by their general practitioners. Results Higher depressive symptoms and lower cognitive and physical activity were associated with an increased risk of subsequent all-cause dementia and Alzheimer's dementia (AD). While neither social engagement nor the general social support scale was associated with subsequent dementia, a higher level of social integration was associated with a lower dementia risk. In combined models, the results for activity variables remained similar, but the strength of the association between depressive symptoms and the subsequent risk of dementia decreased, and the association with social integration disappeared. Conclusions Depressive symptoms increased and activity variables decreased the risk of subsequent dementia; however, activity variables, namely cognitive and physical activity, partly mediated the effect of depressive symptoms on the subsequent risk of all-cause dementia and AD. In many cases, social support was not associated with a risk of subsequent dementia. PMID:25685139
Schindler, R J
Patients with vascular dementia (VaD) and Alzheimer's disease with cerebrovascular disease (AD + CVD) have dementia associated with underlying CVD. Although diagnosis of VaD is challenging, VaD is typically characterized by a stepwise progression of dementia that is closely associated with stroke and focal neurological findings, and a symptom profile that often includes executive dysfunction leading to decreased ability to perform instrumental activities of daily living (IADL). In contrast, AD + CVD patients typically present with progressive deterioration of cognition/memory that may also be influenced by concurrent cerebrovascular events. Early diagnosis and intervention are desirable to prevent further decline due to subsequent vascular events. Management of CVD can limit deterioration of cognitive symptoms in VaD patients, and treatment benefits with cholinesterase inhibitors may be realized as improvement above baseline levels in dementia symptoms. Results from a combined analysis of two 24-week, placebo-controlled clinical trials show that donepezil-treated VaD patients improve in cognition, global function, and performance of IADL. In contrast, AD + CVD patients may continue to decline despite management of CVD, and treatment benefits should be recognized as initial improvements followed by stabilization or slowed decline of dementia symptoms over time. In post-marketing studies, donepezil-treated AD and AD + CVD patients show similar benefits in cognition, global function, and quality of life. The results of these studies support the use of donepezil in treatment of patients with VaD or AD + CVD.
Tachibana, H.; Meyer, J.S.; Okayasu, H.; Shaw, T.G.; Kandula, P.; Rogers, R.L.
Local cerebral blood flow (LCBF) and partition coefficients (L lambda) were measured during inhalation of stable xenon gas with serial CT scanning among normal volunteers (N . 15), individuals with multi-infarct dementia (MID, N . 10), and persons with senile dementia of Alzheimer type (SDAT, N . 8). Mean gray matter flow values were reduced in both MID and SDAT. Age-related declines in LCBF values in normals were marked in frontal cortex and basal ganglia. LCBF values were decreased beyond normals in frontal and temporal cortices and thalamus in MID and SDAT, in basal ganglia only in MID. Unlike SDAT and age-matched normals, L lambda values were reduced in fronto-temporal cortex and thalamus in MID. Multifocal nature of lesions in MID was apparent. Coefficients of variation for LCBFs were greater in MID compared with SDAT and/or age-matched normals.
Shinagawa, Shunichiro; Tsuno, Norifumi; Nakayama, Kazuhiko
Abnormal eating behaviours are specific to frontotemporal lobar degeneration and increase caregiver burden. Topiramate, an anticonvulsant, suppresses cravings for alcohol and other substances and is a potential treatment for binge eating. However, there are few reports on topiramate efficacy for abnormal eating behaviours in frontotemporal lobar degeneration patients. We present three Japanese frontotemporal lobar degeneration patients with abnormal eating behaviours. Topiramate was effective, especially for compulsive eating, in cases with distinct lobar atrophy, but not for all abnormal eating behaviours.
Ajon Gealogo, Gretchel
Much of the current nursing literature on dementia focuses on Alzheimer disease (AD), the dementia subtype most commonly diagnosed in the older adults. There is a paucity of nursing literature on dementia with Lewy bodies (DLB), the second most common subtype of dementia, which is closely associated with Parkinson disease with dementia (PDD), considered the third most common dementia subtype. Both are aging-related disorders attributed to Lewy bodies, abnormal protein aggregates or "clumps" found to cause cumulative neurodegeneration over time. DLB is defined as dementia onset that is preceded by Parkinsonian symptoms for 1 year or less, whereas in PDD, 2 or more years of Parkinsonian symptoms precede dementia onset. Although basic science knowledge of DLB has increased exponentially, the lack of nursing research on DLB indicates that this knowledge excludes the nursing perspective and its implications for nursing practice. The purpose of this article is to provide nurses with a comprehensive overview of DLB as it compares with PDD and Alzheimer disease and to propose key nursing interventions for clinical practice.
