Improving response inhibition systems in frontotemporal dementia with citalopram.

PubMed

Hughes, Laura E; Rittman, Timothy; Regenthal, Ralf; Robbins, Trevor W; Rowe, James B

2015-07-01

Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel

Diagnosis and Management of Behavioral Issues in Frontotemporal Dementia

PubMed Central

Manoochehri, Masood; Huey, Edward D.

2012-01-01

Frontotemporal lobar degeneration (FTLD) is an umbrella term for several different disorders. In behavioral variant frontotemporal dementia (bvFTD), patients show deterioration in cognition and social behavior. New diagnostic criteria proposed by the International Behavioral Variant FTD Consortium provide greater sensitivity in diagnosing bvFTD. Current pharmacological management of symptoms relies on medications borrowed from treating Alzheimer’s Disease (AD) and psychiatric disorders. The evidence for using AD medications such as acetylcholinesterase inhibitors is questionable. Psychiatric medications can be helpful. Trazodone or SSRIs can have some efficacy in reducing disinhibition, repetitive behaviors, sexually inappropriate behaviors, and hyperorality. Small doses of atypical antipsychotics may be helpful in decreasing agitation and verbal outbursts. Non-pharmacological management includes caregiver education and support and behavioral interventions. While symptomatic treatments are likely to remain important behavior management tools, targeting the underlying pathology of bvFTD with disease-modifying agents will hopefully be the future of treatment. PMID:22847063

How preserved is episodic memory in behavioral variant frontotemporal dementia?

PubMed

Hornberger, M; Piguet, O; Graham, A J; Nestor, P J; Hodges, J R

2010-02-09

Studies have shown variable memory performance in patients with behavioral variant frontotemporal dementia (bvFTD). Our study investigated whether this variability is due to the admixture of patients with true bvFTD and phenocopy patients. We also sought to compare performance of patients with bvFTD and patients with Alzheimer disease (AD). We analyzed neuropsychological memory performance in patients with a clinical diagnosis of bvFTD divided into those who progressed (n = 50) and those who remained stable (n = 39), patients with AD (n = 64), and healthy controls (n = 64). Patients with progressive bvFTD were impaired on most memory tests to a similar level to that of patients with early AD. Findings from a subset of patients with progressive bvFTD with confirmed FTLD pathology (n = 10) corroborated these findings. By contrast, patients with phenocopy bvFTD performed significantly better than progressors and patients with AD. Logistic regression revealed that patients with bvFTD can be distinguished to a high degree (85%) on the immediate recall score of a word list learning test (Rey Auditory Verbal Learning Test). Our results provide evidence for an underlying memory deficit in "real" or progressive behavioral variant frontotemporal dementia (bvFTD) similar to Alzheimer disease, though the groups differ in orientation scores, with patients with bvFTD being intact. Exclusion solely based on impaired neuropsychological memory performance can potentially lead to an underdiagnosis of FTD.

Characterizing Sexual Behavior in Frontotemporal Dementia.

PubMed

Ahmed, Rebekah M; Kaizik, Cassandra; Irish, Muireann; Mioshi, Eneida; Dermody, Nadene; Kiernan, Matthew C; Piguet, Olivier; Hodges, John R

2015-01-01

Frontotemporal dementia (FTD) is characterized by a number of prominent behavioral changes. While FTD has been associated with the presence of aberrant or unusual sexual behaviors in a proportion of patients, few studies have formally investigated changes in sexual function in this disease. We aimed to systematically quantify changes in sexual behavior, including current symptoms and changes from prior diagnoses, in behavioral-variant (bvFTD) and semantic dementia (SD), compared to Alzheimer's disease (AD). Carers of 49 dementia patients (21 bvFTD, 11 SD, 17 AD) were interviewed using the Sexual Behavior and Intimacy Questionnaire (SIQ), a survey designed to assess changes in sexual function across multiple domains including initiating, level of affection, and aberrant or unusual sexual behavior. BvFTD patients show prominent hyposexual behavior including decreased affection, initiation, and response to advances by partners, and decreased frequency of sexual relations, compared to AD and to SD patients. The greatest changes in sexual behavior compared to pre-diagnoses were found in the bvFTD group with a 90-100% decrease in initiation, response, and frequency of sexual relations. Notably, aberrant or unusual sexual behavior was reported in a minority of bvFTD and SD patients and occurred in patients who also showed hyposexual behavior toward their partner. Overall loss of affection, reduced initiation of sexual activity, and responsiveness is an overwhelming feature of bvFTD. In contrast, aberrant or unusual sexual behavior is observed in the minority of bvFTD patients. The underlying pathophysiology of these changes likely reflects structural and functional changes in frontoinsular and limbic regions including the hypothalamus.

Hippocampal sclerosis dementia: an amnesic variant of frontotemporal degeneration

PubMed Central

Onyike, Chiadi U.; Pletnikova, Olga; Sloane, Kelly L.; Sullivan, Campbell; Troncoso, Juan C.; Rabins, Peter V.

2013-01-01

OBJECTIVE To describe characteristics of hippocampal sclerosis dementia. METHODS Convenience sample of Hippocampal sclerosis dementia (HSD) recruited from the Johns Hopkins University Brain Resource Center. Twenty-four cases with post-mortem pathological diagnosis of hippocampal sclerosis dementia were reviewed for clinical characterization. RESULTS The cases showed atrophy and neuronal loss localized to the hippocampus, amygdala and entorrhinal cortex. The majority (79.2%) had amnesia at illness onset, and many (54.2%) showed abnormal conduct and psychiatric disorder. Nearly 42% presented with an amnesic state, and 37.5% presented with amnesia plus abnormal conduct and psychiatric disorder. All eventually developed a behavioral or psychiatric disorder. Disorientation, executive dysfunction, aphasia, agnosia and apraxia were uncommon at onset. Alzheimer disease (AD) was the initial clinical diagnosis in 89% and the final clinical diagnosis in 75%. Diagnosis of frontotemporal dementia (FTD) was uncommon (seen in 8%). CONCLUSION HSD shows pathological characteristics of FTD and clinical features that mimic AD and overlap with FTD. The findings, placed in the context of earlier work, support the proposition that HSD belongs to the FTD family, where it may be identified as an amnesic variant. PMID:24363834

Discrete Neural Correlates for the Recognition of Negative Emotions: Insights from Frontotemporal Dementia

PubMed Central

Kumfor, Fiona; Irish, Muireann; Hodges, John R.; Piguet, Olivier

2013-01-01

Patients with frontotemporal dementia have pervasive changes in emotion recognition and social cognition, yet the neural changes underlying these emotion processing deficits remain unclear. The multimodal system model of emotion proposes that basic emotions are dependent on distinct brain regions, which undergo significant pathological changes in frontotemporal dementia. As such, this syndrome may provide important insight into the impact of neural network degeneration upon the innate ability to recognise emotions. This study used voxel-based morphometry to identify discrete neural correlates involved in the recognition of basic emotions (anger, disgust, fear, sadness, surprise and happiness) in frontotemporal dementia. Forty frontotemporal dementia patients (18 behavioural-variant, 11 semantic dementia, 11 progressive nonfluent aphasia) and 27 healthy controls were tested on two facial emotion recognition tasks: The Ekman 60 and Ekman Caricatures. Although each frontotemporal dementia group showed impaired recognition of negative emotions, distinct associations between emotion-specific task performance and changes in grey matter intensity emerged. Fear recognition was associated with the right amygdala; disgust recognition with the left insula; anger recognition with the left middle and superior temporal gyrus; and sadness recognition with the left subcallosal cingulate, indicating that discrete neural substrates are necessary for emotion recognition in frontotemporal dementia. The erosion of emotion-specific neural networks in neurodegenerative disorders may produce distinct profiles of performance that are relevant to understanding the neurobiological basis of emotion processing. PMID:23805313

Quantifying the eating abnormalities in frontotemporal dementia.

PubMed

Ahmed, Rebekah M; Irish, Muireann; Kam, Jonathan; van Keizerswaard, Jolanda; Bartley, Lauren; Samaras, Katherine; Hodges, John R; Piguet, Olivier

2014-12-01

Presence of eating abnormalities is one of the core criteria for the diagnosis of behavioral variant frontotemporal dementia (bvFTD), yet their occurrence in other subtypes of frontotemporal dementia (FTD) and effect on metabolic health is not known. To define and quantify patterns of eating behavior and energy, sugar, carbohydrate, protein, and fat intake, as well as indices of metabolic health in patients with bvFTD and semantic dementia (SD) compared with patients with Alzheimer disease (AD) and healthy control participants. Prospective case-controlled study involving patient and caregiver completion of surveys. Seventy-five participants with dementia (21 with bvFTD, 26 with SD, and 28 with AD) and 18 age- and education-matched healthy controls were recruited from FRONTIER, the FTD research clinic at Neuroscience Research Australia in Sydney. Caregivers of patients with FTD and AD completed validated questionnaires on appetite, eating behaviors, energy consumption, and dietary macronutrient composition. All participants completed surveys on hunger and satiety. Body mass index and weight measurements were prospectively collected. The bvFTD group had significant abnormalities in the domains of appetite (U = 111.0, z = 2.7, P = .007), eating habits (U = 69.5, z = 3.8, P = .001), food preferences (U = 57.0, z = 4.1, P = .001), swallowing (U = 109.0, z = 3.0, P = .003), and other oral behaviors (U = 141.0, z = 2.6, P = .009) compared with the AD group. The bvFTD and SD groups tended to have increased energy consumption. Compared with controls, the bvFTD group had significantly increased carbohydrate intake (251 vs 170 g/d; P = .05) and the SD group had significantly increased sugar intake (114 vs 76 g/d; P = .049). No significant differences in total fat or protein intake between the groups were found. Despite similar energy intake, the SD group had lower hunger and satiety scores compared with the bvFTD group. In contrast, hunger and satiety scores did not differ

Reward deficits in behavioural variant frontotemporal dementia include insensitivity to negative stimuli.

PubMed

Perry, David C; Datta, Samir; Sturm, Virginia E; Wood, Kristie A; Zakrzewski, Jessica; Seeley, William W; Miller, Bruce L; Kramer, Joel H; Rosen, Howard J

2017-12-01

During reward processing individuals weigh positive and negative features of a stimulus to determine whether they will pursue or avoid it. Though patients with behavioural variant frontotemporal dementia display changes in their pursuit of rewards, such as food, alcohol, money, and sex, the basis for these shifts is not clearly established. In particular, it is unknown whether patients' behaviour results from excessive focus on rewards, insensitivity to punishment, or to dysfunction in a particular stage of reward processing, such as anticipation, consumption, or action selection. Our goal was to determine the nature of the reward deficit in behavioural variant frontotemporal dementia and its underlying anatomy. We devised a series of tasks involving pleasant, unpleasant, and neutral olfactory stimuli, designed to separate distinct phases of reward processing. In a group of 25 patients with behavioural variant frontotemporal dementia and 21 control subjects, diagnosis by valence interactions revealed that patients with behavioural variant frontotemporal dementia rated unpleasant odours as less aversive than did controls and displayed lower skin conductance responses when anticipating an upcoming aversive odour. Subjective pleasantness ratings and skin conductance responses did not differ between behavioural variant frontotemporal dementia and controls for pleasant or neutral smells. In a task designed to measure the effort subjects would expend to smell or avoid smelling a stimulus, patients with behavioural variant frontotemporal dementia were less motivated, and therefore less successful than control subjects, at avoiding what they preferred not to smell, but had equivalent success at obtaining stimuli they found rewarding. Voxel-based morphometry of patients with behavioural variant frontotemporal dementia revealed that the inability to subjectively differentiate the valence of pleasant and unpleasant odours correlated with atrophy in right ventral mid

Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia

PubMed Central

Arrant, Andrew E.; Filiano, Anthony J.; Unger, Daniel E.; Young, Allen H.

2017-01-01

Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia, a neurodegenerative disease commonly characterized by disrupted social and emotional behaviour. GRN mutations are thought to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a rational treatment strategy. However, this approach has not been tested in an animal model of frontotemporal dementia and it is unclear if boosting progranulin could correct pre-existing deficits. Here, we show that adeno-associated virus-driven expression of progranulin in the medial prefrontal cortex reverses social dominance deficits in Grn+/– mice, an animal model of frontotemporal dementia due to GRN mutations. Adeno-associated virus-progranulin also corrected lysosomal abnormalities in Grn+/– mice. The adeno-associated virus-progranulin vector only transduced neurons, suggesting that restoring neuronal progranulin is sufficient to correct deficits in Grn+/– mice. To further test the role of neuronal progranulin in the development of frontotemporal dementia-related deficits, we generated two neuronal progranulin-deficient mouse lines using CaMKII-Cre and Nestin-Cre. Measuring progranulin levels in these lines indicated that most brain progranulin is derived from neurons. Both neuronal progranulin-deficient lines developed social dominance deficits similar to those in global Grn+/– mice, showing that neuronal progranulin deficiency is sufficient to disrupt social behaviour. These data support the concept of progranulin-boosting therapies for frontotemporal dementia and highlight an important role for neuron-derived progranulin in maintaining normal social function. PMID:28379303

An investigation of moral judgement in frontotemporal dementia.

PubMed

Mendez, Mario F; Anderson, Eric; Shapira, Jill S

2005-12-01

To investigate the basis of disturbed moral judgment in patients with frontotemporal dementia (FTD). FTD is characterized by difficulty in modulating social behavior. Patients lack social propriety and may perform sociopathic acts. In addition, FTD patients often lack empathy for others. These findings suggest alterations in the nature of morality in patients with FTD. We administered an inventory of moral knowledge and two moral dilemmas to 26 patients with the frontal variant of FTD, 26 patients with Alzheimer disease (AD), and 26 normal control subjects. The FTD patients met Consensus Criteria for FTD and had corroborative frontal abnormalities on functional neuroimaging. The FTD and AD patients were comparably impaired on dementia measures. All these groups showed the retention of knowledge for moral behavior and the ability to make "impersonal" moral judgments. In contrast, the FTD patients were impaired in their ability to make immediate, emotionally based moral judgments compared with the patients with AD and the normal control subjects. These findings are consistent with an attenuation of the automatic emotional identification with others that is part of the innate moral sense. Such a disturbance may result from neurodegenerative disease affecting the ventromedial frontal cortex.

Functional MRI of music emotion processing in frontotemporal dementia.

PubMed

Agustus, Jennifer L; Mahoney, Colin J; Downey, Laura E; Omar, Rohani; Cohen, Miriam; White, Mark J; Scott, Sophie K; Mancini, Laura; Warren, Jason D

2015-03-01

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. © 2014 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Distinct Neuroanatomical Substrates and Cognitive Mechanisms of Figure Copy Performance in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia

ERIC Educational Resources Information Center

Possin, Katherine L.; Laluz, Victor R.; Alcantar, Oscar Z.; Miller, Bruce L.; Kramer, Joel H.

2011-01-01

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…

Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia.

PubMed

Arrant, Andrew E; Filiano, Anthony J; Unger, Daniel E; Young, Allen H; Roberson, Erik D

2017-05-01

Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia, a neurodegenerative disease commonly characterized by disrupted social and emotional behaviour. GRN mutations are thought to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a rational treatment strategy. However, this approach has not been tested in an animal model of frontotemporal dementia and it is unclear if boosting progranulin could correct pre-existing deficits. Here, we show that adeno-associated virus-driven expression of progranulin in the medial prefrontal cortex reverses social dominance deficits in Grn+/- mice, an animal model of frontotemporal dementia due to GRN mutations. Adeno-associated virus-progranulin also corrected lysosomal abnormalities in Grn+/- mice. The adeno-associated virus-progranulin vector only transduced neurons, suggesting that restoring neuronal progranulin is sufficient to correct deficits in Grn+/- mice. To further test the role of neuronal progranulin in the development of frontotemporal dementia-related deficits, we generated two neuronal progranulin-deficient mouse lines using CaMKII-Cre and Nestin-Cre. Measuring progranulin levels in these lines indicated that most brain progranulin is derived from neurons. Both neuronal progranulin-deficient lines developed social dominance deficits similar to those in global Grn+/- mice, showing that neuronal progranulin deficiency is sufficient to disrupt social behaviour. These data support the concept of progranulin-boosting therapies for frontotemporal dementia and highlight an important role for neuron-derived progranulin in maintaining normal social function. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Use of Profanity During Letter Fluency Tasks in Frontotemporal Dementia and Alzheimer's Disease

PubMed Central

Ringman, John M.; Kwon, Eunice; Flores, Deborah L.; Rotko, Carol; Mendez, Mario F.; Lu, Po

2012-01-01

Objective To assess whether the production of profanity during letter fluency testing distinguishes frontotemporal dementia (FTD) and Alzheimer's disease (AD) patients. Background Alterations in language and social behavior typify FTD spectrum disorders. Nonetheless, in can be difficult to distinguish pathologically-defined frontotemporal lobar degeneration (FTLD) from AD clinically. Assessing verbal fluency by having patients generate as many words as they can beginning with specific letters in a given period of time can yield diverse information of diagnostic utility. Method Words produced during FAS letter fluency testing were reviewed and instances of the use of "f*ck", "*ss", and "sh*t" and other words felt to be inappropriate were sought. The frequency of these words was compared between clinically diagnosed FTD and AD patients using chi-square tests. Results We found that 6/32 (18.8%) patients with FTD generated the word "f*ck" during the "F" trial as opposed to none of 38 patients with AD (p = 0.007). Patients who said "f*ck" had diagnoses of either behavioral variant FTD (3/15), progressive non-fluent aphasia (2/8), or semantic dementia (1/3). Conclusions Though the specific neuropathology in these cases is uncertain, generation of "f*ck" during letter fluency testing appears to have utility in differentiating FTD from AD. PMID:20829665

Two distinct subtypes of right temporal variant frontotemporal dementia

PubMed Central

Josephs, K A.; Whitwell, J L.; Knopman, D S.; Boeve, B F.; Vemuri, P; Senjem, M L.; Parisi, J E.; Ivnik, R J.; Dickson, D W.; Petersen, R C.; Jack, C R.

2009-01-01

Background: Right temporal frontotemporal dementia (FTD) is an anatomic variant of FTD associated with relatively distinct behavioral and cognitive symptoms. We aimed to determine whether right temporal FTD is a homogeneous clinical, imaging, and pathologic/genetic entity. Methods: In this case-control study, 101 subjects with FTD were identified. Atlas-based parcellation generated temporal, frontal, and parietal grey matter volumes which were used to identify subjects with a right temporal dominant atrophy pattern. Clinical, neuropsychological, genetic, and neuropathologic features were reviewed. The subjects with right temporal FTD were grouped by initial clinical diagnosis and voxel-based morphometry was used to assess grey matter loss in the different groups, compared to controls, and each other. Results: We identified 20 subjects with right temporal FTD. Twelve had been initially diagnosed with behavioral variant FTD (bvFTD), and the other 8 with semantic dementia (SMD). Personality change and inappropriate behaviors were more frequent in the bvFTD group, while prosopagnosia, word-finding difficulties, comprehension problems, and topographagnosia were more frequent in the SMD group. The bvFTD group showed greater loss in frontal lobes than the SMD group. The SMD group showed greater fusiform loss than the bvFTD group. All 8 bvFTD subjects with pathologic/genetic diagnosis showed abnormalities in tau protein (7 with tau mutations), while all three SMD subjects with pathology showed abnormalities in TDP-43 (p = 0.006). Conclusions: We have identified 2 subtypes of right temporal variant frontotemporal dementia (FTD) allowing further differentiation of FTD subjects with underlying tau pathology from those with TDP-43 pathology. GLOSSARY ADPR = Alzheimer Disease Patient Registry; ADRC = Alzheimer Disease Research Center; bvFTD = behavioral variant frontotemporal dementia; CDR-SB = Clinical Dementia Rating Scale sum of boxes; FDR = False Discovery Rate; FTD

Psychotic-Like Speech in Frontotemporal Dementia.