Chen, Aiqing; Oakley, Arthur E; Monteiro, Maria; Tuomela, Katri; Allan, Louise M; Mukaetova-Ladinska, Elizabeta B; O'Brien, John T; Kalaria, Raj N
Both the inflammatory potential and cognitive function decline during aging. The association between the repertoire of inflammatory biomarkers and cognitive decline is unclear. Inflammatory cytokines have been reported to be increased, decreased, or unchanged in the cerebrospinal fluid and sera of subjects with dementia. We assessed 112 postmortem brains from subjects diagnosed with poststroke dementia (PSD), vascular dementia, mixed dementia, and Alzheimer's disease (AD), comparing those to poststroke nondemented (PSND) subjects and age-matched controls. We analyzed 5 brain regions including the gray and white matter from the frontal and temporal lobes for a panel of cytokine and/or chemokine analytes using multiplex-array assays. Of the 37 analytes, 14 were under or near the detection limits, 7 were close to the lowest detection level, and 16 cytokines were within the linear range of the assay. We observed widely variable concentrations of C-reactive protein (CRP) and serum amyloid A at the high end (1-150 ng/mg protein), whereas several of the interleukins (IL, interferon-gamma and tumor necrosis factor) at the low end (1-10 pg/mg). There were also regional variations; most notable being high concentrations of some cytokines (e.g., CRP and angiogenesis panel) in the frontal white matter. Overall, we found decreased concentrations of several cytokines, including IL-1 beta (p = 0.000), IL-6 (p = 0.000), IL-7 (p = 0.000), IL-8 (p = 0.000), IL-16 (p = 0.001), interferon-inducible protein-10 (0.044), serum amyloid A (p = 0.011), and a trend in IL-1 alpha (p = 0.084) across all dementia groups compared to nondemented controls. IL-6 and IL-8 were significantly lower in dementia subjects than in nondemented subjects in every region. In particular, lower levels of IL-6 and IL-8 were notable in the PSD compared to PSND subjects. Because these 2 stroke groups had comparable degree of vascular pathology, the lower production of IL-6 and IL-8 in PSD reaffirms a
Jagust, W.J.; Budinger, T.F.; Reed, B.R.
Single photon emission computed tomography is a practical modality for the study of physiologic cerebral activity in vivo. We utilized single photon emission computed tomography and N-isopropyl-p-iodoamphetamine iodine 123 to evaluate regional cerebral blood flow in nine patients with Alzheimer's disease (AD), five healthy elderly control subjects, and two patients with multi-infarct dementia. We found that all subjects with AD demonstrated flow deficits in temporoparietal cortex bilaterally, and that the ratio of activity in bilateral temporoparietal cortex to activity in the whole slice allowed the differentiation of all patients with AD from both the controls and from the patients with multi-infarct dementia. Furthermore, this ratio showed a strong correlation with disease severity in the AD group. Single photon emission computed tomography appears to be useful in the differential diagnosis of dementia and reflects clinical features of the disease.
Fernández Martínez, Manuel; Castro Flores, Jessica; Pérez de las Heras, Susana; Mandaluniz Lekumberri, Aitziber; Gordejuela Menocal, María; Zarranz Imirizaldu, Juan José
Background Prevalence of degenerative dementias and dementias associated with cerebrovascular disease is increasing. Dementia is one of the most significant public health problem. In recent years, the role of vascular risk factors (hypertension, diabetes mellitus and hypercholesterolemia) and depression has been evaluated. The incidence of dementia and risk factors has not been fully investigated in Spain. The aim of this study was to identify the risk factors for dementia, Alzheimer's disease (AD) and vascular dementia (VD) in elderly people in Munguialde County (Spain). Methods A two phase, door-to-door populational study was performed. Demographic variables and the presence of vascular risk factors and depression were recorded. The MMSE, the DSM-IV and the conventional criteria for AD and VD were used in the evaluation. The odds ratio for each risk factor was calculated by logistic regression analysis. Results 1756 healthy subjects and 175 patients with dementia participated in the study. Of these, 133 had AD, 15 VD and the remainder other dementias. The risk factors for dementia and AD were female sex (OR = 1.67 and 1.97, respectively); age (OR = 1.14 and 1.15); stroke (OR = 7.84 and 3); and depression (OR = 53.08 and 3.19). Stroke was the only risk factor for VD (OR = 119). Conclusion Greater age, female sex, stroke and depression increase the risk of suffering dementia, AD and VD. The relationship between depression, vascular risk factors and dementia has clear public health implications. Prevention and early treatment of vascular risk factors and depression may have an important impact in lowering the risk of dementia and could modify the natural history of the disease. PMID:18922150
Kuhl, D.E.; Metter, E.J.; Benson, D.F.; Ashford, J.W.; Riege, W.H.; Fujikawa, D.G.; Markham, C.H.; Maltese, A.
In the dementia of probable Alzheimer's Disease (AD), there is a decrease in the metabolic ratio of parietal cortex/caudate-thalamus which relates measures in the most and in the least severely affected locations. Since some demented patients with Parkinson's Disease (PDD) are known to share pathological and neurochemical features with AD patients, the authors evaluated if the distribution of cerebral hypometabolism in PDD and AD were the same. Local cerebral metabolic rates were determined using the FDG method and positron tomography in subjects with AD (N=23), and PDD (N=7), multiple infarct dementia (MID)(N=6), and controls (N=10). In MID, the mean par/caudthal ratio was normal (0.79 +- 0.9, N=6). In AD and PDD patients, this ratio correlated negatively with both the severity (r=-0.624, rho=0.001) and duration (r=-0.657, rho=0.001) of dementia. The ratio was markedly decreased in subjects with mild to severe dementia (0.46 +- 0.09, N=21) and with dementia duration greater than two years (0.44 +- 0.08, N=18), but the ratio was also significantly decreased in patients with less advanced disease, i.e., when dementia was only questionable (0.64 +- 0.14, N=9) (t=2.27, rho<0.037) and when duration was two years or less (0.62 +- 0.13, N=12)(t=2.88, rho<0.009). This similarity of hypometabolism in AD and PDD is additional evidence that a common mechanism may operate in both disorders. The par/caud-thal metabolic ratio may be an index useful in the differential diagnosis of early dementia.
Bucelli, Robert C.; Ances, Beau M.
While the most common dementia is Alzheimer’s disease (AD), a detailed history is needed to rule out rapidly progressive dementias (RPDs). RPDs are less than two years in duration and have a rate of progression faster typical neurodegenerative diseases. Identification of RPDs is important as some are treatable. This review focuses on the spectrum of RPDs, with special emphasis on paraneoplastic disorders and Creutzfeldt-Jakob disease (CJD). PMID:24279195
Diabetes mellitus, particularly type 2 diabetes, is a risk factor for dementia and this holds true for incident vascular dementia and Alzheimer's disease. Cerebrovascular complications of diabetes and chronic mild inflammation in insulin resistant states partly account for this increased risk. In addition, cellular resistance to the trophic effects of insulin on neurons and glial cells favor the accumulation of toxic metabolic products, such as amyloid and hyperphosphorylated tau protein (pTau). Weight loss frequently precedes overt cognitive symptoms of Alzheimer's disease. This results in an increased risk of hypoglycemic episodes in stable diabetic patients who are on suitably adjusted doses of oral insulin or insulinotropic antidiabetic drugs. In turn, hypoglycemic episodes may induce further damage in the vulnerable brains of type 2 diabetes patients. Patients with unexplained weight loss, hypoglycemic episodes and subjective memory complaints must be screened for dementia. Once dementia has been diagnosed the goals of diabetes management must be reevaluated as prevention of hypoglycemia becomes more important than tight metabolic control. As weight loss accelerates the rate of cognitive decline, nutritional goals must aim at stabilizing body weight. There is no available evidence on whether drug treatment of diabetes in middle-aged persons can help to prevent dementia; however, physical exercise, mental activity and higher education have preventive effects on the risk of dementia in later life. In addition, nutritional recommendations that are effective in preventing cardiovascular events have also been shown to reduce the risk of dementia.
Irish, Muireann; Hodges, John R; Piguet, Olivier
Semantic dementia is a progressive neurodegenerative disorder characterized by the amodal and profound loss of semantic knowledge attributable to the degeneration of the left anterior temporal lobe. Although traditionally conceptualized as a language disorder, patients with semantic dementia display significant alterations in behaviour and socioemotional functioning. Recent evidence points to an impaired capacity for theory of mind in predominantly left-lateralized cases of semantic dementia; however, it remains unclear to what extent semantic impairments contribute to these deficits. Further the neuroanatomical signature of such disturbance remains unknown. Here, we sought to determine the neural correlates of theory of mind performance in patients with left predominant semantic dementia (n=11), in contrast with disease-matched cases with behavioural-variant frontotemporal dementia (n=10) and Alzheimer's disease (n=10), and healthy older individuals (n=14) as control participants. Participants completed a simple cartoons task, in which they were required to describe physical and theory of mind scenarios. Irrespective of subscale, patients with semantic dementia exhibited marked impairments relative to control subjects; however, only theory of mind deficits persisted when we covaried for semantic comprehension. Voxel-based morphometry analyses revealed that atrophy in right anterior temporal lobe structures, including the right temporal fusiform cortex, right inferior temporal gyrus, bilateral temporal poles and amygdalae, correlated significantly with theory of mind impairments in the semantic dementia group. Our results point to the marked disruption of cognitive functions beyond the language domain in semantic dementia, not exclusively attributable to semantic processing impairments. The significant involvement of right anterior temporal structures suggests that with disease evolution, the encroachment of pathology into the contralateral hemisphere heralds the
Steis, Melinda R.; Fick, Donna M.