PubMed

Mendez, Mario F; Carr, Andrew R; Paholpak, Pongsatorn

2017-01-01

Behavioral variant frontotemporal dementia (bvFTD) may result in psychotic-like speech without other psychotic features. The authors identified a bvFTD subgroup with pressure of speech, tangentiality, derailment, clanging/rhyming, and punning associated with the right anterior temporal atrophy and sparing of the left frontal lobe.

Towards affordable biomarkers of frontotemporal dementia: A classification study via network's information sharing.

PubMed

Dottori, Martin; Sedeño, Lucas; Martorell Caro, Miguel; Alifano, Florencia; Hesse, Eugenia; Mikulan, Ezequiel; García, Adolfo M; Ruiz-Tagle, Amparo; Lillo, Patricia; Slachevsky, Andrea; Serrano, Cecilia; Fraiman, Daniel; Ibanez, Agustin

2017-06-19

Developing effective and affordable biomarkers for dementias is critical given the difficulty to achieve early diagnosis. In this sense, electroencephalographic (EEG) methods offer promising alternatives due to their low cost, portability, and growing robustness. Here, we relied on EEG signals and a novel information-sharing method to study resting-state connectivity in patients with behavioral variant frontotemporal dementia (bvFTD) and controls. To evaluate the specificity of our results, we also tested Alzheimer's disease (AD) patients. The classification power of the ensuing connectivity patterns was evaluated through a supervised classification algorithm (support vector machine). In addition, we compared the classification power yielded by (i) functional connectivity, (ii) relevant neuropsychological tests, and (iii) a combination of both. BvFTD patients exhibited a specific pattern of hypoconnectivity in mid-range frontotemporal links, which showed no alterations in AD patients. These functional connectivity alterations in bvFTD were replicated with a low-density EEG setting (20 electrodes). Moreover, while neuropsychological tests yielded acceptable discrimination between bvFTD and controls, the addition of connectivity results improved classification power. Finally, classification between bvFTD and AD patients was better when based on connectivity than on neuropsychological measures. Taken together, such findings underscore the relevance of EEG measures as potential biomarker signatures for clinical settings.

Motor signatures of emotional reactivity in frontotemporal dementia.

PubMed

Marshall, Charles R; Hardy, Chris J D; Russell, Lucy L; Clark, Camilla N; Bond, Rebecca L; Dick, Katrina M; Brotherhood, Emilie V; Mummery, Cath J; Schott, Jonathan M; Rohrer, Jonathan D; Kilner, James M; Warren, Jason D

2018-01-18

Automatic motor mimicry is essential to the normal processing of perceived emotion, and disrupted automatic imitation might underpin socio-emotional deficits in neurodegenerative diseases, particularly the frontotemporal dementias. However, the pathophysiology of emotional reactivity in these diseases has not been elucidated. We studied facial electromyographic responses during emotion identification on viewing videos of dynamic facial expressions in 37 patients representing canonical frontotemporal dementia syndromes versus 21 healthy older individuals. Neuroanatomical associations of emotional expression identification accuracy and facial muscle reactivity were assessed using voxel-based morphometry. Controls showed characteristic profiles of automatic imitation, and this response predicted correct emotion identification. Automatic imitation was reduced in the behavioural and right temporal variant groups, while the normal coupling between imitation and correct identification was lost in the right temporal and semantic variant groups. Grey matter correlates of emotion identification and imitation were delineated within a distributed network including primary visual and motor, prefrontal, insular, anterior temporal and temporo-occipital junctional areas, with common involvement of supplementary motor cortex across syndromes. Impaired emotional mimesis may be a core mechanism of disordered emotional signal understanding and reactivity in frontotemporal dementia, with implications for the development of novel physiological biomarkers of socio-emotional dysfunction in these diseases.

Perception of emotion in frontotemporal dementia and Alzheimer disease.

PubMed

Lavenu, I; Pasquier, F; Lebert, F; Petit, H; Van der Linden, M

1999-01-01

Frontotemporal dementia (FTD) is the second cause of degenerative dementia. Behavioral changes occur before the cognitive decline and remain the major feature. A poor perception of emotion could account for some behavioral symptoms. The aim of this study was to assess the perception of emotion in patients with FTD and to compare it with that of patients with Alzheimer disease (AD). Fifty subjects performed the tests: 20 patients with probable AD, 18 patients with FTD, and 12 matched controls. The two patient groups did not differ in age, sex, severity of dementia, duration of the disease, and language tests. Subjects had to recognize and point out the name of one of seven basic emotions (anger, disgust, happiness, fear, sadness, surprise, and contempt) on a set of 28 faces presented on slides. The three groups were equally able to distinguish a face displaying affect from one not displaying affect. Naming of emotion was worse in patients with FTD than in patients with AD (correct answers 46% vs. 62%; p = 0.0006) who did not differ significantly from controls (72%). Anger, sadness, and disgust were less recognized in FTD than in AD patients who did not differ from controls, whereas fear and contempt were poorly recognized in both groups of patients compared with controls. These findings argue for different neural substrates underlying the recognition of various basic emotions. Behavioral disorders in FTD may be partly due to an impaired interpretation of the emotional environment.

Anatomical correlates of reward-seeking behaviours in behavioural variant frontotemporal dementia

PubMed Central

Sturm, Virginia E.; Seeley, William W.; Miller, Bruce L.; Kramer, Joel H.; Rosen, Howard J.

2014-01-01

Behavioural variant frontotemporal dementia is characterized by abnormal responses to primary reward stimuli such as food, sex and intoxicants, suggesting abnormal functioning of brain circuitry mediating reward processing. The goal of this analysis was to determine whether abnormalities in reward-seeking behaviour in behavioural variant frontotemporal dementia are correlated with atrophy in regions known to mediate reward processing. Review of case histories in 103 patients with behavioural variant frontotemporal dementia identified overeating or increased sweet food preference in 80 (78%), new or increased alcohol or drug use in 27 (26%), and hypersexuality in 17 (17%). For each patient, a primary reward-seeking score of 0–3 was created with 1 point given for each target behaviour (increased seeking of food, drugs, or sex). Voxel-based morphometry performed in 91 patients with available imaging revealed that right ventral putamen and pallidum atrophy correlated with higher reward-seeking scores. Each of the reward-related behaviours involved partially overlapping right hemisphere reward circuit regions including putamen, globus pallidus, insula and thalamus. These findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback. PMID:24740987

Genetics Home Reference: frontotemporal dementia with parkinsonism-17

MedlinePlus

... more common than this estimate. FTDP-17 probably accounts for a small percentage of all cases of frontotemporal dementia. Related Information What information about a genetic condition can statistics ...

Episodic Memory in Alzheimer Disease, Frontotemporal Dementia, and Dementia With Lewy Bodies/Parkinson Disease Dementia: Disentangling Retrieval From Consolidation.

PubMed

Economou, Alexandra; Routsis, Christopher; Papageorgiou, Sokratis G

2016-01-01

Differences in episodic memory performance in patients with Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB)/Parkinson disease with dementia (PDD) are inconsistent and task dependent. The inconsistencies may be attributed to the different tasks drawing on different memory processes. Few studies have examined episodic memory impairment in the above groups using memory tests that facilitate encoding, to distinguish memory deficits due to impairment of specific processes. We examined the memory performance of 106 AD patients, 51 FTD patients, 26 DLB/PDD patients, and 37 controls using the Five-Words Test, a 5-item memory test that facilitates encoding. The patient groups did not differ in modified Mini Mental State Examination scores. AD patients scored lowest on the Five-Words Test overall, and showed the greatest reduction from immediate total recall to delayed free recall relative to the other 2 groups, consistent with a predominantly consolidation deficit. DLB/PDD patients showed the largest improvement from delayed free to delayed total recall relative to the other 2 groups, consistent with a predominantly retrieval deficit. Deficits in both consolidation and retrieval underlie the memory impairment of the patients, to different extents, and contribute to the theoretical understanding of the nature of the memory impairment of the patient groups.

Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study.

PubMed

Whitwell, Jennifer L; Przybelski, Scott A; Weigand, Stephen D; Ivnik, Robert J; Vemuri, Prashanthi; Gunter, Jeffrey L; Senjem, Matthew L; Shiung, Maria M; Boeve, Bradley F; Knopman, David S; Parisi, Joseph E; Dickson, Dennis W; Petersen, Ronald C; Jack, Clifford R; Josephs, Keith A

2009-11-01

The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one

Assessment of Iron Deposition in the Brain in Frontotemporal Dementia and Its Correlation with Behavioral Traits.

PubMed

Sheelakumari, R; Kesavadas, C; Varghese, T; Sreedharan, R M; Thomas, B; Verghese, J; Mathuranath, P S

2017-10-01

Brain iron deposition has been implicated as a major culprit in the pathophysiology of neurodegeneration. However, the quantitative assessment of iron in behavioral variant frontotemporal dementia and primary progressive aphasia brains has not been performed, to our knowledge. The aim of our study was to investigate the characteristic iron levels in the frontotemporal dementia subtypes using susceptibility-weighted imaging and report its association with behavioral profiles. This prospective study included 46 patients with frontotemporal dementia (34 with behavioral variant frontotemporal dementia and 12 with primary progressive aphasia) and 34 age-matched healthy controls. We performed behavioral and neuropsychological assessment in all the subjects. The quantitative iron load was determined on SWI in the superior frontal gyrus and temporal pole, precentral gyrus, basal ganglia, anterior cingulate, frontal white matter, head and body of the hippocampus, red nucleus, substantia nigra, insula, and dentate nucleus. A linear regression analysis was performed to correlate iron content and behavioral scores in patients. The iron content of the bilateral superior frontal and temporal gyri, anterior cingulate, putamen, right hemispheric precentral gyrus, insula, hippocampus, and red nucleus was higher in patients with behavioral variant frontotemporal dementia than in controls. Patients with primary progressive aphasia had increased iron levels in the left superior temporal gyrus. In addition, right superior frontal gyrus iron deposition discriminated behavioral variant frontotemporal dementia from primary progressive aphasia. A strong positive association was found between apathy and iron content in the superior frontal gyrus and disinhibition and iron content in the putamen. Quantitative assessment of iron deposition with SWI may serve as a new biomarker in the diagnostic work-up of frontotemporal dementia and help distinguish frontotemporal dementia subtypes. © 2017

FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease.

PubMed

Foster, Norman L; Heidebrink, Judith L; Clark, Christopher M; Jagust, William J; Arnold, Steven E; Barbas, Nancy R; DeCarli, Charles S; Turner, R Scott; Koeppe, Robert A; Higdon, Roger; Minoshima, Satoshi

2007-10-01

Distinguishing Alzheimer's disease (AD) and frontotemporal dementia (FTD) currently relies on a clinical history and examination, but positron emission tomography with [(18)F] fluorodeoxyglucose (FDG-PET) shows different patterns of hypometabolism in these disorders that might aid differential diagnosis. Six dementia experts with variable FDG-PET experience made independent, forced choice, diagnostic decisions in 45 patients with pathologically confirmed AD (n = 31) or FTD (n = 14) using five separate methods: (1) review of clinical summaries, (2) a diagnostic checklist alone, (3) summary and checklist, (4) transaxial FDG-PET scans and (5) FDG-PET stereotactic surface projection (SSP) metabolic and statistical maps. In addition, we evaluated the effect of the sequential review of a clinical summary followed by SSP. Visual interpretation of SSP images was superior to clinical assessment and had the best inter-rater reliability (mean kappa = 0.78) and diagnostic accuracy (89.6%). It also had the highest specificity (97.6%) and sensitivity (86%), and positive likelihood ratio for FTD (36.5). The addition of FDG-PET to clinical summaries increased diagnostic accuracy and confidence for both AD and FTD. It was particularly helpful when raters were uncertain in their clinical diagnosis. Visual interpretation of FDG-PET after brief training is more reliable and accurate in distinguishing FTD from AD than clinical methods alone. FDG-PET adds important information that appropriately increases diagnostic confidence, even among experienced dementia specialists.

Insight in Frontotemporal Dementia: Conceptual Analysis and Empirical Evaluation of the Consensus Criterion ''Loss of Insight'' in Frontotemporal Dementia

ERIC Educational Resources Information Center

Evers, Kathinka; Kilander, Lena; Lindau, Maria

2007-01-01

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…

The tailored activity program (TAP) to address behavioral disturbances in frontotemporal dementia: a feasibility and pilot study.

PubMed

O'Connor, Claire M; Clemson, Lindy; Brodaty, Henry; Low, Lee-Fay; Jeon, Yun-Hee; Gitlin, Laura N; Piguet, Olivier; Mioshi, Eneida

2017-10-15

To explore the feasibility of implementing the Tailored Activity Program with a cohort of people with frontotemporal dementia and their carers (dyads). The Tailored Activity Program is an occupational therapy based intervention that involves working collaboratively with family carers and prescribes personalized activities for behavioral management in people with dementia. Twenty dyads randomized into the study (Tailored Activity Program: n = 9; Control: n = 11) were assessed at baseline and 4-months. Qualitative analyzes evaluated feasibility and acceptability of the program for the frontotemporal dementia cohort, and quantitative analyzes (linear mixed model analyzes, Spearman's rho correlations) measured the impact of the program on the dyads. The Tailored Activity Program was an acceptable intervention for the frontotemporal dementia dyads. Qualitative analyses identified five themes: "carer perceived benefits", "carer readiness to change", "strategies used by carer to engage person with dementia", "barriers to the Tailored Activity Program uptake/implementation", and "person with dementia engagement". Quantitative outcomes showed an overall reduction of behavioral symptoms (F 18.34  = 8.073, p = 0.011) and maintenance of functional performance in the person with dementia (F 18.03  = 0.375, p = 0.548). This study demonstrates the potential for using an activity-based intervention such as the Tailored Activity Program in frontotemporal dementia. Service providers should recognize that while people with frontotemporal dementia present with challenging issues, tailored therapies may support their function and reduce their behavioral symptoms. Implications for rehabilitation The Tailored Activity Program is an occupational therapy based intervention that involves prescribing personalized activities for behavioral management in dementia. The Tailored Activity Program is an acceptable and feasible intervention approach to address some of the

Dissociable executive functions in behavioral variant frontotemporal and Alzheimer dementias

PubMed Central

Feigenbaum, Dana; Rankin, Katherine P.; Smith, Glenn E.; Boxer, Adam L.; Wood, Kristie; Hanna, Sherrie M.; Miller, Bruce L.; Kramer, Joel H.

2013-01-01

Objective: The objective of this study was to determine which aspects of executive functions are most affected in behavioral variant frontotemporal dementia (bvFTD) and best differentiate this syndrome from Alzheimer disease (AD). Methods: We compared executive functions in 22 patients diagnosed with bvFTD, 26 with AD, and 31 neurologically healthy controls using a conceptually driven and comprehensive battery of executive function tests, the NIH EXAMINER battery (http://examiner.ucsf.edu). Results: The bvFTD and the AD patients were similarly impaired compared with controls on tests of working memory, category fluency, and attention, but the patients with bvFTD showed significantly more severe impairments than the patients with AD on tests of letter fluency, antisaccade accuracy, social decision-making, and social behavior. Discriminant function analysis with jackknifed cross-validation classified the bvFTD and AD patient groups with 73% accuracy. Conclusions: Executive function assessment can support bvFTD diagnosis when measures are carefully selected to emphasize frontally specific functions. PMID:23658382

Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia.

PubMed

Harris, Jennifer M; Gall, Claire; Thompson, Jennifer C; Richardson, Anna M T; Neary, David; du Plessis, Daniel; Pal, Piyali; Mann, David M A; Snowden, Julie S; Jones, Matthew

2013-05-14

We aimed to assess sensitivity and specificity of the updated criteria for behavioral variant frontotemporal dementia (bvFTD) based on a large autopsy-confirmed cohort of patients with dementia. Two hundred thirty-nine consecutive pathologically confirmed dementia patients, clinically assessed in a specialist cognitive unit were identified. Patients with predominant aphasia, motor disorders, or insufficient clinical information were excluded. Frontotemporal Dementia Consensus criteria were applied to anonymized clinical data taken from patients' initial assessment by raters who were blinded to clinical and pathologic diagnosis. The final study cohort comprised 156 patients with predominantly early-onset dementia. The updated criteria for possible bvFTD had a sensitivity of 95% and specificity of 82%. Probable bvFTD criteria had a sensitivity of 85% and specificity of 95%. False positives were predominantly patients with presenile Alzheimer disease. Revised diagnostic criteria show encouragingly high sensitivity and specificity when applied to patients with early-onset dementia. They therefore provide a useful tool both for specialist researchers and general clinicians. There is a need for further prospective studies of sensitivity and specificity involving a broader spectrum of patients with dementia.

Genetics Home Reference: CHMP2B-related frontotemporal dementia

MedlinePlus

... CHMP2B -related frontotemporal dementia develop progressive problems with speech and language (aphasia). They may have trouble speaking, although they can often understand others' speech and written text. Affected individuals may also have ...

Person-Based Versus Generalized Impulsivity Disinhibition in Frontotemporal Dementia and Alzheimer Disease.

PubMed

Paholpak, Pongsatorn; Carr, Andrew R; Barsuglia, Joseph P; Barrows, Robin J; Jimenez, Elvira; Lee, Grace J; Mendez, Mario F

2016-09-19

While much disinhibition in dementia results from generalized impulsivity, in behavioral variant frontotemporal dementia (bvFTD) disinhibition may also result from impaired social cognition. To deconstruct disinhibition and its neural correlates in bvFTD vs. early-onset Alzheimer's disease (eAD). Caregivers of 16 bvFTD and 21 matched-eAD patients completed the Frontal Systems Behavior Scale disinhibition items. The disinhibition items were further categorized into (1) "person-based" subscale which predominantly associated with violating social propriety and personal boundary and (2) "generalized-impulsivity" subscale which included nonspecific impulsive acts. Subscale scores were correlated with grey matter volumes from tensor-based morphometry on magnetic resonance images. In comparison to the eAD patients, the bvFTD patients developed greater person-based disinhibition (P < 0.001) but comparable generalized impulsivity. Severity of person-based disinhibition significantly correlated with the left anterior superior temporal sulcus (STS), and generalized-impulsivity correlated with the right orbitofrontal cortex (OFC) and the left anterior temporal lobe (aTL). Person-based disinhibition was predominant in bvFTD and correlated with the left STS. In both dementia, violations of social propriety and personal boundaries involved fronto-parieto-temporal network of Theory of Mind, whereas nonspecific disinhibition involved the OFC and aTL. © The Author(s) 2016.

Bradycardia in frontotemporal dementia.