Delirium is an acute, fluctuating confusional state that results in poor outcomes for older adults. Dementia causes a more convoluted course when coexisting with delirium. This study examined 128 days of documentation to describe what nurses document when caring for patients with dementia who experience delirium. Nurses did not document that they recognized delirium. Common descriptive terms included words and phrases indicating fluctuating mental status, lethargy, confusion, negative behavior, delusions, and restlessness. Delirium is a medical emergency. Nurses are in need of education coupled with clinical and decisional support to facilitate recognition and treatment of underlying causes of delirium in individuals with dementia. PMID:21761816
Daher, Oscar; Nguyen, Sylvain; Smith, Cindi; Büla, Christophe; Démonet, Jean-François
Dementia represents a great challenge for health care providers. Detection of cognitive impairment is critical for early diagnosis of dementia. Early diagnosis allows to initiate individualized management that focuses on maintaining patient's autonomy and supporting their caregivers. Proposed multimodal interventions include physical activity, cognitive training, mediterranean diet, and management of cardiovascular risk factors. Before the initiation of pro-cognitive therapy, medication review is essential to evaluate current treament and determine specific therapeutic objectives, based on patient's overall health and preferences. Overall risk reduction for dementia revolves around similar measures that target physical activity, cognition, diet and management of cardiovascular risk factors.
Mayzel-Oreg, Orna; Assaf, Yaniv; Gigi, Ariela; Ben-Bashat, Dafna; Verchovsky, Ruth; Mordohovitch, M; Graif, M; Hendler, Talma; Korczyn, Amos; Cohen, Yoram
Alzheimer's disease (AD) and Vascular Dementia (VaD) are the most common types of dementia and are progressive diseases affecting millions of people. Despite the high sensitivity of MRI to neurological disorders it has not thus far been found to be specific for the detection of either of these pathologies. In the present study high b-value q-space diffusion-weighted MRI (DWI) was applied to VaD and AD. Controls (N=4), VaD patients (N=8) and AD patients (N=6) were scanned with high b-value DWI, which emphasizes the water component which exhibits restricted diffusion. VaD patients were found to present major WM loss while, in AD, the major pathology found was GM changes, as expected. Also, WM changes in VaD and AD were of a different pattern, more specific to frontal and temporal areas in AD and more widespread in VaD. This pattern of WM changes may be utilized as a diagnosis criterion. Conventional diffusion tensor imaging did not show significant changes between either of the groups and controls. These results demonstrate the potential of high b-value DWI in the diagnosis of dementia.
Luna-Lario, Pilar; Azcárate-Jiménez, Leire; Seijas-Gómez, Raquel; Tirapu-Ustárroz, Javier
The early and etiological diagnosis of dementia syndrome in the clinical practice remains the neuropsychological assessment through the study of the cognitive profile of the patient and the qualitative and quantitative analysis of the functions, both impaired and preserved. In this article, we describe a neuropsychological battery of cognitive evaluation to detect mild cognitive impairment in any of its clinical forms and dementia; as well as discriminate between the main profiles of dementia syndrome, based on its topographic and etiological classification (frontotemporal, temporoparietal, subcortical, cortico-subcortical and multifocal). This battery is implemented in the neuropsychological assessment specialized surgery from Navarra Hospital Center Neurology Service. Not only the tests that form the assessment protocol are presented, but also the theoretical models that are considered more appropriate for their interpretation.
Kokjohn, Tyler A; Maarouf, Chera L; Daugs, Ian D; Hunter, Jesse M; Whiteside, Charisse M; Malek-Ahmadi, Michael; Rodriguez, Emma; Kalback, Walter; Jacobson, Sandra A; Sabbagh, Marwan N; Beach, Thomas G; Roher, Alex E
Dementia pugilistica (DP), a suite of neuropathological and cognitive function declines after chronic traumatic brain injury (TBI), is present in approximately 20% of retired boxers. Epidemiological studies indicate TBI is a risk factor for neurodegenerative disorders including Alzheimer disease (AD) and Parkinson disease (PD). Some biochemical alterations observed in AD and PD may be recapitulated in DP and other TBI persons. In this report, we investigate long-term biochemical changes in the brains of former boxers with neuropathologically confirmed DP. Our experiments revealed biochemical and cellular alterations in DP that are complementary to and extend information already provided by histological methods. ELISA and one-dimensional and two dimensional Western blot techniques revealed differential expression of select molecules between three patients with DP and three age-matched non-demented control (NDC) persons without a history of TBI. Structural changes such as disturbances in the expression and processing of glial fibrillary acidic protein, tau, and α-synuclein were evident. The levels of the Aβ-degrading enzyme neprilysin were reduced in the patients with DP. Amyloid-β levels were elevated in the DP participant with the concomitant diagnosis of AD. In addition, the levels of brain-derived neurotrophic factor and the axonal transport proteins kinesin and dynein were substantially decreased in DP relative to NDC participants. Traumatic brain injury is a risk factor for dementia development, and our findings are consistent with permanent structural and functional damage in the cerebral cortex and white matter of boxers. Understanding the precise threshold of damage needed for the induction of pathology in DP and TBI is vital.
Kokjohn, Tyler A.; Maarouf, Chera L.; Daugs, Ian D.; Hunter, Jesse M.; Whiteside, Charisse M.; Malek-Ahmadi, Michael; Rodriguez, Emma; Kalback, Walter; Jacobson, Sandra A.; Sabbagh, Marwan N.; Beach, Thomas G.
Abstract Dementia pugilistica (DP), a suite of neuropathological and cognitive function declines after chronic traumatic brain injury (TBI), is present in approximately 20% of retired boxers. Epidemiological studies indicate TBI is a risk factor for neurodegenerative disorders including Alzheimer disease (AD) and Parkinson disease (PD). Some biochemical alterations observed in AD and PD may be recapitulated in DP and other TBI persons. In this report, we investigate long-term biochemical changes in the brains of former boxers with neuropathologically confirmed DP. Our experiments revealed biochemical and cellular alterations in DP that are complementary to and extend information already provided by histological methods. ELISA and one-dimensional and two dimensional Western blot techniques revealed differential expression of select molecules between three patients with DP and three age-matched non-demented control (NDC) persons without a history of TBI. Structural changes such as disturbances in the expression and processing of glial fibrillary acidic protein, tau, and α-synuclein were evident. The levels of the Aβ–degrading enzyme neprilysin were reduced in the patients with DP. Amyloid-β levels were elevated in the DP participant with the concomitant diagnosis of AD. In addition, the levels of brain-derived neurotrophic factor and the axonal transport proteins kinesin and dynein were substantially decreased in DP relative to NDC participants. Traumatic brain injury is a risk factor for dementia development, and our findings are consistent with permanent structural and functional damage in the cerebral cortex and white matter of boxers. Understanding the precise threshold of damage needed for the induction of pathology in DP and TBI is vital. PMID:23268705
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Sampson, E; Warren, J; Rossor, M
Young onset dementia is a challenging clinical problem with potentially devastating medical and social consequences. The differential diagnosis is wide, and includes a number of rare sporadic and hereditary diseases. However, accurate diagnosis is often possible, and all patients should be thoroughly investigated to identify treatable processes. This review presents an approach to the diagnosis, investigation, and management of patients with young onset dementia, with particular reference to common and treatable causes. PMID:15016933
The tremendous increase in dementia has created a need for improved diagnostic techniques, and each of the newly established brain imaging techniques has been applied to this problem. Several, particularly computerized tomography (CT), magnetic resonance imaging (MRI), and isotope emission tomography, have proved valuable. Each procedure has strengths--specific disorders that can be diagnosed--and weaknesses--types of dementia that cannot be demonstrated.
Panegyres, Peter K; Berry, Renee; Burchell, Jennifer
As the population of the world increases, there will be larger numbers of people with dementia and an emerging need for prompt diagnosis and treatment. Early dementia screening is the process by which a patient who might be in the prodromal phases of a dementing illness is determined as having, or not having, the hallmarks of a neurodegenerative condition. The concepts of mild cognitive impairment, or mild neurocognitive disorder, are useful in analyzing the patient in the prodromal phase of a dementing disease; however, the transformation to dementia may be as low as 10% per annum. The search for early dementia requires a comprehensive clinical evaluation, cognitive assessment, determination of functional status, corroborative history and imaging (including MRI, FDG-PET and maybe amyloid PET), cerebrospinal fluid (CSF) examination assaying Aβ1-42, T-τ and P-τ might also be helpful. Primary care physicians are fundamental in the screening process and are vital in initiating specialist investigation and treatment. Early dementia screening is especially important in an age where there is a search for disease modifying therapies, where there is mounting evidence that treatment, if given early, might influence the natural history-hence the need for cost-effective screening measures for early dementia.
Panegyres, Peter K.; Berry, Renee; Burchell, Jennifer
As the population of the world increases, there will be larger numbers of people with dementia and an emerging need for prompt diagnosis and treatment. Early dementia screening is the process by which a patient who might be in the prodromal phases of a dementing illness is determined as having, or not having, the hallmarks of a neurodegenerative condition. The concepts of mild cognitive impairment, or mild neurocognitive disorder, are useful in analyzing the patient in the prodromal phase of a dementing disease; however, the transformation to dementia may be as low as 10% per annum. The search for early dementia requires a comprehensive clinical evaluation, cognitive assessment, determination of functional status, corroborative history and imaging (including MRI, FDG-PET and maybe amyloid PET), cerebrospinal fluid (CSF) examination assaying Aβ1–42, T-τ and P-τ might also be helpful. Primary care physicians are fundamental in the screening process and are vital in initiating specialist investigation and treatment. Early dementia screening is especially important in an age where there is a search for disease modifying therapies, where there is mounting evidence that treatment, if given early, might influence the natural history—hence the need for cost-effective screening measures for early dementia. PMID:26838803
Duron, Emmanuelle; Hanon, Olivier
Chronic hypertension is associated with an increased risk of both vascular dementia and Alzheimer's disease (AD). In this context, the role of anti-hypertensive therapy for the prevention and delay of cognitive decline and dementia is of central importance. Most longitudinal studies have shown a significant inverse association between anti-hypertensive therapies and dementia incidence and for some of these, particularly in AD. Seven randomized, double blind placebo-controlled trials have evaluated the benefit of antihypertensive treatments on cognition. Three of them found positive results in term of prevention of dementia (SYST-EUR) or cognitive decline (PROGRESS, HOPE). Others disclosed non-significant results (MRC, SHEP, SCOPE, HYVET-COG). This discrepancy emphasizes the difficulty to perform such trials: the follow-up has to be long enough to disclose a benefit, a large number of patients is needed for these studies, and because of ethical reasons some anti-hypertensive treatments are often prescribed in the placebo group. Results of the two more recent meta-analyses are inconsistent, possibly due to methodological issues. Antihypertensive treatments could be beneficial to cognitive function by lowering blood pressure and/or by specific neuroprotective effect. Three main antihypertensive subclasses have been associated with a beneficial effect on cognitive function beyond blood pressure reduction (calcium channel blockers, angiotensin converting enzyme inhibitor, angiotensin-AT1-receptor-blockers). Further long-term randomized trials, designed especially to assess a link between antihypertensive therapy and cognitive decline or dementia are therefore needed with cognition as the primary outcome. A low blood pressure threshold that could be deleterious for cognitive function should also be determined.