PubMed

Robles Bayón, A; Gude Sampedro, F; Torregrosa Quesada, J M

2014-03-01

Numerous regions of the brain, such as the medial frontal cortex, orbitofrontal cortex, insula, and amygdala, participate in the autonomic control of cardiovascular functions such as heart rate. The degenerative process in frontotemporal dementia (FTD) involves the listed anatomical structures and may therefore produce dysautonomic cardiovascular symptoms. To observe whether or not non-cardiogenic bradycardia was more frequent in a group of patients with FTD than in subjects with mild cognitive impairment or dementia of a different aetiology. Once patients with primary cardiac arrhythmia were excluded, we registered the heart rates of 258 patients with cognitive symptoms (36 with FTD, 22 with Alzheimer disease, 23 with vascular dementia, 10 with other dementias, and 167 with non-dementia cognitive impairment). Bradycardia (<60 beats/minute) was significantly more frequent in patients with FTD. This difference remained significant after excluding subjects undergoing treatment with a potentially bradycardic effect. Bradycardia was more prevalent in behavioural FTD cases than in cases of the aphasic variant, and we detected a trend toward higher frequency among patients with more pronounced right hemisphere atrophy. Moreover, mean systolic blood pressure in FTD patients was lower than in other participants, and systolic hypotension (<120 and <100mm Hg) was more prevalent. Bradycardia was more frequent in the FTD sample than in other patients with cognitive symptoms. Further investigations will be necessary before we may consider bradycardia to be a sign supporting diagnosis of FTD or its behavioural variant. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia

PubMed Central

Vatsavayai, Sarat C; Yoon, Soo Jin; Gardner, Raquel C; Gendron, Tania F; Vargas, Jose Norberto S; Trujillo, Andrew; Pribadi, Mochtar; Phillips, Joanna J; Gaus, Stephanie E; Hixson, John D; Garcia, Paul A; Rabinovici, Gil D; Coppola, Giovanni; Geschwind, Daniel H; Petrucelli, Leonard; Miller, Bruce L; Seeley, William W

2016-01-01

See Scaber and Talbot (doi:10.1093/aww264) for a scientific commentary on this article. A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72 repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia–motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation. PMID:27797809

Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia

PubMed Central

Schaffer, Barbara A. J.; Bertram, Lars; Miller, Bruce L.; Mullin, Kristina; Weintraub, Sandra; Johnson, Nancy; Bigio, Eileen H.; Mesulam, Marsel; Wiedau-Pazos, Martina; Jackson, George R.; Cummings, Jeffrey L.; Cantor, Rita M.; Levey, Allan I.; Tanzi, Rudolph E.; Geschwind, Daniel H.

2009-01-01

Background Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found. Objective To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. Design, Setting, and Participants Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer’s Genetics Study). Results Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2−68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer’s Genetics sample showed the same direction of association as the case-control sample. Conclusions To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets. PMID:18852354

The Power of Neuroimaging Biomarkers for Screening Frontotemporal Dementia

PubMed Central

McMillan, Corey T.; Avants, Brian B.; Cook, Philip; Ungar, Lyle; Trojanowski, John Q.; Grossman, Murray

2014-01-01

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disease that can result from either frontotemporal lobar degeneration (FTLD) or Alzheimer’s disease (AD) pathology. It is critical to establish statistically powerful biomarkers that can achieve substantial cost-savings and increase feasibility of clinical trials. We assessed three broad categories of neuroimaging methods to screen underlying FTLD and AD pathology in a clinical FTD series: global measures (e.g., ventricular volume), anatomical volumes of interest (VOIs) (e.g., hippocampus) using a standard atlas, and data-driven VOIs using Eigenanatomy. We evaluated clinical FTD patients (N=93) with cerebrospinal fluid, gray matter (GM) MRI, and diffusion tensor imaging (DTI) to assess whether they had underlying FTLD or AD pathology. Linear regression was performed to identify the optimal VOIs for each method in a training dataset and then we evaluated classification sensitivity and specificity in an independent test cohort. Power was evaluated by calculating minimum sample sizes (mSS) required in the test classification analyses for each model. The data-driven VOI analysis using a multimodal combination of GM MRI and DTI achieved the greatest classification accuracy (89% SENSITIVE; 89% SPECIFIC) and required a lower minimum sample size (N=26) relative to anatomical VOI and global measures. We conclude that a data-driven VOI approach employing Eigenanatomy provides more accurate classification, benefits from increased statistical power in unseen datasets, and therefore provides a robust method for screening underlying pathology in FTD patients for entry into clinical trials. PMID:24687814

Diagnosing Frontotemporal Lobar Degeneration

ClinicalTrials.gov

2016-11-10

Corticobasal Syndrome; Progressive Supranuclear Palsy; Behavioral Variant Frontotemporal Dementia; Semantic Dementia; Progressive Nonfluent Aphasia; Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia

What's in a Name: Voxel-Based Morphometric Analyses of MRI and Naming Difficulty in Alzheimer's Disease, Frontotemporal Dementia and Corticobasal Degeneration

ERIC Educational Resources Information Center

Grossman, Murray; McMillan, Corey; Moore, Peachie; Ding, Lijun; Glosser, Guila; Work, Melissa; Gee, James

2004-01-01

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…

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

PubMed Central

Goedert, Michel; Ghetti, Bernardino; Spillantini, Maria Grazia

2012-01-01

Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are inherited in an autosomal-dominant manner. Mutations in seven genes cause FTD, with those in tau (MAPT), chromosome 9 open reading frame 72 (C9ORF72), and progranulin (GRN) being the most common. Mutations in MAPT give rise to FTLD-tau and mutations in C9ORF72 and GRN to FTLD-TDP. The other four genes are transactive response–DNA binding protein-43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). Mutations in TARDBP and VCP give rise to FTLD-TDP, mutations in FUS to FTLD-FUS, and mutations in CHMP2B to FTLD-UPS. The discovery that mutations in MAPT cause neurodegeneration and dementia has important implications for understanding Alzheimer disease. PMID:22355793

The Accuracy of INECO Frontal Screening in the Diagnosis of Executive Dysfunction in Frontotemporal Dementia and Alzheimer Disease.

PubMed

Bahia, Valéria S; Cecchini, Mário A; Cassimiro, Luciana; Viana, Rene; Lima-Silva, Thais B; de Souza, Leonardo Cruz; Carvalho, Viviane Amaral; Guimarães, Henrique C; Caramelli, Paulo; Balthazar, Márcio L F; Damasceno, Benito; Brucki, Sônia M D; Nitrini, Ricardo; Yassuda, Mônica S

2018-05-04

Executive dysfunction is a common symptom in neurodegenerative disorders and is in need of easy-to-apply screening tools that might identify it. The aims of the present study were to examine some of the psychometric characteristics of the Brazilian version of the INECO frontal screening (IFS), and to investigate its accuracy to diagnose executive dysfunction in dementia and its accuracy to differentiate Alzheimer disease (AD) from the behavioral variant of frontotemporal dementia (bvFTD). Patients diagnosed with bvFTD (n=18) and AD (n=20), and 15 healthy controls completed a neuropsychological battery, the Neuropsychiatric Inventory, the Cornell Scale for Depression in Dementia, the Clinical Dementia Rating, and the IFS. The IFS had acceptable internal consistency (α=0.714) and was significantly correlated with general cognitive measures and with neuropsychological tests. The IFS had adequate accuracy to differentiate patients with dementia from healthy controls (AUC=0.768, cutoff=19.75, sensitivity=0.80, specificity=0.63), but low accuracy to differentiate bvFTD from AD (AUC=0.594, cutoff=16.75, sensitivity=0.667, specificity=0.600). The present study suggested that the IFS may be used to screen for executive dysfunction in dementia. Nonetheless, it should be used with caution in the differential diagnosis between AD and bvFTD.

Profiles of White Matter Tract Pathology in Frontotemporal Dementia

PubMed Central

Mahoney, Colin J; Ridgway, Gerard R; Malone, Ian B; Downey, Laura E; Beck, Jonathan; Kinnunen, Kirsi M; Schmitz, Nicole; Golden, Hannah L; Rohrer, Jonathan D; Schott, Jonathan M; Rossor, Martin N; Ourselin, Sebastien; Mead, Simon; Fox, Nick C; Warren, Jason D

2014-01-01

Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template-based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co-localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies. PMID:24510641

Emotional quotient in frontotemporal dementia vs. Alzheimer's disease: the role of socioemotional agnosia.

PubMed

Carr, Andrew R; Samimi, Mersal S; Paholpak, Pongsatorn; Jimenez, Elvira E; Mendez, Mario F

2017-01-01

Socioemotional dysfunction distinguishes behavioural variant frontotemporal dementia (bvFTD) from other dementias. Patients with bvFTD not only have early social impairment and emotional blunting, but they also have agnosia of their socioemotional dysfunction. To investigate the relationship between agnosia and dysfunction, we assessed self-knowledge of socioemotional dysfunction with an emotional quotient (EQ) scale administered to 12 patients with bvFTD and a comparison group of 12 age-matched patients with Alzheimer's disease (AD), and compared these self-ratings to caregiver ratings of social dysfunction and emotional blunting. The bvFTD patients self-rated as having higher EQs than the AD patients, particularly higher self-ratings of their Social Skills, an EQ subscale which correlated with increased emotional blunting. On within-groups analysis, the bvFTD patients' high self-ratings of their EQ Appraisal of Emotions correlated with increased socioemotional dysfunction, whereas all of the AD patients' self-ratings correlated appropriately with their degree of dysfunction. Large socioemotional agnosia scores (EQ minus function) distinguishes bvFTD from AD. Additionally, in bvFTD, agnosia specifically for their ability to appreciate others' emotions correlates with the degree of socioemotional dysfunction, suggesting a role for socioemotional agnosia in increasing socioemotional dysfunction.

Factors Underpinning Caregiver Burden in Frontotemporal Dementia Differ in Spouses and their Children

PubMed Central

Kaizik, Cassandra; Caga, Jashelle; Camino, Julieta; O’Connor, Claire M.; McKinnon, Colleen; Oyebode, Jan R.; Piguet, Olivier; Hodges, John R.; Mioshi, Eneida

2017-01-01

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

All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity.

PubMed

Midorikawa, Akira; Leyton, Cristian E; Foxe, David; Landin-Romero, Ramon; Hodges, John R; Piguet, Olivier

2016-09-06

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. 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). 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. 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. 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.

Concurrent white and gray matter degeneration of disease-specific networks in early-stage Alzheimer's disease and behavioral variant frontotemporal dementia.

PubMed

Steketee, Rebecca M E; Meijboom, Rozanna; de Groot, Marius; Bron, Esther E; Niessen, Wiro J; van der Lugt, Aad; van Swieten, John C; Smits, Marion

2016-07-01

This study investigates regional coherence between white matter (WM) microstructure and gray matter (GM) volume and perfusion measures in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) using a correlational approach. WM-GM coherence, compared with controls, was stronger between cingulum WM and frontotemporal GM in AD, and temporoparietal GM in bvFTD. In addition, in AD compared with controls, coherence was stronger between inferior fronto-occipital fasciculus WM microstructure and occipital GM perfusion. In this first study assessing regional WM-GM coherence in AD and bvFTD, we show that WM microstructure and GM volume and perfusion measures are coherent, particularly in regions implicated in AD and bvFTD pathology. This indicates concurrent degeneration in disease-specific networks. Our methodology allows for the detection of incipient abnormalities that go undetected in conventional between-group analyses. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical update on frontotemporal dementia: diagnosis and treatment.

PubMed

Mocellin, Ramon; Scholes, Amelia; Walterfang, Mark; Looi, Jeffrey C L; Velakoulis, Dennis

2015-10-01

To provide a clinical update for general psychiatrists on frontotemporal dementias (FTDs) using a selective narrative review of recent findings and advances in conceptualising, diagnosing and treating FTD. General psychiatrists can apply their skills to support patients, carers, GPs and allied health workers in comprehensive care of persons with FTD. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Emergence of artistic talent in frontotemporal dementia.

PubMed

Miller, B L; Cummings, J; Mishkin, F; Boone, K; Prince, F; Ponton, M; Cotman, C

1998-10-01

To describe the clinical, neuropsychological, and imaging features of five patients with frontotemporal dementia (FTD) who acquired new artistic skills in the setting of dementia. Creativity in the setting of dementia has recently been reported. We describe five patients who became visual artists in the setting of FTD. Sixty-nine FTD patients were interviewed regarding visual abilities. Five became artists in the early stages of FTD. Their history, artistic process, neuropsychology, and anatomy are described. On SPECT or pathology, four of the five patients had the temporal variant of FTD in which anterior temporal lobes are involved but the dorsolateral frontal cortex is spared. Visual skills were spared but language and social skills were devastated. Loss of function in the anterior temporal lobes may lead to the "facilitation" of artistic skills. Patients with the temporal lobe variant of FTD offer a window into creativity.

My belief or yours? Differential theory of mind deficits in frontotemporal dementia and Alzheimer's disease.

PubMed

Le Bouc, Raphaël; Lenfant, Pierre; Delbeuck, Xavier; Ravasi, Laura; Lebert, Florence; Semah, Franck; Pasquier, Florence

2012-10-01

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

Genetic variability in CHMP2B and frontotemporal dementia.

PubMed

Momeni, Parastoo; Rogaeva, Ekaterina; Van Deerlin, Vivianna; Yuan, Wuxing; Grafman, Jordan; Tierney, Michael; Huey, Edward; Bell, Jason; Morris, Chris M; Kalaria, Rajesh N; van Rensburg, Susan J; Niehaus, Dana; Potocnik, Felix; Kawarai, Toshitaka; Salehi-Rad, Shabnam; Sato, Christine; St George-Hyslop, Peter; Hardy, John

2006-01-01

A nonsense/protein chain-terminating mutation in the CHMP2B gene has recently been reported as a cause of frontotemporal dementia (FTD) in the single large family known to show linkage to chromosome 3. Screening for mutations in this gene in a large series of FTD families and individual patients led to the identification of a protein-truncating mutation in 2 unaffected members of an Afrikaner family with FTD, but not in their affected relatives. The putative pathogenicity of CHMP2B mutations for dementia is discussed.

Enhancing caregivers' understanding of dementia and tailoring activities in frontotemporal dementia: two case studies.

PubMed

O'Connor, Claire M; Clemson, Lindy; Brodaty, Henry; Gitlin, Laura N; Piguet, Olivier; Mioshi, Eneida

2016-01-01

The purpose of this study is to describe the intervention process and results of the Tailored Activities Program (TAP) in two people diagnosed with Frontotemporal Dementia (FTD). TAP is an occupational therapy (OT) community-based intervention program that prescribes personalised activities to reduce difficult behaviours of dementia. The OT works with carers over a 4-month period (assessment, activity prescription and generalisation of strategies). Study measures were collected (blind researcher) pre- and post-intervention: cognition, functional disability, behavioural symptoms and Caregiver Confidence and Vigilance. A 51-year-old woman with behavioural-variant FTD could consistently engage in more activities post-intervention, with scores indicating improvements to behaviour, function and caregiver confidence. A 63-year-old man with semantic variant FTD engaged well in the prescribed activities, with scores reflecting reduced carer distress regarding challenging behaviours and improved caregiver vigilance. TAP is efficacious in FTD, allowing for differences in approach for FTD subtype, where behavioural symptoms are very severe and pervasive. The Tailored Activities Program is an intervention which can be tailored to account for unique behavioural and language profiles inherent across frontotemporal dementia (FTD) subtypes. Maintaining a flexible approach when applying an intervention in FTD allows for tailoring to individual case variability within FTD subtypes.

False-belief understanding in frontotemporal dementia and Alzheimer's disease.

PubMed

Fernandez-Duque, Diego; Baird, Jodie A; Black, Sandra E

2009-05-01

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.

Therapeutic and diagnostic challenges for frontotemporal dementia

PubMed Central

D’Alton, Simon; Lewis, Jada

2014-01-01

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

One size does not fit all: face emotion processing impairments in semantic dementia, behavioural-variant frontotemporal dementia and Alzheimer's disease are mediated by distinct cognitive deficits.

PubMed

Miller, Laurie A; Hsieh, Sharpley; Lah, Suncica; Savage, Sharon; Hodges, John R; Piguet, Olivier

2012-01-01

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.

False Recognition in Lewy-Body Disease and Frontotemporal Dementia

ERIC Educational Resources Information Center

de Boysson, C.; Belleville, S.; Phillips, N. A.; Johns, E. K.; Goupil, D.; Souchay, C.; Bouchard, R.; Chertkow, H.

2011-01-01

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…

Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia.

PubMed

Benussi, Alberto; Di Lorenzo, Francesco; Dell'Era, Valentina; Cosseddu, Maura; Alberici, Antonella; Caratozzolo, Salvatore; Cotelli, Maria Sofia; Micheli, Anna; Rozzini, Luca; Depari, Alessandro; Flammini, Alessandra; Ponzo, Viviana; Martorana, Alessandro; Caltagirone, Carlo; Padovani, Alessandro; Koch, Giacomo; Borroni, Barbara

2017-08-15

To determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish Alzheimer disease (AD) from frontotemporal dementia (FTD). Paired-pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis. A total of 175 participants met the inclusion criteria. We diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. We found that while patients with AD are characterized by a specific impairment of SAI, FTD shows a remarkable dysfunction of SICI-ICF intracortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8% and specificity of 88.6%, AD from HC with a sensitivity of 84.8% and specificity of 90.6%, and FTD from HC with a sensitivity of 90.2% and specificity of 78.1%. These results were confirmed in patients with mild disease. TMS is a noninvasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice. This study provides Class III evidence that TMS measures can distinguish patients with AD from those with FTD. © 2017 American Academy of Neurology.

Quantitative Balance and Gait Measurement in Patients with Frontotemporal Dementia and Alzheimer Diseases: A Pilot Study.

PubMed

Velayutham, Selva Ganapathy; Chandra, Sadanandavalli Retnaswami; Bharath, Srikala; Shankar, Ravi Girikamatha

2017-01-01

Alzhiemers disease and Frontotemporal dementia are common neurodegenerative dementias with a wide prevalence. Falls are a common cause of morbidity in these patients. Identifying subclinical involvement of these parameters might serve as a tool in differential analysis of these distinct parameters involved in these conditions and also help in planning preventive strategies to prevent falls. Eight patients in age and gender matched patients in each group were compared with normal controls. Standardizes methods of gait and balance aseesment were done in all persons. Results revealed subclinical involvement of gait and balancesin all groups specially during divided attention. The parameters were significantly more affected in patients. Patients with AD and FTD had involement of over all ambulation index balance more affected in AD patients FTD patients showed step cycle, stride length abnormalities. There is balance and gait involvement in normal ageing as well as patients with AD and FTD. The pattern of involvement in AD correlates with WHERE pathway involvement and FTD with frontal subcortical circuits involvement. Identification the differential patterns of involvement in subclinical stage might help to differentiate normal ageing and the different types of cortical dementias. This could serve as an additional biomarker and also assist in initiating appropriate training methods to prevent future falls.

Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia.

PubMed

Steinbart, E J; Smith, C O; Poorkaj, P; Bird, T D

2001-11-01

DNA testing of persons at risk for hereditary, degenerative neurologic diseases is relatively new. Only anecdotal reports of such testing in familial Alzheimer disease (FAD) exist, and little is know about the personal and social impact of such testing. In a descriptive, observational study, individuals at 50% risk for autosomal dominant, early-onset FAD or frontotemporal dementia with parkinsonism linked to chromosome 17 underwent DNA testing for the genetic mutations previously identified in affected family members. Individuals were followed up for (1/2) to 3 years and were interviewed regarding attitudes toward the testing process and the impact of the results. Twenty-one (8.4%) of 251 persons at risk for FAD or frontotemporal dementia requested genetic testing. The most common reasons for requesting testing were concern about early symptoms of dementia, financial or family planning, and relief from anxiety. Twelve individuals had positive DNA test results, and 6 of these had early symptoms of dementia; 8 had negative results; and 1 has not yet received results. Of 14 asymptomatic individuals completing testing, 13 believed the testing was beneficial. Two persons reported moderate anxiety and 1 reported moderate depression. As expected, persons with negative test results had happier experiences overall, but even they had to deal with ongoing anxiety and depression. Thus far, there have been no psychiatric hospitalizations, suicide attempts, or denials of insurance. Genetic testing in early-onset FAD and frontotemporal dementia can be completed successfully. Most individuals demonstrate effective coping skills and find the testing to be beneficial, but long-term effects remain unknown.