Goossens, Joery; Vanmechelen, Eugeen; Trojanowski, John Q; Lee, Virginia M Y; Van Broeckhoven, Christine; van der Zee, Julie; Engelborghs, Sebastiaan
Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer's disease. A high-ranking candidate to become a diagnostic marker for a major pathological subtype of FTLD is the transactive response DNA binding protein of 43 kDa (TDP-43). The main objective is to elucidate which antibodies are specific for pathological TDP-43, with special interest in its modified isoforms. Indeed, TDP-43 has been shown to be hyperphosphorylated and truncated in disease. A secondary objective is to review existing immunoassays that quantify TDP-43 in biofluids. A systematic review of literature was performed by searching PubMed and Web of Science using predefined keywords. Of considered research papers the methods section was reviewed to select publications that enabled us to answer our learning objective. After quality assessment, antibody characteristics and related outcomes were extracted. We identified a series of well-characterized antibodies based on a scoring system that assessed the ability of each antibody to detect TDP-43 pathology. A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once. This systematic review provides an overview of antibodies that are reported to detect pathological TDP-43. These antibodies can be used in future studies of TDP-43 proteinopathies. Additionally, selected antibodies hold the potential to be used in the development of novel immunoassays for the quantification of TDP-43 in biofluids, as a possible biomarker for FTLD-TDP.
Neto, Emanuel; Biessmann, Felix; Aurlien, Harald; Nordby, Helge; Eichele, Tom
The present study explores if EEG spectral parameters can discriminate between healthy elderly controls (HC), Alzheimer's disease (AD) and vascular dementia (VaD) using. We considered EEG data recorded during normal clinical routine with 114 healthy controls (HC), 114 AD, and 114 VaD patients. The spectral features extracted from the EEG were the absolute delta power, decay from lower to higher frequencies, amplitude, center and dispersion of the alpha power and baseline power of the entire frequency spectrum. For discrimination, we submitted these EEG features to regularized linear discriminant analysis algorithm with a 10-fold cross-validation. To check the consistency of the results obtained by our classifiers, we applied bootstrap statistics. Four binary classifiers were used to discriminate HC from AD, HC from VaD, AD from VaD, and HC from dementia patients (AD or VaD). For each model, we measured the discrimination performance using the area under curve (AUC) and the accuracy of the cross-validation (cv-ACC). We applied this procedure using two different sets of predictors. The first set considered all the features extracted from the 22 channels. For the second set of features, we automatically rejected features poorly correlated with their labels. Fairly good results were obtained when discriminating HC from dementia patients with AD or VaD (AUC = 0.84). We also obtained AUC = 0.74 for discrimination of AD from HC, AUC = 0.77 for discrimination of VaD from HC, and finally AUC = 0.61 for discrimination of AD from VaD. Our models were able to separate HC from dementia patients, and also and to discriminate AD from VaD above chance. Our results suggest that these features may be relevant for the clinical assessment of patients with dementia.
Neto, Emanuel; Biessmann, Felix; Aurlien, Harald; Nordby, Helge; Eichele, Tom
The present study explores if EEG spectral parameters can discriminate between healthy elderly controls (HC), Alzheimer’s disease (AD) and vascular dementia (VaD) using. We considered EEG data recorded during normal clinical routine with 114 healthy controls (HC), 114 AD, and 114 VaD patients. The spectral features extracted from the EEG were the absolute delta power, decay from lower to higher frequencies, amplitude, center and dispersion of the alpha power and baseline power of the entire frequency spectrum. For discrimination, we submitted these EEG features to regularized linear discriminant analysis algorithm with a 10-fold cross-validation. To check the consistency of the results obtained by our classifiers, we applied bootstrap statistics. Four binary classifiers were used to discriminate HC from AD, HC from VaD, AD from VaD, and HC from dementia patients (AD or VaD). For each model, we measured the discrimination performance using the area under curve (AUC) and the accuracy of the cross-validation (cv-ACC). We applied this procedure using two different sets of predictors. The first set considered all the features extracted from the 22 channels. For the second set of features, we automatically rejected features poorly correlated with their labels. Fairly good results were obtained when discriminating HC from dementia patients with AD or VaD (AUC = 0.84). We also obtained AUC = 0.74 for discrimination of AD from HC, AUC = 0.77 for discrimination of VaD from HC, and finally AUC = 0.61 for discrimination of AD from VaD. Our models were able to separate HC from dementia patients, and also and to discriminate AD from VaD above chance. Our results suggest that these features may be relevant for the clinical assessment of patients with dementia. PMID:27965568
Janelidze, Shorena; Hertze, Joakim; Nägga, Katarina; Nilsson, Karin; Nilsson, Christer; Wennström, Malin; van Westen, Danielle; Blennow, Kaj; Zetterberg, Henrik; Hansson, Oskar
Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF biomarkers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage.