Double dissociation of social functioning in frontotemporal dementia

PubMed Central

Rankin, Katherine P.; Kramer, Joel H.; Mychack, Paula; Miller, Bruce L.

2009-01-01

Background Efforts to characterize changes in social functioning in frontotemporal dementia (FTD) have failed to elicit clear dissociation between frontal and temporal variants of the disease based on behavioral measures. Methods This study obtained premorbid and current first-degree relative ratings using an established measure of interpersonal functioning, the Interpersonal Adjectives Scales, to measure personality change in 16 patients with frontal variant (FLV) and 13 with temporal variant (TLV) FTD, and in a control group of 16 patients with AD. Results All three groups showed significant change over time in multiple domains, including increased introversion (FG) and submissiveness (HI). However, patients with both FTD subtypes evidenced significantly greater increases in overall interpersonal pathology vector length [VL] than did patients with AD, who remained within the normal range on all scores. Patients with FLV showed a 2 SD increase in submissiveness (HI), but their cold-heartedness (DE) change scores were not significantly different from those of patients with AD. Conversely, the TLV cold-heartedness (DE) score increased 2 SD compared to minimal change for the AD and FLV groups, yet change in submissiveness (HI) did not differentiate between AD and TLV groups. Conclusions The Interpersonal Adjectives Scales differentiated both FTD groups from patients with AD on the basis of both degree and direction of personality change. Also, the two subtypes of FTD showed distinctly different patterns of change in social functioning: patients with temporal variant shifted toward severe interpersonal coldness with mild loss of dominance, whereas patients with frontal variant showed the opposite pattern. PMID:12552042

Prospective Memory Impairments in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia: Clinical and Neural Correlates.

PubMed

Dermody, Nadene; Hornberger, Michael; Piguet, Olivier; Hodges, John R; Irish, Muireann

2016-01-01

Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer's disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown. To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD). Twelve AD, 12 bvFTD, and 12 healthy older Control participants completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI. AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy were found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes. Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient's daily life.

Meta-Analysis of Facial Emotion Recognition in Behavioral Variant Frontotemporal Dementia: Comparison With Alzheimer Disease and Healthy Controls.

PubMed

Bora, Emre; Velakoulis, Dennis; Walterfang, Mark

2016-07-01

Behavioral disturbances and lack of empathy are distinctive clinical features of behavioral variant frontotemporal dementia (bvFTD) in comparison to Alzheimer disease (AD). The aim of this meta-analytic review was to compare facial emotion recognition performances of bvFTD with healthy controls and AD. The current meta-analysis included a total of 19 studies and involved comparisons of 288 individuals with bvFTD and 329 healthy controls and 162 bvFTD and 147 patients with AD. Facial emotion recognition was significantly impaired in bvFTD in comparison to the healthy controls (d = 1.81) and AD (d = 1.23). In bvFTD, recognition of negative emotions, especially anger (d = 1.48) and disgust (d = 1.41), were severely impaired. Emotion recognition was significantly impaired in bvFTD in comparison to AD in all emotions other than happiness. Impairment of emotion recognition is a relatively specific feature of bvFTD. Routine assessment of social-cognitive abilities including emotion recognition can be helpful in better differentiating between cortical dementias such as bvFTD and AD. © The Author(s) 2016.

An investigation of care-based vs. rule-based morality in frontotemporal dementia, Alzheimer's disease, and healthy controls.

PubMed

Carr, Andrew R; Paholpak, Pongsatorn; Daianu, Madelaine; Fong, Sylvia S; Mather, Michelle; Jimenez, Elvira E; Thompson, Paul; Mendez, Mario F

2015-11-01

Behavioral changes in dementia, especially behavioral variant frontotemporal dementia (bvFTD), may result in alterations in moral reasoning. Investigators have not clarified whether these alterations reflect differential impairment of care-based vs. rule-based moral behavior. This study investigated 18 bvFTD patients, 22 early onset Alzheimer's disease (eAD) patients, and 20 healthy age-matched controls on care-based and rule-based items from the Moral Behavioral Inventory and the Social Norms Questionnaire, neuropsychological measures, and magnetic resonance imaging (MRI) regions of interest. There were significant group differences with the bvFTD patients rating care-based morality transgressions less severely than the eAD group and rule-based moral behavioral transgressions more severely than controls. Across groups, higher care-based morality ratings correlated with phonemic fluency on neuropsychological tests, whereas higher rule-based morality ratings correlated with increased difficulty set-shifting and learning new rules to tasks. On neuroimaging, severe care-based reasoning correlated with cortical volume in right anterior temporal lobe, and rule-based reasoning correlated with decreased cortical volume in the right orbitofrontal cortex. Together, these findings suggest that frontotemporal disease decreases care-based morality and facilitates rule-based morality possibly from disturbed contextual abstraction and set-shifting. Future research can examine whether frontal lobe disorders and bvFTD result in a shift from empathic morality to the strong adherence to conventional rules. Published by Elsevier Ltd.

Quantitative Balance and Gait Measurement in Patients with Frontotemporal Dementia and Alzheimer Diseases: A Pilot Study

PubMed Central

Velayutham, Selva Ganapathy; Chandra, Sadanandavalli Retnaswami; Bharath, Srikala; Shankar, Ravi Girikamatha

2017-01-01

Introduction: Alzhiemers disease and Frontotemporal dementia are common neurodegenerative dementias with a wide prevalence. Falls are a common cause of morbidity in these patients. Identifying subclinical involvement of these parameters might serve as a tool in differential analysis of these distinct parameters involved in these conditions and also help in planning preventive strategies to prevent falls. Patients and Methods: Eight patients in age and gender matched patients in each group were compared with normal controls. Standardizes methods of gait and balance aseesment were done in all persons. Results: Results revealed subclinical involvement of gait and balancesin all groups specially during divided attention. The parameters were significantly more affected in patients. Patients with AD and FTD had involement of over all ambulation index balance more affected in AD patients FTD patients showed step cycle, stride length abnormalities. Discussion: There is balance and gait involvement in normal ageing as well as patients with AD and FTD. The pattern of involvement in AD correlates with WHERE pathway involvement and FTD with frontal subcortical circuits involvement. Conclusion: Identification the differential patterns of involvement in subclinical stage might help to differentiate normal ageing and the different types of cortical dementias. This could serve as an additional biomarker and also assist in initiating appropriate training methods to prevent future falls. PMID:28515555

A Scale of Socioemotional Dysfunction in Frontotemporal Dementia

PubMed Central

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.

2014-01-01

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

Using the Disease State Fingerprint Tool for Differential Diagnosis of Frontotemporal Dementia and Alzheimer's Disease

PubMed Central

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

2016-01-01

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

The attribution of animacy and agency in frontotemporal dementia versus Alzheimer's disease.

PubMed

Fong, Sylvia S; Paholpak, Pongsatorn; Daianu, Madelaine; Deutsch, Mariel B; Riedel, Brandalyn C; Carr, Andrew R; Jimenez, Elvira E; Mather, Michelle M; Thompson, Paul M; Mendez, Mario F

2017-07-01

Impaired attribution of animacy (state of living or being sentient) and of agency (capability of intrinsically-driven action) may underlie social behavior disturbances in behavioral variant frontotemporal dementia (bvFTD). We presented the Heider and Simmel film of moving geometric shapes to 11 bvFTD patients, 11 Alzheimer's disease (AD) patients, and 12 healthy controls (HCs) and rated their recorded verbal responses for animacy attribution and agency attribution. All participants had skin conductance (SC) continuously recorded while viewing the film, and all dementia participants underwent magnetic resonance imaging (MRI) for regions of interest. The bvFTD patients, but not the AD patients, were impaired in animacy attribution, compared to the HCs. In contrast, both bvFTD and AD groups were impaired in agency attribution, compared to the HCs, and only the HCs had increasing SC responsiveness during viewing of the film. On MRI analysis of cortical thicknesses, animacy scores significantly correlated across groups with the right pars orbitalis and opercularis; agency scores with the left inferior and superior parietal cortices and the supramarginal gyrus; and both scores with the left cingulate isthmus involved in visuospatial context. These findings suggest that bvFTD is specifically associated with impaired animacy attribution from right inferior frontal atrophy. In contrast, both dementias may have impaired agency attribution from left parietal cortical atrophy and absent SC increases during the film, a sympathetic indicator of attribution of a social "story" to the moving shapes. These findings clarify disease-related changes in social attribution and corroborate the neuroanatomical origins of animacy and agency. Copyright © 2017 Elsevier Ltd. All rights reserved.

Virtual reality for the assessment of frontotemporal dementia, a feasibility study.

PubMed

Mendez, Mario F; Joshi, Aditi; Jimenez, Elvira

2015-03-01

Behavioral variant frontotemporal dementia (bvFTD) is a non-Alzheimer dementia characterized by difficulty in documenting social-emotional changes. Few investigations have used virtual reality (VR) for documentation and rehabilitation of non-Alzheimer dementias. Five bvFTD patients underwent insight interviews while immersed in a virtual environment. They were interviewed by avatars, their answers were recorded, and their heart rates were monitored. They were asked to give ratings of their stress immediately at the beginning and at the end of the session. The patients tolerated the head-mounted display and VR without nausea or disorientation, heart rate changes, or worsening stress ratings. Their insight responses were comparable to real world interviews. All bvFTD patients showed their presence in the VR environment as they moved their heads to face and respond to each avatar's questions. The bvFTD patients tended to greater verbal elaboration of answers with larger mean length of utterances compared to their real world interviews. VR is feasible and well-tolerated in bvFTD. These patients may have VR responses comparable to real world performance and they may display a presence in the virtual environment which could even facilitate assessment. Further research can explore the promise of VR for the evaluation and rehabilitation of dementias beyond Alzheimer's disease. Implications for Rehabilitation Clinicians need effective evaluation and rehabilitation strategies for dementia, a neurological syndrome of epidemic proportions and a leading cause of disability. Memory and cognitive deficits are the major disabilities and targets for rehabilitation in Alzheimer's disease, the most common dementia. In contrast, social and emotional disturbances are the major disabilities and targets for rehabilitation in behavioral variant frontotemporal dementia (bvFTD), an incompletely understood non-Alzheimer dementia. Virtual reality is a technology that holds great promise for

An Investigation of Care-Based vs. Rule-Based Morality in Frontotemporal Dementia, Alzheimer’s Disease, and Healthy Controls

PubMed Central

Carr, Andrew R.; Paholpak, Pongsatorn; Daianu, Madelaine; Fong, Sylvia S.; Mather, Michelle; Jimenez, Elvira E.; Thompson, Paul; Mendez, Mario F.

2015-01-01

Behavioral changes in dementia, especially behavioral variant frontotemporal dementia (bvFTD), may result in alterations in moral reasoning. Investigators have not clarified whether these alterations reflect differential impairment of care-based vs. rule-based moral behavior. This study investigated 18 bvFTD patients, 22 early onset Alzheimer’s disease (eAD) patients, and 20 healthy age-matched controls on care-based and rule-based items from the Moral Behavioral Inventory and the Social Norms Questionnaire, neuropsychological measures, and magnetic resonance imaging (MRI) regions of interest. There were significant group differences with the bvFTD patients rating care-based morality transgressions less severely than the eAD group and rule-based moral behavioral transgressions more severely than controls. Across groups, higher care-based morality ratings correlated with phonemic fluency on neuropsychological tests, whereas higher rule-based morality ratings correlated with increased difficulty set-shifting and learning new rules to tasks. On neuroimaging, severe care-based reasoning correlated with cortical volume in right anterior temporal lobe, and rule-based reasoning correlated with decreased cortical volume in the right orbitofrontal cortex. Together, these findings suggest that frontotemporal disease decreases care-based morality and facilitates rule-based morality possibly from disturbed contextual abstraction and set-shifting. Future research can examine whether frontal lobe disorders and bvFTD result in a shift from empathic morality to the strong adherence to conventional rules. PMID:26432341

Frontotemporal Degeneration in a Child.

PubMed

Terrill, Tyler; Pascual, Juan M

2017-07-01

There is a predilection for the frontal and temporal lobes in certain cases of dementia in the adult, leading to the syndrome of frontotemporal dementia. However, this syndrome has seemed to elude the developing brain until now. We describe an example of apparently selective neurodegeneration of the frontal and temporal regions during development associated with some of the clinical, magnetic resonance imaging, and fludeoxyglucose positron emission tomography (FDG PET) scan features of canonical frontotemporal dementia in the adult. This patient does not have any of the common frontotemporal dementia-causing mutations or known progressive brain disorders of children. This patient illustrates that symptomatic, selective, and progressive vulnerability of the frontal and temporal lobes is not restricted to adulthood, expanding the phenotype of frontotemporal degeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessment of free and cued recall in Alzheimer's disease and vascular and frontotemporal dementia with 24-item Grober and Buschke test.

PubMed

Cerciello, Milena; Isella, Valeria; Proserpi, Alice; Papagno, Costanza

2017-01-01

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 [8]. 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) [8] 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.

Reduced frequency of T lymphocytes expressing CTLA-4 in frontotemporal dementia compared to Alzheimer's disease.

PubMed

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

2014-01-03

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. © 2013 Elsevier Inc. All rights reserved.

Behavioral phenomenology in Alzheimer's disease, frontotemporal dementia, and late-life depression: a retrospective analysis.

PubMed

Swartz, J R; Miller, B L; Lesser, I M; Booth, R; Darby, A; Wohl, M; Benson, D F

1997-04-01

Often patients in the early stages of Alzheimer's disease (AD), frontotemporal dementia (FTD), and late-life depression can be difficult to differentiate clinically. Although subtle cognitive distinctions exist between these disorders, noncognitive behavioral phenomenology may provide additional discriminating power. In 19 subjects with AD, 19 with FTD, 16 with late-life psychotic depression (LLPD), and 19 with late-life nonpsychotic depression (LLNPD), noncognitive behavioral symptoms were quantified retrospectively using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and compared using both a one-way ANOVA and a multivariate stepwise discriminant analysis, which utilized a jackknife procedure. The FTD group showed the highest mean total SCAN score, while the AD group showed the lowest. ANOVA showed significant differences in the mean total SCAN scores between the four diagnostic groups (P < .0001). With the discriminant analysis, the four disorders demonstrated different clusters of behavioral abnormalities and were differentiated by these symptoms (P < .0001). A subset of 14 SCAN item group symptoms was identified that collectively classified the following percentages of subjects in each diagnostic category: AD 94.7%, FTD 100%, LLPD 87.5%, and LLNPD 100%. These results indicate that AD, FTD, LLPD, and LLNPD were distinguished retrospectively by the SCAN without using cognitive data. Better definition of the longitudinal course of noncognitive behavioral symptoms in different dementias and psychiatric disorders will be valuable both for diagnosis and to help define behavioral syndromes that are associated with selective neuroanatomic and neurochemical brain pathology.

Comparing moral judgments of patients with frontotemporal dementia and frontal stroke.

PubMed

Baez, Sandra; Couto, Blas; Torralva, Teresa; Sposato, Luciano A; Huepe, David; Montañes, Patricia; Reyes, Pablo; Matallana, Diana; Vigliecca, Nora S; Slachevsky, Andrea; Manes, Facundo; Ibanez, Agustin

2014-09-01

Several clinical reports have stated that patients with prefrontal lesions or patients with the behavioral variant of frontotemporal dementia share social cognition impairments. Moral reasoning is impaired in both conditions but there have been few investigations that directly compare this domain in the 2 groups. This work compared the moral judgments of these patient groups using a task designed to disentangle the contributions of intentions and outcomes in moral judgment. For both disorders, patients judged scenarios where the protagonists believed that they would cause harm but did not as being more permissible than the control group. Moreover, patients with frontotemporal dementia judged harmful outcomes in the absence of harmful intentions as less permissible than the control participants. There were no differences between the 2 conditions. Both disorders involved impairments in integrating intention and outcome information for moral judgment. This study was the first, to our knowledge, to directly compare a social cognition domain in 2 frontal pathologies with different etiology. Our results highlighted the importance of comparing patients with vascular lesions and patients with neurodegenerative diseases.

Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study.

PubMed

Li, Pan; Zhou, Yu-Ying; Lu, Da; Wang, Yan; Zhang, Hui-Hong

2016-05-01

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.

Common and unique gray matter correlates of episodic memory dysfunction in frontotemporal dementia and Alzheimer's disease.

PubMed

Irish, Muireann; Piguet, Olivier; Hodges, John R; Hornberger, Michael

2014-04-01

Conflicting evidence exists regarding the integrity of episodic memory in the behavioral variant of frontotemporal dementia (bvFTD). Recent converging evidence suggests that episodic memory in progressive cases of bvFTD is compromised to the same extent as in Alzheimer's disease (AD). The underlying neural substrates of these episodic memory deficits, however, likely differ contingent on dementia type. In this study we sought to elucidate the neural substrates of episodic memory performance, across recall and recognition tasks, in both patient groups using voxel-based morphometry (VBM) analyses. We predicted that episodic memory dysfunction would be apparent in both patient groups but would relate to divergent patterns of neural atrophy specific to each dementia type. We assessed episodic memory, across verbal and visual domains, in 19 bvFTD, 18 AD patients, and 19 age- and education-matched controls. Behaviorally, patient groups were indistinguishable for immediate and delayed recall, across verbal and visual domains. Whole-brain VBM analyses revealed regions commonly implicated in episodic retrieval across groups, namely the right temporal pole, right frontal lobe, left paracingulate gyrus, and right anterior hippocampus. Divergent neural networks specific to each group were also identified. Whereas a widespread network including posterior regions such as the posterior cingulate cortex, parietal and occipital cortices was exclusively implicated in AD, the frontal and anterior temporal lobes underpinned the episodic memory deficits in bvFTD. Our results point to distinct neural changes underlying episodic memory decline specific to each dementia syndrome. Copyright © 2013 Wiley Periodicals, Inc.

Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic innervation. Immunocytochemical and quantitative study using a graph method.

PubMed

Yang, Y; Schmitt, H P

2001-03-01

A graph method was employed to analyze the spatial neuronal patterns of nuclear grays of the pontine tegmentum with ascending aminergic projections to the forebrain in 12 cases of frontotemporal dementia (FTD). The nuclear grays examined were the nucleus centralis superior (NCS), a part of the nucleus raphae dorsalis (NRD), and the locus coeruleus (LC). The results were compared with 30 cases of Alzheimer's disease (AD) and 35 non-demented controls. In addition to the graph evaluations, neuronal cytoplasmic inclusion bodies were stained by silver impregnation and ubiquitin (Ub) and tau immunohistochemistry. The FTD cases showed a significant, 40%, decline in number of neurons in the NCS and NRD, while the LC was spared. The magnitude of neuronal loss matched that of AD where, by contrast, the LC was also severely changed. Amyloid deposition and Alzheimer neurofibrillary tangles occurred in the aminergic nuclei almost exclusively in AD and, to a minor extent, in some aged controls. No cytoplasmic inclusion bodies were found in the aminergic nuclei of the FTD cases. However, 6 cases had Ub-positive but tau-negative neuronal inclusions in the hippocampal dentate fascia and in layer 2 of the prefrontal isocortex, and 3 showed clinical and histological signs of motor neuron disease. Our results suggest that the serotoninergic raphe nuclei with ascending projections to the forebrain, but not the LC, become directly or indirectly involved in frontotemporal dementia both with and without motor neuron disease.

Comparative Study of Subcortical Atrophy in Patients with Frontotemporal Dementia and Dementia with Extrapyramidal Signs

PubMed Central

Caixeta, Leonardo; Vieira, Renata Teles; Paes, Flávia; Carta, Mauro Giovanni; Nardi, Antonio Egidio; Arias-Carrión, Oscar; Rocha, Nuno B. F; Budde, Henning; Machado, Sergio

2015-01-01

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

Frontotemporal Dementia in Eight Chinese Individuals

PubMed Central

Chao, Steven Z.; Rosen, Howard J.; Azor, Virgina; Ong, Hilary; Tse, Marian M.; Lai, Ngan Betty; Hou, Craig E.; Seeley, William W.; Miller, Bruce L.; Matthews, Brandy R.

2012-01-01

Frontotemporal dementia (FTD) has rarely been reported in Chinese populations. There are many potential reasons for this, including possible hesitancy on the part of patients or families to bring FTD-related symptoms to medical attention. Here, we present data on eight Chinese individuals, all of whom met criteria for the behavioral variant of FTD or the semantic variant of primary progressive aphasia. These patients presented for neurological evaluation at a relatively advanced stage. The mean MMSE score at initial presentation was 15. Behavioral symptoms were common and usually elicited during the medical history only after direct questioning. Delay in presentation was attributed to a variety of issues, including family disagreements about whether the symptoms represented a disease and lack of medical insurance. These cases illustrate that the symptoms of FTD in Chinese Americans are similar to those in Caucasians but various factors, some potentially culturally-relevant, may influence the likelihood and timing of clinical presentation for FTD, as well as other dementias. Additional study of FTD in diverse ethnic groups needs to address barriers to clinical presentation, including factors that may be culturally specific. PMID:23311888

Fair play: social norm compliance failures in behavioural variant frontotemporal dementia.

PubMed

O'Callaghan, Claire; Bertoux, Maxime; Irish, Muireann; Shine, James M; Wong, Stephanie; Spiliopoulos, Leonidas; Hodges, John R; Hornberger, Michael

2016-01-01

Adherence to social norms is compromised in a variety of neuropsychiatric conditions. Functional neuroimaging studies have investigated social norm compliance in healthy individuals, leading to the identification of a network of fronto-subcortical regions that underpins this ability. However, there is a lack of corroborative evidence from human lesion models investigating the structural anatomy of norm compliance across this fronto-subcortical network. To address this, we developed a neuroeconomic task to investigate social norm compliance in a neurodegenerative lesion model: behavioural variant frontotemporal dementia, a condition characterized by gross social dysfunction. The task assessed norm compliance across three behaviours that are well-studied in the neuroeconomics literature: fairness, prosocial and punishing behaviours. We administered our novel version of the Ultimatum Game in 22 patients with behavioural variant frontotemporal dementia and 22 age-matched controls, to assess how decision-making behaviour was modulated in response to (i) fairness of monetary offers; and (ii) social context of monetary offers designed to produce either prosocial or punishing behaviours. Voxel-based morphometry was used to characterize patterns of grey matter atrophy associated with task performance. Acceptance rates between patients and controls were equivalent when only fairness was manipulated. However, patients were impaired in modulating their decisions in response to social contextual information. Patients' performance in the punishment condition was consistent with a reduced tendency to engage in punishment; this was associated with decreased grey matter volume in the anterior cingulate, orbitofrontal cortex, left dorsolateral prefrontal cortex and right inferior frontal gyrus. In the prosocial condition, patients' performance suggested a reduced expression of prosocial behaviour, associated with decreased grey matter in the anterior insula, lateral orbitofrontal

Memory Test Performance on Analogous Verbal and Nonverbal Memory Tests in Patients with Frontotemporal Dementia and Alzheimer's Disease.

PubMed

Baldock, Deanna; Miller, Justin B; Leger, Gabriel C; Banks, Sarah Jane

2016-01-01

Patients with frontotemporal dementia (FTD) typically have initial deficits in language or changes in personality, while the defining characteristic of Alzheimer's disease (AD) is memory impairment. Neuropsychological findings in the two diseases tend to differ, but can be confounded by verbal impairment in FTD impacting performance on memory tests in these patients. Twenty-seven patients with FTD and 102 patients with AD underwent a neuropsychological assessment before diagnosis. By utilizing analogous versions of a verbal and nonverbal memory test, we demonstrated differences in these two modalities between AD and FTD. Better differentiation between AD and FTD is found in a nonverbal memory test, possibly because it eliminates the confounding variable of language deficits found in patients with FTD. These results highlight the importance of nonverbal learning tests with multiple learning trials in diagnostic testing.

Behavioral and language variants of frontotemporal dementia: a review of key symptoms.

PubMed

Laforce, Robert

2013-12-01

While recent advances in the development of neuroimaging and molecular biomarkers for studying neurodegenerative conditions have revolutionized the field, dementia remains a clinical diagnosis. No component of the diagnostic process is more crucial than obtaining a good history. Getting to know the first manifestations of the disease, tracking their evolution and functional impact, combined with a targeted neurological examination, further guides differential diagnosis. This paper summarizes the key symptoms of the behavioral and language variants of frontotemporal dementia. The behavioral variant of frontotemporal dementia (bvFTD) is characterized by severe changes in behavior and personality such as disinhibition, apathy, loss of empathy, or stereotypic behavior, leading to a loss of social competence. Executive functions are impaired, while memory and visuospatial skills are relatively better preserved. By contrast, the language variants or primary progressive aphasias (PPAs) are marked by prominent language disturbances that can be subclassified into a non-fluent/agrammatic variant (naPPA), a semantic variant (svPPA), and a logopenic variant (lvPPA). Although combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis of such heterogeneous conditions, the author emphasizes the importance of accurate recognition of key symptoms that can lead to better identification of underlying neuropathology and appropriate treatment approaches.

Problems Inhibiting Attentional Capture by Irrelevant Stimuli in Patients with Frontotemporal Dementia

ERIC Educational Resources Information Center

Piquard, Ambre; Lacomblez, Lucette; Derouesne, Christian; Sieroff, Eric

2009-01-01

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…

Longitudinal white matter change in frontotemporal dementia subtypes and sporadic late onset Alzheimer's disease.

PubMed

Elahi, Fanny M; Marx, Gabe; Cobigo, Yann; Staffaroni, Adam M; Kornak, John; Tosun, Duygu; Boxer, Adam L; Kramer, Joel H; Miller, Bruce L; Rosen, Howard J

2017-01-01

Degradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD. To quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI). 60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%). All FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). Bv

Functional correlates of musical and visual ability in frontotemporal dementia.

PubMed

Miller, B L; Boone, K; Cummings, J L; Read, S L; Mishkin, F

2000-05-01

The emergence of new skills in the setting of dementia suggests that loss of function in one brain area can release new functions elsewhere. To characterise 12 patients with frontotemporal dementia (FTD) who acquired, or sustained, new musical or visual abilities despite progression of their dementia. Twelve patients with FTD who acquired or maintained musical or artistic ability were compared with 46 patients with FTD in whom new or sustained ability was absent. The group with musical or visual ability performed better on visual, but worse on verbal tasks than did the other patients with FTD. Nine had asymmetrical left anterior dysfunction. Nine showed the temporal lobe variant of FTD. Loss of function in the left anterior temporal lobe may lead to facilitation of artistic or musical skills. Patients with the left-sided temporal lobe variant of FTD offer an unexpected window into the neurological mediation of visual and musical talents.

[Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia].

PubMed

Hayashi, Yukiko

2013-01-01

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget's disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.

Increased subjective experience of non-target emotions in patients with frontotemporal dementia and Alzheimer’s disease

PubMed Central

Chen, Kuan-Hua; Lwi, Sandy J.; Hua, Alice Y.; Haase, Claudia M.; Miller, Bruce L.; Levenson, Robert W.

2017-01-01

Although laboratory procedures are designed to produce specific emotions, participants often experience mixed emotions (i.e., target and non-target emotions). We examined non-target emotions in patients with frontotemporal dementia (FTD), Alzheimer’s disease (AD), other neurodegenerative diseases, and healthy controls. Participants watched film clips designed to produce three target emotions. Subjective experience of non-target emotions was assessed and emotional facial expressions were coded. Compared to patients with other neurodegenerative diseases and healthy controls, FTD patients reported more positive and negative non-target emotions, whereas AD patients reported more positive non-target emotions. There were no group differences in facial expressions of non-target emotions. We interpret these findings as reflecting deficits in processing interoceptive and contextual information resulting from neurodegeneration in brain regions critical for creating subjective emotional experience. PMID:29457053

Late onset bipolar disorder and frontotemporal dementia with mutation in progranulin gene: a case report.

PubMed

Rubino, Elisa; Vacca, Alessandro; Gallone, Salvatore; Govone, Flora; Zucca, Milena; Gai, Annalisa; Ferrero, Patrizia; Fenoglio, Pierpaola; Giordana, Maria Teresa; Rainero, Innocenzo

2017-11-01

Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations.

Abnormal network connectivity in frontotemporal dementia: evidence for prefrontal isolation.

PubMed

Farb, Norman A S; Grady, Cheryl L; Strother, Stephen; Tang-Wai, David F; Masellis, Mario; Black, Sandra; Freedman, Morris; Pollock, Bruce G; Campbell, Karen L; Hasher, Lynn; Chow, Tiffany W

2013-01-01

Degraded social function, disinhibition, and stereotypy are defining characteristics of frontotemporal dementia (FTD), manifesting in both the behavioral variant of frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Recent neuroimaging research also associates FTD with alterations in the brain's intrinsic connectivity networks. The present study explored the relationship between neural network connectivity and specific behavioral symptoms in FTD. Resting-state functional magnetic resonance imaging was employed to investigate neural network changes in bvFTD and SD. We used independent components analysis (ICA) to examine changes in frontolimbic network connectivity, as well as several metrics of local network strength, such as the fractional amplitude of low-frequency fluctuations, regional homogeneity, and seed-based functional connectivity. For each analysis, we compared each FTD subgroup to healthy controls, characterizing general and subtype-unique network changes. The relationship between abnormal connectivity in FTD and behavior disturbances was explored. Across multiple analytic approaches, both bvFTD and SD were associated with disrupted frontolimbic connectivity and elevated local connectivity within the prefrontal cortex. Even after controlling for structural atrophy, prefrontal hyperconnectivity was robustly associated with apathy scores. Frontolimbic disconnection was associated with lower disinhibition scores, suggesting that abnormal frontolimbic connectivity contributes to positive symptoms in dementia. Unique to bvFTD, stereotypy was associated with elevated default network connectivity in the right angular gyrus. The behavioral variant was also associated with marginally higher apathy scores and a more diffuse pattern of prefrontal hyperconnectivity than SD. The present findings support a theory of FTD as a disorder of frontolimbic disconnection leading to unconstrained prefrontal connectivity. Prefrontal hyperconnectivity may

Lost and forgotten? Orientation versus memory in Alzheimer's disease and frontotemporal dementia.

PubMed

Yew, Belinda; Alladi, Suvarna; Shailaja, Mekala; Hodges, John R; Hornberger, Michael

2013-01-01

Recent studies suggest that significant memory problems are not specific to Alzheimer's disease (AD) but can be also observed in other neurodegenerative conditions, such as behavioral variant frontotemporal dementia (bvFTD). We investigated whether orientation (spatial & temporal) information is a better diagnostic marker for AD compared to memory and whether their atrophy correlates of orientation and memory differ. A large sample (n = 190) of AD patients (n = 73), bvFTD patients (n = 54), and healthy controls (n = 63) underwent testing. A subset of the patients (n = 72) underwent structural imaging using voxel-based morphometry analysis of magnetic resonance brain imaging. Orientation and memory scores from the Addenbrooke's Cognitive Examination showed that AD patients had impaired orientation and memory, while bvFTD patients performing at control level for orientation but had impaired memory. A logistic regression showed that 78% of patients could be classified on the basis of orientation and memory scores alone at clinic presentation. Voxel-based morphometry analysis was conducted using orientation and memory scores as covariates, which showed that the neural correlates for orientation and memory also dissociated with posterior hippocampus cortex being related to orientation in AD, while the anterior hippocampus was associated with memory performance in the AD and bvFTD patients. Orientation and memory measures discriminate AD and bvFTD to a high degree and tap into different hippocampal regions. Disorientation and posterior hippocampus appears therefore specific to AD and will allow clinicians to discriminate AD patients from other neurodegenerative conditions with similar memory deficits at clinic presentation.

Motor Speech Phenotypes of Frontotemporal Dementia, Primary Progressive Aphasia, and Progressive Apraxia of Speech

ERIC Educational Resources Information Center

Poole, Matthew L.; Brodtmann, Amy; Darby, David; Vogel, Adam P.

2017-01-01

Purpose: Our purpose was to create a comprehensive review of speech impairment in frontotemporal dementia (FTD), primary progressive aphasia (PPA), and progressive apraxia of speech in order to identify the most effective measures for diagnosis and monitoring, and to elucidate associations between speech and neuroimaging. Method: Speech and…

Clinicopathological correlations in behavioural variant frontotemporal dementia.

PubMed

Perry, David C; Brown, Jesse A; Possin, Katherine L; Datta, Samir; Trujillo, Andrew; Radke, Anneliese; Karydas, Anna; Kornak, John; Sias, Ana C; Rabinovici, Gil D; Gorno-Tempini, Maria Luisa; Boxer, Adam L; De May, Mary; Rankin, Katherine P; Sturm, Virginia E; Lee, Suzee E; Matthews, Brandy R; Kao, Aimee W; Vossel, Keith A; Tartaglia, Maria Carmela; Miller, Zachary A; Seo, Sang Won; Sidhu, Manu; Gaus, Stephanie E; Nana, Alissa L; Vargas, Jose Norberto S; Hwang, Ji-Hye L; Ossenkoppele, Rik; Brown, Alainna B; Huang, Eric J; Coppola, Giovanni; Rosen, Howard J; Geschwind, Daniel; Trojanowski, John Q; Grinberg, Lea T; Kramer, Joel H; Miller, Bruce L; Seeley, William W

2017-12-01

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual

Meta-analytic Review of Memory Impairment in Behavioral Variant Frontotemporal Dementia.

PubMed

Poos, Jackie M; Jiskoot, Lize C; Papma, Janne M; van Swieten, John C; van den Berg, Esther

2018-03-19

A meta-analysis of the extent, nature and pattern of memory performance in behavioral variant frontotemporal dementia (bvFTD). Multiple observational studies have challenged the relative sparing of memory in bvFTD as stated in the current diagnostic criteria. We performed a meta-analytic review covering the period 1967 to February 2017 of case-control studies on episodic memory in bvFTD versus control participants (16 studies, 383 patients, 603 control participants), and patients with bvFTD versus those with Alzheimer's disease (AD) (20 studies, 452 bvFTD, 874 AD). Differences between both verbal and non-verbal working memory, episodic memory learning and recall, and recognition memory were examined. Data were extracted from the papers and combined into a common metric measure of effect, Hedges' d. Patients with bvFTD show large deficits in memory performance compared to controls (Hedges' d -1.10; 95% confidence interval [CI] [-1.23, -0.95]), but perform significantly better than patients with AD (Hedges' d 0.85; 95% CI [0.69, 1.03]). Learning and recall tests differentiate best between patients with bvFTD and AD (p<.01). There is 37-62% overlap in test scores between the two groups. This study points to memory disorders in patients with bvFTD, with performance at an intermediate level between controls and patients with AD. This indicates that, instead of being an exclusion criterion for bvFTD diagnosis, memory deficits should be regarded as a potential integral part of the clinical spectrum. (JINS, 2018, 24, 1-13).

Dissociation in Rating Negative Facial Emotions between Behavioral Variant Frontotemporal Dementia and Major Depressive Disorder.

PubMed

Chiu, Isabelle; Piguet, Olivier; Diehl-Schmid, Janine; Riedl, Lina; Beck, Johannes; Leyhe, Thomas; Holsboer-Trachsler, Edith; Berres, Manfred; Monsch, Andreas U; Sollberger, Marc

2016-11-01

Features of behavioral variant frontotemporal dementia (bvFTD) such as executive dysfunction, apathy, and impaired empathic abilities are also observed in major depressive disorder (MDD). This may contribute to the reason why early stage bvFTD is often misdiagnosed as MDD. New assessment tools are thus needed to improve early diagnosis of bvFTD. Although emotion processing is affected in bvFTD and MDD, growing evidence indicates that the pattern of emotion processing deficits varies between the two disorders. As such, emotion processing paradigms have substantial potentials to distinguish bvFTD from MDD. The current study compared 25 patients with bvFTD, 21 patients with MDD, 21 patients with Alzheimer disease (AD) dementia, and 31 healthy participants on a novel facial emotion intensity rating task. Stimuli comprised morphed faces from the Ekman and Friesen stimulus set containing faces of each sex with two different degrees of emotion intensity for each of the six basic emotions. Analyses of covariance uncovered a significant dissociation between bvFTD and MDD patients in rating the intensity of negative emotions overall (i.e., bvFTD patients underrated negative emotions overall, whereas MDD patients overrated negative emotions overall compared with healthy participants). In contrast, AD dementia patients rated negative emotions similarly to healthy participants, suggesting no impact of cognitive deficits on rating facial emotions. By strongly differentiating bvFTD and MDDpatients through negative facial emotions, this sensitive and short rating task might help improve the early diagnosis of bvFTD. Copyright © 2016 American Association for Geriatric Psychiatry. All rights reserved.

Emotion recognition in frontotemporal dementia and Alzheimer's disease: A new film-based assessment.

PubMed

Goodkind, Madeleine S; Sturm, Virginia E; Ascher, Elizabeth A; Shdo, Suzanne M; Miller, Bruce L; Rankin, Katherine P; Levenson, Robert W

2015-08-01

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. (c) 2015 APA, all rights reserved).

Emotion Recognition in Frontotemporal Dementia and Alzheimer's Disease: A New Film-Based Assessment

PubMed Central

Goodkind, Madeleine S.; Sturm, Virginia E.; Ascher, Elizabeth A.; Shdo, Suzanne M.; Miller, Bruce L.; Rankin, Katherine P.; Levenson, Robert W.

2015-01-01

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

Bilingualism delays the onset of behavioral but not aphasic forms of frontotemporal dementia.

PubMed

Alladi, Suvarna; Bak, Thomas H; Shailaja, Mekala; Gollahalli, Divyaraj; Rajan, Amulya; Surampudi, Bapiraju; Hornberger, Michael; Duggirala, Vasanta; Chaudhuri, Jaydip Ray; Kaul, Subhash

2017-05-01

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. Copyright © 2017 Elsevier Ltd. All rights reserved.

No added diagnostic value of non-phosphorylated tau fraction (p-taurel) in CSF as a biomarker for differential dementia diagnosis.

PubMed

Goossens, Joery; Bjerke, Maria; Struyfs, Hanne; Niemantsverdriet, Ellis; Somers, Charisse; Van den Bossche, Tobi; Van Mossevelde, Sara; De Vil, Bart; Sieben, Anne; Martin, Jean-Jacques; Cras, Patrick; Goeman, Johan; De Deyn, Peter Paul; Van Broeckhoven, Christine; van der Zee, Julie; Engelborghs, Sebastiaan

2017-07-14

The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ 1-42 , t-tau, and p-tau 181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-tau rel ), may improve differential dementia diagnosis. The goal of this study is to investigate if p-tau rel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis. The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ 1-42 , t-tau, p-tau 181 , and p-tau rel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests. The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-tau rel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-tau rel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-tau rel when differentiating between AD or non-AD dementias and controls. The addition of p-tau rel to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.

Differences in quantitative EEG between frontotemporal dementia and Alzheimer's disease as revealed by LORETA.