Beyreuther, K; Masters, C L
The common feature in neurodegeneration with dementia is neuronal dysfunction which is mainly and primarily expressed as synaptic dysfunction. The consequence of this dysfunction is neuronal disconnection and dementia if the corresponding hippocampal, basal forebrain and cortical structures are damaged. Neuronal loss is not necessarily a prerequisite for dementia, although it may be observed in some neurodegenerative diseases. If neuronal loss is not the major cause of the symptoms, in principle non-invasive treatment with the aim of cure should be possible, provided intervention occurs early enough. In dementias in which neuronal loss is a major event implantation of nerve cells may become an important aspect in treatment. The latter may apply to vascular dementia (VaD). In contrast neuronal dysfunction may apply for the most common form of dementia, Alzheimer's disease (AD). AD shares some of the characteristic clinical features of VaD, the second most prominent cause of dementia, in which mental deterioration affecting normal brain leads to a loss or impairment of intellectual functions of memory, power of reason and intelligence with interference with patient's conduct of the customary affairs of life. As we begin to understand some of the underlying pathogenetic mechanisms and causes of AD, this most frequent dementing condition is well suited to serve as model system to study the common principles of neurodegenerative diseases. Much of the present knowledge on the molecular and genetic processes that occur in AD came directly or indirectly from the identification of the beta A4 (A beta, beta) amyloid protein and its precursor which is termed amyloid precursor protein, and abbreviated as APP.(ABSTRACT TRUNCATED AT 250 WORDS)
Whitehouse, P J; Gambetti, P; Harik, S I; Kalaria, R N; Perry, G; Younkin, S I; Tabaton, M; Unnerstall, J R
Neurochemical research in dementia needs to move beyond descriptive inventories of neurotransmitter systems affected in the specific disorders and to link to molecular studies of mechanism and clinical studies of cognition. New advances in Alzheimer's Disease (AD), Huntington's Disease (HD), and Parkinson's Disease (PD) are being guided by models of how nerve cells die in these disorders. Theories of pathophysiology which address the cellular level need to explain the selective vulnerability of neuronal populations in the different diseases. Clinically, the importance of neurochemical studies will be increased by understanding the bridges between neural and cognitive processes. Clinicians are concerned about the nosology of dementias, diagnostic tests, and more effective therapies. The value of neurochemical studies will be enhanced to the extent that they can contribute to understanding and modifying the clinical phenomenology of these disorders. In this paper, we will briefly review what is known about the neurochemistry of dementia but focus most of our attention on establishing the linkage between this level of description and the levels of description which are either "downstream" (molecular biology) or "upstream" (cognition) in terms of a reductionistic conception of understanding the disease process. We will explore how understanding neurochemistry relates to our understanding of disease mechanism and what constraints neurochemical studies place on understanding clinical aspects of disease. We will conclude by briefly discussing some of the problems with our current understanding of the neurochemistry of dementia and how we can address those problems in the future.
Jagust, W.J. . Dept. of Neurology Lawrence Berkeley Lab., CA )
Dementia is a medical problem of increasingly obvious importance. The most common cause of dementia, Alzheimer's disease (AD) accounts for at least 50% of all cases of dementia, with multi-infarct dementia the next most common cause of the syndrome. While the accuracy of diagnosis of AD may range from 80 to 90%, there is currently no laboratory test to confirm the diagnosis. Functional imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) offer diagnostic advantages since brain function is unequivocally disturbed in all dementing illnesses. Both PET and SPECT have been utilized in the study of dementia. While both techniques rely on principles of emission tomography to produce three dimensional maps of injected radiotracers, the differences between positron and single photon emission have important consequences for the practical applications of the two procedures. This briefly reviews the technical differences between PET and SPECT, and discusses how both techniques have been used in our laboratory to elucidate the pathophysiology of dementia. 32 refs., 2 figs.
Recent findings assessing the utility of biomarkers are reviewed that help identify the basis for disease in patients with frontotemporal lobar degeneration (FTLD) spectrum pathology. Biofluid studies identify about 15% of patients with FTLD due to a genetic mutation that is associated with the specific histopathologic features of TDP-43 or a tauopathy. Other genetically based risk factors and targeted proteomic searches of plasma and cerebrospinal fluid have suggested additional markers that may be useful in sporadic cases of FTLD. While progress has been made in developing biomarkers for FTLD, additional work is needed to extend these advances so that the histopathologic abnormality causing FTLD can be specified in an individual patient.
Sanders, Amy E; Hall, Charles B; Katz, Mindy J; Lipton, Richard B
Cognitive reserve is invoked to explain the protective effects of education and cognitively-stimulating activities against all-cause dementia and Alzheimer's disease (AD). For non-native English speakers (n-NES), speaking English may be a cognitive activity associated with lower dementia risk. We hypothesized that n-NES have lower risk of incident dementia/AD and that educational level might modify this relationship. Participants took part in the Einstein Aging Study (Bronx, NY), a longitudinal study of aging and dementia. All (n = 1779) spoke fluent English and self-reported birthplace and whether English was their first language. n-NES additionally reported mother tongue, age of English acquisition, and current percentile-use of a non-English language. Nested Cox proportional hazards models progressively adjusted for gender, race, education, and immigrant and marital status estimated hazard ratios (HR) for incident dementia/AD as a function of n-NES status. 390 (22%) participants were n-NES. 126 incident dementia cases occurred during 4174 person-years of follow-up (median 1.44; range 0-16); 101 individuals met criteria for probable/possible AD. There was no statistically-significant association between n-NES status and incident dementia in the fully-adjusted model (HR 1.26; 95% CI 0.76-2.09; p = 0.36). Results were similar for AD. Stratification of education into three groups revealed increased risk of dementia for n-NES with ≥ 16 years of education (HR 3.97; 95% CI 1.62-9.75; p = 0.003). We conclude that n-NES status does not appear to have an independent protective effect against incident dementia/AD, and that n-NES status may contribute to risk of dementia in an education-dependent manner.
Gualtieri, C Thomas
The preclinical phase of dementia usually precedes the clinical diagnosis by many years. Early detection of dementing conditions during this preclinical phase may provide opportunities for treatments that may slow or mitigate progression. Conventional assessment tools usually can only detect dementia when the symptoms are overt and the disease is well-established. Computerized neurocognitive screening tools hold promise for diagnosing dementia in its early phase. The use, performance and development of several computerized screening tools to diagnose and monitor patients with pre-dementias and dementia are reviewed. The ability to accurately assess the presence of dementia clearly has direct relevance to insurance risk assessment and risk management. As new treatments appear, their role in clinical management of dementia patients will increase as well. In a future issue, the differential diagnosis of dementias related to the findings on these screening tools will be reviewed.
... usually memory problems, changes in their way of speaking, such as forgetting words, and personality problems. Cognitive symptoms of dementia include poor problem solving, difficulty with learning new skills and impaired decision making. Other causes of dementia ...
Although Alzheimer's disease (AD) is a common cause of memory impairment and dementia in the elderly disturbed memory function is a widespread subjective and/or objective symptom in a variety of medical conditions. The early detection and correct distinction of AD from non-AD memory impairment is critically important to detect possibly treatable and reversible underlying causes. In the context of clinical research, it is crucial to correctly distinguish between AD or non-AD memory impairment in order to build homogenous study populations for the assessment of new therapeutic possibilities. The distinction of AD from non-AD memory impairment may be difficult, especially in mildly affected patients, due to an overlap of clinical symptoms and biomarker alterations between AD and certain non-AD conditions. This review aims to describe recent aspects of the differential diagnosis of AD and non-AD related memory impairment and how these may be considered in the presence of memory deficits.
Toyoshima, Yasuko; Piao, Yue-Shan; Tan, Chun-Feng; Morita, Masahiro; Tanaka, Masaharu; Oyanagi, Kiyomitsu; Okamoto, Koichi; Takahashi, Hitoshi
We report two patients with motor neuron disease-inclusion dementia, with special reference to the pathology of the motor neuron system and hippocampal formation. The ages of the patients at death were 55 and 62 years, and the disease durations were 8 and 3 years, respectively. The two patients exhibited progressive frontotemporal dementia in the absence of motor neuron signs. At autopsy, both cases exhibited frontotemporal lobar atrophy with ubiquitin-positive, and tau- and alpha-synuclein-negative neuronal inclusions. As expected from the clinical signs, in both cases, the upper and lower motor neuron systems were well preserved: no Bunina bodies or ubiquitinated inclusions were detected in the motor neurons. However, of great importance was that when visualized immunohistochemically, the Golgi apparatus and trans-Golgi network often exhibited fragmentation in the lower motor neurons (the spinal anterior horn cells). In one of the cases, a decrease in the amount of Golgi apparatus was also a frequent feature in the upper motor neurons (Betz cells in the motor cortex). Moreover, in both cases, circumscribed degeneration affecting the CA1-subiculum border zone was evident in the hippocampal formation. These findings further strengthen the idea that, pathologically, motor neuron disease-inclusion dementia is a rare phenotype of amyotrophic lateral sclerosis.