PubMed

Nishida, K; Yoshimura, M; Isotani, T; Yoshida, T; Kitaura, Y; Saito, A; Mii, H; Kato, M; Takekita, Y; Suwa, A; Morita, S; Kinoshita, T

2011-09-01

To determine the electrophysiological characteristics of frontotemporal dementia (FTD) and the distinction with Alzheimer's disease (AD). We performed analyses of global field power (GFP) which is a measure of whole brain electric field strength, and EEG neuroimaging analyses with sLORETA (standardized low resolution electromagnetic tomography), in the mild stages of FTD (n = 19; mean age = 68.11 ± 7.77) and AD (n = 19; mean age = 69.42 ± 9.57) patients, and normal control (NC) subjects (n = 22; mean age = 66.13 ± 6.02). In the GFP analysis, significant group effects were observed in the delta (1.5-6.0 Hz), alpha1 (8.5-10.0 Hz), and beta1 (12.5-18.0 Hz) bands. In sLORETA analysis, differences in activity were observed in the alpha1 band (NC > FTD) in the orbital frontal and temporal lobe, in the delta band (AD>NC) in widespread areas including the frontal lobe, and in the beta1 band (FTD > AD) in the parietal lobe and sensorimotor area. Differential patterns of brain regions and EEG frequency bands were observed between the FTD and AD groups in terms of pathological activity. FTD and AD patients in the early stages displayed different patterns in the cortical localization of oscillatory activity across different frequency bands. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Behavioral and autonomic reactivity to moral dilemmas in frontotemporal dementia versus Alzheimer's disease.

PubMed

Fong, Sylvia S; Navarrete, Carlos David; Perfecto, Sean E; Carr, Andrew R; Jimenez, Elvira E; Mendez, Mario F

2017-08-01

The personal/impersonal distinction of moral decision-making postulates intuitive emotional responses from medial frontal activity and rational evaluation from lateral frontal activity. This model can be analyzed in behavioral variant frontotemporal dementia (bvFTD), a disorder characterized by impaired emotional intuitions, ventromedial prefrontal cortex (vmPFC) involvement, and relative sparing of lateral frontal regions. Moral dilemmas were presented to 10 bvFTD, 11 Alzheimer's disease (AD), and 9 healthy control (HC) participants while recording skin conductance responses, a measure of emotional arousal. We evaluated their personal versus impersonal conflict, subjective discomfort, and adherence to social norms. Replicating prior work, bvFTD participants were more willing to harm in the personal, but not the impersonal, dilemma compared to AD and HC groups. BvFTD participants had lower arousal and less of an increase in conflict on the personal versus the impersonal dilemma, in contrast to increased arousal and conflict for the AD and HC groups. Furthermore, bvFTD participants verbalized less discomfort, a correlate of low adherence to social norms. These findings support impaired emotional reactions to moral dilemmas in bvFTD and vmPFC lesions and the personal/impersonal model. It suggests a reversion to utilitarian-like considerations when emotional intuition is impaired in the brain.

Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging.

PubMed

Bouts, Mark J R J; Möller, Christiane; Hafkemeijer, Anne; van Swieten, John C; Dopper, Elise; van der Flier, Wiesje M; Vrenken, Hugo; Wink, Alle Meije; Pijnenburg, Yolande A L; Scheltens, Philip; Barkhof, Frederik; Schouten, Tijn M; de Vos, Frank; Feis, Rogier A; van der Grond, Jeroen; de Rooij, Mark; Rombouts, Serge A R B

2018-01-01

Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

Friedrich Nietzsche's mental illness--general paralysis of the insane vs. frontotemporal dementia.

PubMed

Orth, M; Trimble, M R

2006-12-01

For a long time it was thought that Nietzsche suffered from general paralysis of the insane (GPI). However, this diagnosis has been questioned recently, and alternative diagnoses have been proposed. We have charted Friedrich Nietzsche's final fatal illness, and viewed the differential diagnosis in the light of recent neurological understandings of dementia syndromes. It is unclear that Nietzsche ever had syphilis. He lacked progressive motor and other neurological features of a progressive syphilitic central nervous system (CNS) infection and lived at least 12 years following the onset of his CNS signs, which would be extremely rare for patients with untreated GPI. Finally, his flourish of productivity in 1888 would be quite uncharacteristic of GPI, but in keeping with reports of burgeoning creativity at some point in the progression of frontotemporal dementia (FTD). We suggest that Nietzsche did not have GPI, but died from a chronic dementia, namely FTD.

Detection and Differentiation of Frontotemporal Dementia and Related Disorders From Alzheimer Disease Using the Montreal Cognitive Assessment.

PubMed

Coleman, Kristy K L; Coleman, Brenda L; MacKinley, Julia D; Pasternak, Stephen H; Finger, Elizabeth C

2016-01-01

The Montreal Cognitive Assessment (MoCA) is a cognitive screening tool used by practitioners worldwide. The efficacy of the MoCA for screening frontotemporal dementia (FTD) and related disorders is unknown. The objectives were: (1) to determine whether the MoCA detects cognitive impairment (CI) in FTD subjects; (2) to determine whether Alzheimer disease (AD) and FTD subtypes and related disorders can be parsed using the MoCA; and (3) describe longitudinal MoCA performance by subtype. We extracted demographic and testing data from a database of patients referred to a cognitive neurology clinic who met criteria for probable AD or FTD (N=192). Logistic regression was used to determine whether dementia subtypes were associated with overall scores, subscores, or combinations of subscores on the MoCA. Initial MoCA results demonstrated CI in the majority of FTD subjects (87%). FTD subjects (N=94) performed better than AD subjects (N=98) on the MoCA (mean scores: 18.1 vs. 16.3; P=0.02). Subscores parsed many, but not all subtypes. FTD subjects had a larger decline on the MoCA within 13 to 36 months than AD subjects (P=0.02). The results indicate that the MoCA is a useful tool to identify and track progression of CI in FTD. Further, the data informs future research on scoring models for the MoCA to enhance cognitive screening and detection of FTD patients.

Core features of frontotemporal dementia recapitulated in progranulin knockout mice

PubMed Central

Ghoshal, N.; Dearborn, J.T.; Wozniak, D.F.; Cairns, N.J.

2011-01-01

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

Financial and health literacy predict incident AD dementia and AD pathology

PubMed Central

Yu, Lei; Wilson, Robert S.; Schneider, Julie A.; Bennett, David A.; Boyle, Patricia A.

2017-01-01

Background Domain specific literacy is a multidimensional construct that requires multiple resources including cognitive and non-cognitive factors. Objective We test the hypothesis that domain specific literacy is associated with AD dementia and AD pathology after controlling for cognition. Methods Participants were community based older persons who completed a baseline literacy assessment, underwent annual clinical evaluations for up to 8 years and agreed to organ donation after death. Financial and health literacy was measured using 32 questions and cognition was measured using 19 tests. Annual diagnosis of AD dementia followed standard criteria. AD pathology was examined post-mortem by quantifying plaques and tangles. Cox models examined the association of literacy with incident AD dementia. Performance of model prediction for incident AD dementia was assessed using indices for integrated discrimination improvement and continuous net reclassification improvement. Linear regression models examined the independent association of literacy with AD pathology in autopsied participants. Results All 805 participants were free of dementia at baseline and 102 (12.7%) developed AD dementia during the follow-up. Lower literacy was associated with higher risk for incident AD dementia (p<0.001), and the association persisted after controlling for cognition (Hazard Ratio=1.50, p=0.004). The model including the literacy measure had better predictive performance than the one with demographics and cognition only. Lower literacy also was associated with higher burden of AD pathology after controlling for cognition (β=0.07, p=0.035). Conclusion Literacy predicts incident AD dementia and AD pathology in community-dwelling older persons, and the association is independent of traditional measures of cognition. PMID:28157101

TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease

PubMed Central

Mishra, Manjari; Hatanpaa, Kimmo J.; White, Charles L.; Johnson, Nancy; Rademaker, Alfred; Weitner, Bing Bing; Deng, Han-Xiang; Dubner, Steven D.; Weintraub, Sandra; Mesulam, Marsel

2010-01-01

The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain–behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinicoanatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies. PMID:20361198

Frontotemporal dementia and amyotrophic lateral sclerosis: revisiting one of the first case reports with neuropathology examination

PubMed Central

Nitrini, Ricardo

2014-01-01

The occurrence of dementia in amyotrophic lateral sclerosis (ALS) was only widely recognized in the late 20th century. Hitherto, it was believed that dementia was a rare event due to the fortuitous association with other diseases. In 1924, Kostantin Nikolaevich Tretiakoff and Moacyr de Freitas Amorim reported a case of dementia with features of frontotemporal dementia (FTD) that preceded the motor signs of ALS. Neuropathological examination confirmed ALS and found no signs of other dementia-causing diseases. The authors hypothesized that dementia was part of ALS and recommended the search for signs of involvement of motor neurons in cases of dementia with an ill-defined clinical picture, a practice currently accepted in the investigation of cases of FTD. This was one of the first descriptions of dementia preceding the motor impairments of ALS and was published in Portuguese and French in Memórias do Hospício de Juquery. PMID:29213884

Utility of behavioral versus cognitive measures in differentiating between subtypes of frontotemporal lobar degeneration and Alzheimer's disease.

PubMed

Heidler-Gary, Jennifer; Gottesman, Rebecca; Newhart, Melissa; Chang, Shannon; Ken, Lynda; Hillis, Argye E

2007-01-01

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

Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study

PubMed Central

Premi, Enrico; Grassi, Mario; van Swieten, John; Galimberti, Daniela; Graff, Caroline; Masellis, Mario; Tartaglia, Carmela; Tagliavini, Fabrizio; Rowe, James B.; Laforce Jr, Robert; Finger, Elizabeth; Frisoni, Giovanni B.; de Mendonça, Alexandre; Sorbi, Sandro; Gazzina, Stefano; Cosseddu, Maura; Archetti, Silvana; Gasparotti, Roberto; Manes, Marta; Alberici, Antonella; Cardoso, Manuel J.; Bocchetta, Martina; Cash, David M.; Ourselin, Sebastian; Padovani, Alessandro; Rohrer, Jonathan D.

2017-01-01

Abstract Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it

What are the different initial presentations of frontotemporal dementia?

PubMed

Chow, Tiffany W

2011-11-01

Frontotemporal dementia (FTD) symptoms at the beginning of illness are in either the realm of behavioral disturbance or in language disruption, also known as aphasia. Based on specific constellations of behavioral change or characteristics of the aphasia, physicians can anticipate the type of protein that is abnormal in the brain. Family history rich with similar instances of illness can further guide the cause of illness in an individual. Knowing the type of protein abnormality (proteinopathy) from among the three most common in FTD (tau, TDP-43, or fused in sarcoma) can help treating clinicians to advise families on the future course of illness and future clinical drug trials that would be most applicable to each patient.

Behavioral variant frontotemporal dementia patients do not succumb to the Allais paradox.

PubMed

Bertoux, Maxime; Cova, Florian; Pessiglione, Mathias; Hsu, Ming; Dubois, Bruno; Bourgeois-Gironde, Sacha

2014-01-01

The Allais Paradox represents one of the earliest empirical challenges to normative models of decision-making, and suggests that choices in one part of a gamble may depend on the possible outcome in another, independent, part of the gamble-a violation of the so-called "independence axiom." To account for Allaisian behavior, one well-known class of models propose that individuals' choices are influenced not only by possible outcomes resulting from one's choices, but also the anticipation of regret for foregone options. Here we test the regret hypothesis using a population of patients with behavioral variant frontotemporal dementia (bvFTD), a clinical population known to present ventromedial prefrontal cortex dysfunctions and associated with impaired regret processing in previous studies of decision-making. Compared to matched controls and Alzheimer's disease (AD) patients, we found a striking diminution of Allaisian behavior among bvFTD patients. These results are consistent with the regret hypothesis and furthermore suggest a crucial role for prefrontal regions in choices that typically stands in contradiction with a basic axiom of rational decision-making.

A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

PubMed

Hafkemeijer, Anne; Möller, Christiane; Dopper, Elise G P; Jiskoot, Lize C; van den Berg-Huysmans, Annette A; van Swieten, John C; van der Flier, Wiesje M; Vrenken, Hugo; Pijnenburg, Yolande A L; Barkhof, Frederik; Scheltens, Philip; van der Grond, Jeroen; Rombouts, Serge A R B

2017-01-01

Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy. We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups. At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls. We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

Dissociation between controlled and automatic processes in the behavioral variant of fronto-temporal dementia.

PubMed

Collette, Fabienne; Van der Linden, Martial; Salmon, Eric

2010-01-01

A decline of cognitive functioning affecting several cognitive domains was frequently reported in patients with frontotemporal dementia. We were interested in determining if these deficits can be interpreted as reflecting an impairment of controlled cognitive processes by using an assessment tool specifically developed to explore the distinction between automatic and controlled processes, namely the process dissociation procedure (PDP) developed by Jacoby. The PDP was applied to a word stem completion task to determine the contribution of automatic and controlled processes to episodic memory performance and was administered to a group of 12 patients with the behavioral variant of frontotemporal dementia (bv-FTD) and 20 control subjects (CS). Bv-FTD patients obtained a lower performance than CS for the estimates of controlled processes, but no group differences was observed for estimates of automatic processes. The between-groups comparison of the estimates of controlled and automatic processes showed a larger contribution of automatic processes to performance in bv-FTD, while a slightly more important contribution of controlled processes was observed in control subjects. These results are clearly indicative of an alteration of controlled memory processes in bv-FTD.

Criminal behavior in frontotemporal dementia and Alzheimer disease.

PubMed

Liljegren, Madeleine; Naasan, Georges; Temlett, Julia; Perry, David C; Rankin, Katherine P; Merrilees, Jennifer; Grinberg, Lea T; Seeley, William W; Englund, Elisabet; Miller, Bruce L

2015-03-01

Neurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life. To investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder. We conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups. Frequencies of criminal behavior and χ² statistics were calculated. Of the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (P < .001) and 6.4% were statistically significantly more likely to exhibit violence compared with 2% of patients with AD (P = .003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast with those in the AD group, who commonly committed traffic violations, often

Art and the brain: the influence of frontotemporal dementia on an accomplished artist.

PubMed

Mell, Joshua Chang; Howard, Sara M; Miller, Bruce L

2003-05-27

A talented artist developed a progressive aphasia syndrome associated with frontotemporal dementia (FTD). As her disease progressed, language and executive skills declined, but her paintings became freer and more original. She demonstrates that artistic development can occur in the setting of language-dominant types of FTD. The study of artistic development in the setting of FTD suggests that language is not required for, and may even inhibit, certain types of visual creativity.

Poor Gait Performance and Prediction of Dementia: Results From a Meta-Analysis.

PubMed

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

2016-06-01

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. 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. 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). 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. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

[The neurochemistry and neuropharmacology of frontotemporal dementia].

PubMed

Alonso-Navarro, H; Jabbour-Wadih, T; Ayuso-Peralta, L; Jiménez-Jiménez, F J

To review the neurochemical features and therapeutic options for frontotemporal dementia (FTD). The main neurochemical alterations in FTD are the serotoninergic and dopamine depletion. In contrast with Alzheimer's and diffuse Lewy bodies disease, there are not significant alterations of the cholinergic system. Cerebral perfusion and glucose metabolism studies usually show hypoperfusion or hypometabolism, with predominant involvement of temporal and frontal cortices. There have been described some alterations related with oxidative stress and apoptosis, although its pathogenetic role in FTD is not well known. Treatment of FTD is not well established, because there are only a few studies with some drugs. The most studied drugs are serotonin reuptake inhibitors, however, despite the well-known serotoninergic deficiency described in FTD, the results are not conclusive. The main neurochemical alterations of FTD are serotoninergic and dopaminergic deficiencies. The treatment is not well established, although it should be theoretically ideal to use drugs which modulate these neurotransmitter systems.

Structural Anatomical Investigation of Long-Term Memory Deficit in Behavioral Frontotemporal Dementia.

PubMed

Bertoux, Maxime; Flanagan, Emma C; Hobbs, Matthew; Ruiz-Tagle, Amparo; Delgado, Carolina; Miranda, Marcelo; Ibáñez, Agustín; Slachevsky, Andrea; Hornberger, Michael

2018-01-01

Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD.

Diagnosis and Management of Behavioral Variant Frontotemporal Dementia

PubMed Central

Pressman, Peter; Miller, Bruce L

2014-01-01

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

Strategic value-directed learning and memory in Alzheimer's disease and behavioural-variant frontotemporal dementia.

PubMed

Wong, Stephanie; Irish, Muireann; Savage, Greg; Hodges, John R; Piguet, Olivier; Hornberger, Michael

2018-02-12

In healthy adults, the ability to prioritize learning of highly valued information is supported by executive functions and enhances subsequent memory retrieval for this information. In Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD), marked deficits are evident in learning and memory, presenting in the context of executive dysfunction. It is unclear whether these patients show a typical memory bias for higher valued stimuli. We administered a value-directed word-list learning task to AD (n = 10) and bvFTD (n = 21) patients and age-matched healthy controls (n = 22). Each word was assigned a low, medium or high point value, and participants were instructed to maximize the number of points earned across three learning trials. Participants' memory for the words was assessed on a delayed recall trial, followed by a recognition test for the words and corresponding point values. Relative to controls, both patient groups showed poorer overall learning, delayed recall and recognition. Despite these impairments, patients with AD preferentially recalled high-value words on learning trials and showed significant value-directed enhancement of recognition memory for the words and points. Conversely, bvFTD patients did not prioritize recall of high-value words during learning trials, and this reduced selectivity was related to inhibitory dysfunction. Nonetheless, bvFTD patients showed value-directed enhancement of recognition memory for the point values, suggesting a mismatch between memory of high-value information and the ability to apply this in a motivationally salient context. Our findings demonstrate that value-directed enhancement of memory may persist to some degree in patients with dementia, despite pronounced deficits in learning and memory. © 2018 The British Psychological Society.

Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL)

ClinicalTrials.gov

2018-05-01

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)

The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis.

PubMed

Chakrabarty, Trisha; Sepehry, Amir A; Jacova, Claudia; Hsiung, Ging-Yuek Robin

2015-01-01

Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. PubMed, EMBASE and PsychINFO were queried for 'depression' and/or 'depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.

Language, Executive Function and Social Cognition in the Diagnosis of Frontotemporal Dementia Syndromes

PubMed Central

Harciarek, Michał; Cosentino, Stephanie

2015-01-01

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

Diagnosis and management of behavioral variant frontotemporal dementia.

PubMed

Pressman, Peter S; Miller, Bruce L

2014-04-01

Frontotemporal dementia 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 might 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 might further diagnosis, treatment, and research. © 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.

Tower of London test: a comparison between conventional statistic approach and modelling based on artificial neural network in differentiating fronto-temporal dementia from Alzheimer's disease.

PubMed

Franceschi, Massimo; Caffarra, Paolo; Savarè, Rita; Cerutti, Renata; Grossi, Enzo

2011-01-01

The early differentiation of Alzheimer's disease (AD) from frontotemporal dementia (FTD) may be difficult. The Tower of London (ToL), thought to assess executive functions such as planning and visuo-spatial working memory, could help in this purpose. Twentytwo Dementia Centers consecutively recruited patients with early FTD or AD. ToL performances of these groups were analyzed using both the conventional statistical approaches and the Artificial Neural Networks (ANNs) modelling. Ninety-four non aphasic FTD and 160 AD patients were recruited. ToL Accuracy Score (AS) significantly (p < 0.05) differentiated FTD from AD patients. However, the discriminant validity of AS checked by ROC curve analysis, yielded no significant results in terms of sensitivity and specificity (AUC 0.63). The performances of the 12 Success Subscores (SS) together with age, gender and schooling years were entered into advanced ANNs developed by Semeion Institute. The best ANNs were selected and submitted to ROC curves. The non-linear model was able to discriminate FTD from AD with an average AUC for 7 independent trials of 0.82. The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients.

Behavioral and activities of daily living inventories in the diagnosis of frontotemporal lobar degeneration and Alzheimer’s disease

PubMed Central

Bahia, Valéria Santoro; da Silva, Mari-Nilva Maia; Viana, Rene; Smid, Jerusa; Damin, Antonio Eduardo; Radanovic, Márcia; Nitrini, Ricardo

2008-01-01

The differential diagnosis between frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) is often challenging. Objectives To verify the usefulness of behavioral and activities of daily living inventories in the differential diagnosis between FTLD and AD. Methods Caregivers of 12 patients with FTLD (nine with frontotemporal dementia, two with semantic dementia and one with progressive non-fluent aphasia) and of 12 patients with probable AD were interviewed. The Brazilian version of the Frontal Behavioral Inventory (FBI) and Disability Assessment for Dementia (DAD ) were used. Results The mean of the MMSE score was 12.4±10.7for patients with FTLD and 11.9±6.2for patients with AD (p=0.93). Mean scores on the DAD were 33.7±27.7in patients with FTLD and 55.6±29.7in patients with AD (p=0.06), while for the FBI they were 42.6±10.0for FTLD and 16.7±11.7for AD (p<0.01). Conclusions In this study, FBI was found to be a helpful tool for the differential diagnosis between FTLD and AD. Although the DAD was not useful in differential diagnosis in our sample we believe it to be important for measuring the severity of the disease through quantitative and qualitative assessment of functional deficits of the patients. PMID:29213552

Quantitative neurohistological features of frontotemporal degeneration.

PubMed

Arnold, S E; Han, L Y; Clark, C M; Grossman, M; Trojanowski, J Q

2000-01-01

Frontotemporal degeneration (FTD) is a neurodegenerative condition that has been principally associated with frontal lobe dementia. In this study, we compared neuropathological abnormalities in frontal, hippocampal, and calcarine cortices from patients assigned a diagnosis of FTD, normal elderly and Alzheimer's disease (AD). Densities of Nissl-stained neurons and lesions which were immunolabeled for tau, beta-amyloid (Abeta), alpha- and beta-synuclein, ubiquitin, glial fibrillary acidic protein (GFAP) and CD68 antigen were determined using computer-assisted, non-biased quantitative microscopy. We found that FTD frontal and hippocampal regions exhibited marked neuron loss, abundant ubiquitin-immunoreactive (ir) dystrophic neurites, GFAP-ir astrocytes, and CD68-ir microglia, while calcarine cortex was spared. No alpha- or beta-synuclein-ir lesions were observed, and neither the density of tau-ir neurofibrillary tangles nor that of Abeta-ir plaques in FTD exceeded normal controls. In addition, there were no neuropathological differences between FTD subjects who presented clinically with a frontal lobe dementia versus an AD-like dementia. These findings indicate that FTD is a category of neurodegnerative dementias with varying clinical presentations that is characterized by the progressive degeneration of select populations of cortical neurons. The molecular neurodegenerative mechanisms that lead to FTD remain to be elucidated.

False Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease-Disinhibition or Amnesia?

PubMed

Flanagan, Emma C; Wong, Stephanie; Dutt, Aparna; Tu, Sicong; Bertoux, Maxime; Irish, Muireann; Piguet, Olivier; Rao, Sulakshana; Hodges, John R; Ghosh, Amitabha; Hornberger, Michael

2016-01-01

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.

Criminal Behavior in Frontotemporal Dementia and Alzheimer Disease

PubMed Central

Liljegren, Madeleine; Naasan, Georges; Temlett, Julia; Perry, David C.; Rankin, Katherine P.; Merrilees, Jennifer; Grinberg, Lea T.; Seeley, William W.; Englund, Elisabet; Miller, Bruce L

2015-01-01

Importance Neurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life. Objective To investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder. Design, Setting, and Participants We conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups. Main Outcomes and Measures Frequencies of criminal behavior and χ2 statistics were calculated. Results Of the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (P < .001) and 6.4% were statistically significantly more likely to exhibit violence compared with 2% of patients with AD (P = .003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast

Degradation of cognitive timing mechanisms in behavioural variant frontotemporal dementia

PubMed Central

Henley, Susie M.D.; Downey, Laura E.; Nicholas, Jennifer M.; Kinnunen, Kirsi M.; Golden, Hannah L.; Buckley, Aisling; Mahoney, Colin J.; Crutch, Sebastian J.

2014-01-01

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

Can cognitive assessment really discriminate early stages of Alzheimer's and behavioural variant frontotemporal dementia at initial clinical presentation?

PubMed

Reul, Sophia; Lohmann, Hubertus; Wiendl, Heinz; Duning, Thomas; Johnen, Andreas

2017-08-09

Neuropsychological testing is considered crucial for differential diagnosis of Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD). In-depth neuropsychological assessment revealed specific dysfunctions in the two dementia syndromes. However, a significant overlap of cognitive impairments exists in early disease stages. We questioned whether a standard neuropsychological assessment at initial clinical presentation can delineate patients with AD versus bvFTD. In a retrospective approach, we evaluated and compared how cognitive profiles assessed at initial clinical presentation predicted the diagnosis of later verified AD (n = 43) and bvFTD (n = 26). Additionally, the neuropsychological standard domains memory, language, visuospatial skills, executive functions, praxis and social cognition were subjected to stepwise discriminant analysis to compare their differential contribution to diagnosis. Regardless of diagnosis, a percentage of patients presented with major deterioration in a wide range of cognitive domains when compared with age-matched normative data. Only few significant differences were detected on the group level: Patients with AD were relatively more impaired in the verbal recall, verbal recognition, figure copy, and surprisingly in the executive subdomains, set shifting and processing speed whereas bvFTD was characterised by more deficits in imitation of face postures. A combination of tests for verbal recall, imitation of limb and face postures, and figure copy showed the greatest discriminatory power. Our results imply that the contribution of a standard neuropsychological assessment is limited for differential diagnosis of AD and bvFTD at initial presentation. In contrast to current clinical guidelines, executive functions are neither particularly nor exclusively impaired in patients with bvFTD when assessed within a standard clinical neuropsychological test battery. The significant overlap of bvFTD and AD

Distinct patterns of brain atrophy in Genetic Frontotemporal Dementia Initiative (GENFI) cohort revealed by visual rating scales.

PubMed

Fumagalli, Giorgio G; Basilico, Paola; Arighi, Andrea; Bocchetta, Martina; Dick, Katrina M; Cash, David M; Harding, Sophie; Mercurio, Matteo; Fenoglio, Chiara; Pietroboni, Anna M; Ghezzi, Laura; van Swieten, John; Borroni, Barbara; de Mendonça, Alexandre; Masellis, Mario; Tartaglia, Maria C; Rowe, James B; Graff, Caroline; Tagliavini, Fabrizio; Frisoni, Giovanni B; Laforce, Robert; Finger, Elizabeth; Sorbi, Sandro; Scarpini, Elio; Rohrer, Jonathan D; Galimberti, Daniela

2018-05-24

In patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms. Magnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas). Intra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers. These simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.

Perception of emotion on faces in frontotemporal dementia and Alzheimer's disease: a longitudinal study.

PubMed

Lavenu, I; Pasquier, F

2005-01-01

Frontotemporal dementia (FTD) is a neurodegenerative disease characterised by behavioural disorders that suggest abnormalities of emotional processing. In a previous study, we showed that patients with Alzheimer's disease (AD) and with FTD were equally able to distinguish a face displaying affect from one not displaying affect. However, recognition of emotion was worse in patients with FTD than in patients with AD who did not differ significantly from controls. The aim of this study was to follow up the perception of emotions on faces in these patients. The poor perception of emotion could worsen differently in AD and in FTD, with the progression of atrophy of the amygdala, the anterior temporal cortex and the orbital frontal cortex, structures that are components of the brain's emotional processing systems. Patients with AD or with FTD had to recognise and point out the name of one of seven basic emotions (anger, disgust, happiness, fear, sadness, surprise and contempt) on a set of 28 faces presented on slides at the first visit and 3 years later. Thirty-seven patients (AD = 19, FTD = 18) performed the tests initially. The two patient groups did not differ for age, sex and duration of the disease. During the follow-up, 12 patients died, 4 patients refused to perform the tests and 8 could not be tested because of the severity of the disease. Finally, 7 patients with AD and 6 patients with FTD performed the two tests at a mean delay of 40 months. All patients with AD had worse results at follow-up on the perception of emotion despite the prescription of inhibitors of cholinesterase in all patients and of selective serotonin reuptake inhibitors (SSRIs) in 4 patients. As a whole, patients with FTD had better results in the second than in the first assessment (however, 3 of them had worse results) independently of the prescription of trazodone (n = 2), other SSRIs (n = 2), or the absence of treatment (n = 2), and of possible cognitive change. Recognition of emotion on

Behavioral Interventions for Enhancing Life Participation in behavioral variant Frontotemporal Dementia and Primary Progressive Aphasia

PubMed Central

Kortte, Kathleen B.; Rogalski, Emily J.

2013-01-01

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

An Italian family with inclusion-body myopathy and frontotemporal dementia due to mutation in the VCP gene.

PubMed

Gidaro, Teresa; Modoni, Anna; Sabatelli, Mario; Tasca, Giorgio; Broccolini, Aldobrando; Mirabella, Massimiliano

2008-01-01

Mutations of the valosin-containing protein gene (VCP) are responsible for autosomal-dominant hereditary inclusion-body myopathy associated with frontotemporal dementia and Paget's disease of bone. We identified the p.R155C missense mutation in the VCP gene segregating in an Italian family with three affected siblings, two of whom had a progressive myopathy associated with dementia, whereas one exhibited a progressive myopathy and preclinical signs of Paget's disease of bone. Our study demonstrates that VCP mutations are found in patients of Italian background and may lead to a variable clinical phenotype even within the same kinship.

Neuropsychological Testing in Pathologically Verified Alzheimer Disease and Frontotemporal Dementia: How Well Do the Uniform Data Set Measures Differentiate Between Diseases?

PubMed

Ritter, Aaron R; Leger, Gabriel C; Miller, Justin B; Banks, Sarah J

2017-01-01

Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in

R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia

PubMed Central

CF, Slattery; J, Beck; L, Harper; G, Adamson; Z, Abdi; J, Uphill; T, Campbell; R, Druyeh; CJ, Mahoney; JD, Rohrer; J, Kenny; J, Lowe; KK, Leung; J, Barnes; SL, Clegg; M, Blair; JM, Nicholas; RJ, Guerreiro; JB, Rowe; C, Ponto; I, Zerr; H, Kretzschmar; P, Gambetti; SJ, Crutch; JD, Warren; MN, Rossor; NC, Fox; J, Collinge; JM, Schott; S, Mead

2015-01-01

Background Rare TREM2 variants are significant risk factors for Alzheimer’s disease. Methods We used next generation sequencing of the whole gene (n=700), exon 2 Sanger sequencing (n=2634), p.R47H genotyping (n=3518) and genome wide association study imputation (n=13048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with Alzheimer’s disease (n=1002), frontotemporal dementia (n=358), sporadic (n=2500) and variant (n=115) Creutzfeldt-Jakob disease. Results We confirm only p.R47H as a risk factor for Alzheimer’s disease (OR=2.19; 95%CI=1.04-4.51; P=0.03). p.R47H does not significantly alter risk for frontotemporal dementia (OR=0.81), variant or sporadic Creutzfeldt-Jakob disease (OR=1.06 95%CI=0.66-1.69) in our cohorts. Individuals with p.R47H associated Alzheimer’s (n=12) had significantly earlier symptom onset than individuals with no TREM2 variants (n=551) (55.2years vs. 61.7years, P=0.02). We note that heterozygous p.R47H Alzheimer’s disease is memory led and otherwise indistinguishable from “typical” sporadic Alzheimer’s. Conclusion We find p.R47H is a risk factor for Alzheimer’s disease, but not frontotemporal dementia or prion disease. PMID:25160042

First TV ad for dementia care.

PubMed

2008-12-10

Last month, viewers saw the first-ever TV advertisement about providing care for people with dementia. Screened as part of Bupa's initiative, bringing the issue of dementia care 'out of the shadows,' the ad features Ernie visiting his sister June, who has dementia, in a Bupa care home and shows the personalised care being delivered by specially trained staff.

Altered Sense of Humor in Dementia

PubMed Central

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.

2015-01-01

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

A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

PubMed

Fanganiello, R D; Kimonis, V E; Côrte, C C; Nitrini, R; Passos-Bueno, M R

2011-04-01

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.

Diagnosing, monitoring and managing behavioural variant frontotemporal dementia.

PubMed

Piguet, Olivier; Kumfor, Fiona; Hodges, John

2017-09-02

Behavioural variant frontotemporal dementia is characterised by insidious changes in personality and interpersonal conduct that reflect progressive disintegration of the neural circuits involved in social cognition, emotion regulation, motivation and decision making. The underlying pathology is heterogeneous and classified according to the presence of intraneuronal inclusions of tau, TDP-43 or, occasionally, fused in sarcoma proteins. Biomarkers to detect these histopathological changes in life are increasingly important with the development of disease-modifying drugs. A number of gene abnormalities have been identified, the most common being an expansion in the C9orf72 gene, which together account for most familial cases. The 2011 international consensus criteria propose three levels of diagnostic certainty: possible, probable and definite. Detailed history taking from family members to elicit behavioural features underpins the diagnostic process, with support from neuropsychological testing designed to detect impairment in decision making, emotion processing and social cognition. Brain imaging is important for increasing the level of diagnosis certainty over time. Carer education and support remain of paramount importance.

Caregiver Burden in Semantic Dementia with Right- and Left-Sided Predominant Cerebral Atrophy and in Behavioral-Variant Frontotemporal Dementia.

PubMed

Koyama, Asuka; Hashimoto, Mamoru; Fukuhara, Ryuji; Ichimi, Naoko; Takasaki, Akihiro; Matsushita, Masateru; Ishikawa, Tomohisa; Tanaka, Hibiki; Miyagawa, Yusuke; Ikeda, Manabu

2018-01-01

Caregiver burden is a serious concern for family caregivers of dementia patients, but its nature is unclear in patients with semantic dementia (SD). This study aimed to clarify caregiver burden for right- (R > L) and left-sided (L > R) predominant SD versus behavioral-variant frontotemporal dementia (bvFTD) patients. Using the Japanese version of the Zarit Burden Interview (ZBI) and the Neuropsychiatric Inventory, we examined caregiver burden and behavioral and psychological symptoms of dementia (BPSD) in 43 first-visit outpatient/family caregiver dyads (bvFTD, 20 dyads; SD [L > R], 13 dyads; SD [R > L], 10 dyads). We found a significant difference in ZBI score between the 3 diagnostic groups. Post hoc tests revealed a significantly higher ZBI score in the bvFTD than in the SD (L > R) group. The ZBI scores in the SD (L > R) and SD (R > L) groups were not significantly different, although the effect size was large. Caregiver burden was significantly correlated with BPSD scores in all groups and was correlated with activities of daily living and instrumental activities of daily living decline in the bvFTD and SD (R > L) groups. Caregiver burden was highest in the bvFTD group, comparatively high in the SD (R > L) group, and lowest in the SD (L > R) group. Adequate support and intervention for caregivers should be tailored to differences in caregiver burden between these patient groups.

The unique predisposition to criminal violations in frontotemporal dementia.

PubMed

Mendez, Mario F

2010-01-01

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.

Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

PubMed

Weishaupt, Jochen H; Hyman, Tony; Dikic, Ivan

2016-09-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative diseases in which predominantly motor neurons and cerebral cortex neurons, respectively, are affected. Several novel ALS and FTD disease genes have been recently discovered, pointing toward a few overarching pathways in ALS/FTD pathogenesis. Nevertheless, a precise picture of how various cellular processes cause neuronal death, or how different routes leading to ALS and FTD are functionally connected is just emerging. Moreover, how the most recent milestone findings in the ALS/FTD field might lead to improved diagnosis and treatment is actively being explored. We highlight some of the most exciting recent topics in the field, which could potentially facilitate the identification of further links between the pathogenic ALS/FTD pathways related to autophagy, vesicle trafficking, and RNA metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

Physiological phenotyping of dementias using emotional sounds.

PubMed

Fletcher, Phillip D; Nicholas, Jennifer M; Shakespeare, Timothy J; Downey, Laura E; Golden, Hannah L; Agustus, Jennifer L; Clark, Camilla N; Mummery, Catherine J; Schott, Jonathan M; Crutch, Sebastian J; Warren, Jason D

2015-06-01

Emotional behavioral disturbances are hallmarks of many dementias but their pathophysiology is poorly understood. Here we addressed this issue using the paradigm of emotionally salient sounds. Pupil responses and affective valence ratings for nonverbal sounds of varying emotional salience were assessed in patients with behavioral variant frontotemporal dementia (bvFTD) (n = 14), semantic dementia (SD) (n = 10), progressive nonfluent aphasia (PNFA) (n = 12), and AD (n = 10) versus healthy age-matched individuals (n = 26). Referenced to healthy individuals, overall autonomic reactivity to sound was normal in Alzheimer's disease (AD) but reduced in other syndromes. Patients with bvFTD, SD, and AD showed altered coupling between pupillary and affective behavioral responses to emotionally salient sounds. Emotional sounds are a useful model system for analyzing how dementias affect the processing of salient environmental signals, with implications for defining pathophysiological mechanisms and novel biomarker development.

SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

PubMed

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

2013-11-01

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. To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. 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. Primary care or referral center. An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. 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. 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.

Episodic Memory Dysfunction in Behavioral Variant Frontotemporal Dementia: A Clinical And FDG-PET Study.

PubMed

Fernández-Matarrubia, Marta; Matías-Guiu, Jordi A; Cabrera-Martín, María Nieves; Moreno-Ramos, Teresa; Valles-Salgado, María; Carreras, José Luis; Matías-Guiu, Jorge

2017-01-01

Episodic memory disturbance is still considered as an exclusion criterion for behavioral variant frontotemporal dementia (bvFTD), but growing evidence suggests that memory can be impaired. Our main purposes were to assess episodic memory in a group of bvFTD patients comparatively with Alzheimer's disease (AD) patients, and analyze the relationship between episodic memory and brain metabolism measured using positron emission tomography imaging with 18F-fluorodeoxyglucose (FDG-PET). Twenty-six bvFTD, 29 AD, and 24 healthy controls were included. Episodic memory was assessed by the Free and Cued Selective Reminding Test (FCSRT), which controls for effective encoding and measures memory consolidation processing. All participants underwent FDG-PET brain scans to provide data for voxel-based brain mapping analysis. Half of bvFTD patients had a deficit of total, free delayed, and total free delayed recall as severe as AD patients (amnestic-FTD). The other half had FCSRT scores similar to controls (non-amnestic-FTD). Imaging analyses revealed that amnestic-FTD showed bilateral lower metabolism than non-amnestic-FTD in anterior parahippocampal and inferior temporal gyri. Additionally, FCSRT total and total delayed scores were inversely correlated with parahippocampal metabolism in both bvFTD and AD. Besides, bvFTD showed an inverse association among FCSRT and inferior temporal metabolism. Our findings support that bvFTD could present a genuine amnesia affecting storage and consolidation abilities, which involves structures implicated in the Papez circuit, as occurs in AD, and also inferior temporal regions. These results contribute to understanding the mechanisms underpinning memory dysfunction in bvFTD, and may be relevant to further revisions of the current diagnostic criteria.

Factors associated with a depressive disorder in Alzheimer's disease are different from those found for other dementia disorders.

PubMed

Barca, Maria Lage; Engedal, Knut; Laks, Jerson; Selbaek, Geir

2012-01-01

This study explores factors associated with depression in Alzheimer's disease (AD) compared with mild cognitive impairment (MCI) and other dementia disorders. In a prospective study we included 195 patients: 31 with MCI, 112 with AD and 52 with other dementias. According to the ICD-10 and the DSM-IV criteria, 88 (44.1%) and 59 (30.3%), respectively, had a depressive disorder. An adjusted multiple regression analysis showed that previous depression (p < 0.05) was significantly associated with depression in AD patients. Severity of dementia (p < 0.05) was significantly associated with a depressive disorder in a group of patients with frontotemporal dementia, vascular dementia, or dementia due to Lewy Body disease or Parkinson's disease. We found different factors associated with a depressive disorder in AD compared to those found for other dementia disorders.

C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients.

PubMed

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

2013-01-01

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.

COMPARATIVE EFFECTIVENESS OF MCI and DEMENTIA TREATMENTS IN A COMMUNITY-BASED DEMENTIA PRACTICE

ClinicalTrials.gov

2016-08-04

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

Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers.

PubMed

Dodich, Alessandra; Cerami, Chiara; Cappa, Stefano F; Marcone, Alessandra; Golzi, Valeria; Zamboni, Michele; Giusti, Maria Cristina; Iannaccone, Sandro

2018-01-01

Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult. In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups. We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD. Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD. Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.

Mentalising music in frontotemporal dementia.

PubMed

Downey, Laura E; Blezat, Alice; Nicholas, Jennifer; Omar, Rohani; Golden, Hannah L; Mahoney, Colin J; Crutch, Sebastian J; Warren, Jason D

2013-01-01

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mentalising music in frontotemporal dementia

PubMed Central

Downey, Laura E.; Blezat, Alice; Nicholas, Jennifer; Omar, Rohani; Golden, Hannah L.; Mahoney, Colin J.; Crutch, Sebastian J.; Warren, Jason D.

2013-01-01

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

Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

PubMed

Watts, G D J; Thomasova, D; Ramdeen, S K; Fulchiero, E C; Mehta, S G; Drachman, D A; Weihl, C C; Jamrozik, Z; Kwiecinski, H; Kaminska, A; Kimonis, V E

2007-11-01

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of 'myopathic' changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.

SQSTM1 Mutations in French Patients With Frontotemporal Dementia or Frontotemporal Dementia With Amyotrophic Lateral Sclerosis

PubMed Central

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

2014-01-01

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

Factors Associated with a Depressive Disorder in Alzheimer's Disease Are Different from Those Found for Other Dementia Disorders

PubMed Central

Barca, Maria Lage; Engedal, Knut; Laks, Jerson; Selbaek, Geir

2012-01-01

Background This study explores factors associated with depression in Alzheimer's disease (AD) compared with mild cognitive impairment (MCI) and other dementia disorders. Method In a prospective study we included 195 patients: 31 with MCI, 112 with AD and 52 with other dementias. Results According to the ICD-10 and the DSM-IV criteria, 88 (44.1%) and 59 (30.3%), respectively, had a depressive disorder. An adjusted multiple regression analysis showed that previous depression (p < 0.05) was significantly associated with depression in AD patients. Severity of dementia (p < 0.05) was significantly associated with a depressive disorder in a group of patients with frontotemporal dementia, vascular dementia, or dementia due to Lewy Body disease or Parkinson's disease. Conclusion We found different factors associated with a depressive disorder in AD compared to those found for other dementia disorders. PMID:22479262

Interrater reliability of the new criteria for behavioral variant frontotemporal dementia.

PubMed

Lamarre, Amanda K; Rascovsky, Katya; Bostrom, Alan; Toofanian, Parnian; Wilkins, Sarah; Sha, Sharon J; Perry, David C; Miller, Zachary A; Naasan, Georges; Laforce, Robert; Hagen, Jayne; Takada, Leonel T; Tartaglia, Maria Carmela; Kang, Gail; Galasko, Douglas; Salmon, David P; Farias, Sarah Tomaszewski; Kaur, Berneet; Olichney, John M; Quitania Park, Lovingly; Mendez, Mario F; Tsai, Po-Heng; Teng, Edmond; Dickerson, Bradford Clark; Domoto-Reilly, Kimiko; McGinnis, Scott; Miller, Bruce L; Kramer, Joel H

2013-05-21

To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings. The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD ("almost perfect agreement"). Interrater reliability for 4 of the 6 core features had "substantial" agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61-0.80), whereas 2 had "moderate" agreement (apathy/inertia, neuropsychological; κ = 0.41-0.6). Clinician years of experience did not significantly influence rater accuracy. The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Fully automated structural MRI of the brain in clinical dementia workup.

PubMed

Persson, Karin; Selbæk, Geir; Brækhus, Anne; Beyer, Mona; Barca, Maria; Engedal, Knut

2017-06-01

Background The dementia syndrome has been regarded a clinical diagnosis but the focus on supplemental biomarkers is increasing. An automatic magnetic resonance imaging (MRI) volumetry method, NeuroQuant® (NQ), has been developed for use in clinical settings. Purpose To evaluate the clinical usefulness of NQ in distinguishing Alzheimer's disease dementia (AD) from non-dementia and non-AD dementia. Material and Methods NQ was performed in 275 patients diagnosed according to the criteria of ICD-10 for AD, vascular dementia and Parkinson's disease dementia (PDD); the Winblad criteria for mild cognitive impairment; the Lund-Manchester criteria for frontotemporal dementia; and the revised consensus criteria for Lewy body dementia (LBD). Receiver operating curve (ROC) analyses with calculation of area under the curve (AUC) and regression analyses were carried out. Results Forebrain parenchyma (AUC 0.82), hippocampus (AUC 0.80), and inferior lateral ventricles (AUC 0.78) yielded the highest AUCs for AD/non-dementia discrimination. Only hippocampus (AUC 0.62) and cerebellum (AUC 0.67) separated AD from non-AD dementia. Cerebellum separated AD from PDD-LBD (AUC 0.83). Separate multiple regression analyses adjusted for age and gender, showed that memory (CERAD 10-word delayed recall) (beta 0.502, P < 0.001) was more strongly associated to the hippocampus volume than the diagnostic distinction of AD versus non-dementia (beta -0.392, P < 0.001). Conclusion NQ measures could separate AD from non-dementia fairly well but generally poorer from non-AD dementia. Degree of memory impairment, age, and gender, but not diagnostic distinction, were associated to the hippocampus volume in adjusted analyses. Surprisingly, cerebellum was found relevant in separating AD from PDD-LBD.

Longitudinal patterns of semantic and episodic memory in frontotemporal lobar degeneration and Alzheimer's disease.

PubMed

Xie, Sharon X; Libon, David J; Wang, Xingmei; Massimo, Lauren; Moore, Peachie; Vesely, Luisa; Khan, Alea; Chatterjee, Anjan; Coslett, H Branch; Hurtig, Howard I; Liang, Tsao-Wei; Grossman, Murray

2010-03-01

The longitudinal assessment of episodic and semantic memory was obtained from 236 patients diagnosed with Alzheimer's disease (AD, n = 128) and with frontotemporal lobar degeneration (FTLD, n = 108), including patients with a social comportment/dysexecutive (SOC/EXEC) disorder, progressive nonfluent aphasia (PNFA), semantic dementia (SemD), and corticobasal syndrome (CBS). At the initial assessment, AD patients obtained a lower score on the delayed free recall test than other patients. Longitudinal analyses for delayed free recall found converging performance, with all patients reaching the same level of impairment as AD patients. On the initial evaluation for delayed recognition, AD patients also obtained lower scores than other groups. Longitudinal analyses for delayed recognition test performance found that AD patients consistently produced lower scores than other groups and no convergence between AD and other dementia groups was seen. For semantic memory, there were no initial between-group differences. However, longitudinal analyses for semantic memory revealed group differences over illness duration, with worse performance for SemD versus AD, PNFA, SOC/EXEC, and CBS patients. These data suggest the presence of specific longitudinal patterns of impairment for episodic and semantic memory in AD and FTLD patients suggesting that all forms of dementia do not necessarily converge into a single phenotype.

C9ORF72 Repeat Expansion in Australian and Spanish Frontotemporal Dementia Patients

PubMed Central

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.

2013-01-01

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. PMID:23437264

Distinct subtypes of behavioral-variant frontotemporal dementia based on patterns of network degeneration

PubMed Central

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

2016-01-01

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

Adaptation and validation of a Spanish-language version of the Frontotemporal Dementia Rating Scale (FTD-FRS).

PubMed

Turró-Garriga, O; Hermoso Contreras, C; Olives Cladera, J; Mioshi, E; Pelegrín Valero, C; Olivera Pueyo, J; Garre-Olmo, J; Sánchez-Valle, R

2017-06-01

The Frontotemporal Dementia Rating Scale (FTD-FRS) is a tool designed to aid with clinical staging and assessment of the progression of frontotemporal dementia (FTD-FRS). Present a multicentre adaptation and validation study of a Spanish version of the FRS. The adapted version was created using 2 translation-back translation processes (English to Spanish, Spanish to English) and verified by the scale's original authors. We validated the adapted version in a sample of consecutive patients diagnosed with FTD. The procedure included evaluating internal consistency, testing unidimensionality with the Rasch model, analysing construct validity and discriminant validity, and calculating the degree of agreement between the Clinical Dementia Rating scale (CDR) and FTD-FRS for FTD cases. The study included 60 patients with DFT. The mean score on the FRS was 12.1 points (SD=6.5; range, 2-25) with inter-group differences (F=120.3; df=3; P<.001). Cronbach's alpha was 0.897 and principal component analysis of residuals delivered an acceptable eigenvalue for 5 contrasts (1.6-2.7) and 36.1% raw variance. FRS was correlated with the Mini-mental State Examination (r=0.572; P<.001) and functional capacity (DAD; r=0.790; P<.001). FTD-FRS also showed a significant correlation with CDR (r=-0.641; P<.001), but we did observe variability in the severity levels; cases appeared to be less severe according to the CDR than when measured with the FTD-FRS (kappa=0.055). This process of validating the Spanish translation of the FTD-FRS yielded satisfactory results for validity and unidimensionality (severity) in the assessment of patients with FTD. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Frontotemporal Dementia Selectively Impairs Transitive Reasoning About Familiar Spatial Environments

PubMed Central

Vartanian, Oshin; Goel, Vinod; Tierney, Michael; Huey, Edward D.; Grafman, Jordan

2010-01-01

Although patients with frontotemporal dementia (FTD) are known to exhibit a wide range of cognitive and personality difficulties, some evidence suggests that there may be a degree of selectivity in their reasoning impairments. Based on a recent review of the neuroimaging literature on reasoning, the authors hypothesized that the presence or absence of familiar content may have a selective impact on the reasoning abilities of patients with FTD. Specifically, the authors predicted that patients with frontalvariant FTD would be more impaired when reasoning about transitive arguments involving familiar spatial environments than when reasoning about identical logical arguments involving unfamiliar spatial environments. As predicted, patients with FTD were less accurate than normal controls only when the content of arguments involved familiar spatial environments. These results indicate a degree of selectivity in the cognitive deficits of this patient population and suggest that the frontal-temporal lobe system may play a necessary role in reasoning about familiar material. PMID:19702415

CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients.

PubMed

Skillbäck, Tobias; Delsing, Louise; Synnergren, Jane; Mattsson, Niklas; Janelidze, Shorena; Nägga, Katarina; Kilander, Lena; Hicks, Ryan; Wimo, Anders; Winblad, Bengt; Hansson, Oskar; Blennow, Kaj; Eriksdotter, Maria; Zetterberg, Henrik

2017-11-01

A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology. Copyright © 2017 Elsevier Inc. All rights reserved.

Primary empathy deficits in frontotemporal dementia.

PubMed

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

2014-01-01

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.

Primary empathy deficits in frontotemporal dementia

PubMed Central

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

2014-01-01

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

Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients.

PubMed

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

2016-01-01

'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.

Self-Awareness and Self-Monitoring of Cognitive and Behavioral Deficits in Behavioral Variant Frontotemporal Dementia, Primary Progressive Aphasia and Probable Alzheimer's Disease

ERIC Educational Resources Information Center

Banks, Sarah; Weintraub, Sandra

2008-01-01

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.…

The behavioural variant frontotemporal dementia (bvFTD) syndrome in psychiatry

PubMed Central

Lanata, Serggio C; Miller, Bruce L

2016-01-01

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

First Symptoms and Neurocognitive Correlates of Behavioral Variant Frontotemporal Dementia.

PubMed

Santamaría-García, Hernando; Reyes, Pablo; García, Adolfo; Baéz, Sandra; Martinez, Angela; Santacruz, José Manuel; Slachevsky, Andrea; Sigman, Mariano; Matallana, Diana; Ibañez, Agustín

2016-10-04

Previous works highlight the neurocognitive differences between apathetic and disinhibited clinical presentations of the behavioral variant frontotemporal dementia (bvFTD). However, little is known regarding how the early presentation (i.e., first symptom) is associated to the neurocognitive correlates of the disease's clinical presentation at future stages of disease. We analyzed the neurocognitive correlates of patients with bvFTD who debuted with apathy or disinhibition as first symptom of disease. We evaluated the neuropsychological, clinical, and neuroanatomical (3T structural images) correlates in a group of healthy controls (n = 30) and two groups of bvFTD patients (presented with apathy [AbvFTD, n = 18] or disinhibition [DbvFTD, n = 16]). To differentiate groups according to first symptoms, we used multivariate analyses. The first symptom in patients described the evolution of the disease. AbvFTD and DbvFTD patients showed increased brain atrophy and increased levels of disinhibition and apathy, respectively. Whole brain analyzes in AbvFTD revealed atrophy in the frontal, insular, and temporal areas. DbvFTD, in turn, presented atrophy in the prefrontal regions, temporoparietal junction, insula, and temporoparietal region. Increased atrophy in DbvFTD patients (compared to AbvFTD) was observed in frontotemporal regions. Multivariate analyses confirmed that a set of brain areas including right orbitofrontal, right dorsolateral prefrontal, and left caudate were enough to distinguish the patients' subgroups.∥Conclusion: First symptom in bvFTD patients described the neurocognitive impairments after around three years of disease, playing an important role in the early detection, disease tracking, and neuroanatomical specification of bvFTD, as well as in future research on potential disease-modifying treatments.

The Frontal Behavioural Inventory (Italian version) differentiates frontotemporal lobar degeneration variants from Alzheimer's disease.

PubMed

Alberici, A; Geroldi, C; Cotelli, M; Adorni, A; Calabria, M; Rossi, G; Borroni, B; Padovani, A; Zanetti, O; Kertesz, A

2007-04-01

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.

Evaluation of brain perfusion in specific Brodmann areas in Frontotemporal dementia and Alzheimer disease using automated 3-D voxel based analysis

NASA Astrophysics Data System (ADS)

Valotassiou, V.; Papatriantafyllou, J.; Sifakis, N.; Karageorgiou, C.; Tsougos, I.; Tzavara, C.; Zerva, C.; Georgoulias, P.

2009-05-01

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.

Epidemiology of early-onset dementia: a review of the literature

PubMed Central

Vieira, Renata Teles; Caixeta, Leonardo; Machado, Sergio; Silva, Adriana Cardoso; Nardi, Antonio Egidio; Arias-Carrión, Oscar; Carta, Mauro Giovanni

2013-01-01

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

Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias

PubMed Central

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

2016-01-01

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

Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer's Disease and Frontotemporal Dementia: An Extended Case Series.

PubMed

Moodley, Kuven K; Perani, Daniela; Minati, Ludovico; Della Rosa, Pasquale Anthony; Pennycook, Frank; Dickson, John C; Barnes, Anna; Contarino, Valeria Elisa; Michopoulou, Sofia; D'Incerti, Ludovico; Good, Catriona; Fallanca, Federico; Vanoli, Emilia Giovanna; Ell, Peter J; Chan, Dennis

2015-01-01

Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen's kappa. Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0-0.25 for PCA to 0.29-0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice.

Causes of Death According to Death Certificates in Individuals with Dementia: A Cohort from the Swedish Dementia Registry.

PubMed

Garcia-Ptacek, Sara; Kåreholt, Ingemar; Cermakova, Pavla; Rizzuto, Debora; Religa, Dorota; Eriksdotter, Maria

2016-11-01

The causes of death in dementia are not established, particularly in rarer dementias. The aim of this study is to calculate risk of death from specific causes for a broader spectrum of dementia diagnoses. Cohort study. Swedish Dementia Registry (SveDem), 2007-2012. Individuals with incident dementia registered in SveDem (N = 28,609); median follow-up 741 days. Observed deaths were 5,368 (19%). Information on number of deaths and causes of mortality was obtained from death certificates. Odds ratios for the presence of dementia on death certificates were calculated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox hazards regression for cause-specific mortality, using Alzheimer's dementia (AD) as reference. Hazard ratios for death for each specific cause of death were compared with hazard ratios of death from all causes (P-values from t-tests). The most frequent underlying cause of death in this cohort was cardiovascular (37%), followed by dementia (30%). Dementia and cardiovascular causes appeared as main or contributory causes on 63% of certificates, followed by respiratory (26%). Dementia was mentioned less in vascular dementia (VaD; 57%). Compared to AD, cardiovascular mortality was higher in individuals with VaD than in those with AD (HR = 1.82, 95% CI = 1.64-2.02). Respiratory death was higher in individuals with Lewy body dementia (LBD, including Parkinson's disease dementia and dementia with Lewy bodies, HR = 2.16, 95% CI = 1.71-2.71), and the risk of respiratory death was higher than expected from the risk for all-cause mortality. Participants with frontotemporal dementia were more likely to die from external causes of death than those with AD (HR = 2.86, 95% CI = 1.53-5.32). Dementia is underreported on death certificates as main and contributory causes. Individuals with LBD had a higher risk of respiratory death than those with AD. © 2016 The Authors. The Journal of the American Geriatrics Society published by Wiley

[False recognition of faces associated with fronto-temporal dementia with prosopagnosia].

PubMed

Verstichel, P

2005-09-01

The association of prosopagnosia and false recognition of faces is unusual and contributes to our understanding of the generation of facial familiarity. A 67-year-old man with a left prefrontal traumatic lesion, developed a temporal variety of fronto-temporal dementia (semantic dementia) with amyotrophic lateral sclerosis. Cerebral imagery demonstrated a bilateral, temporal anterior atrophy predominating in the right hemisphere. The main cognitive signs consisted in severe difficulties to recognize faces of familiar people (prosopagnosia), associated with systematic false recognition of unfamiliar people. Neuropsychological testing indicated that the prosopagnosia probably resulted from the association of an associative/mnemonic mechanism (inability to activate the Face Recognition Units (FRU) from the visual input) and a semantic mechanism (degradation of semantic/biographical information or deconnexion between FRU and this information). At the early stage of the disease, the patient could activate residual semantic information about individuals from their names, but after a 4-year course, he failed to do so. This worsening could be attributed to the extension of the degenerative lesions to the left temporal lobe. Familiar and unfamiliar faces triggered a marked feeling of knowing. False recognition concerned all the unfamiliar faces, and the patient claimed spontaneously that they corresponded to actors, but he could not provide any additional information about their specific identities. The coexistence of prosopagnosia and false recognition suggests the existence of different interconnected systems processing face recognition, one intended to identification of individuals, and the other producing the sense of familiarity. Dysfunctions at different stages of one or the other of these two processes could result in distortions in the feeling of knowing. From this case and others reported in literature, we propose to complete the classical model of face processing

How much do physicians in Latin America know about behavioral variant frontotemporal dementia?

PubMed

Gleichgerrcht, Ezequiel; Flichtentrei, Daniel; Manes, Facundo

2011-11-01

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.

Longitudinal cognitive biomarkers predicting symptom onset in presymptomatic frontotemporal dementia.

PubMed

Jiskoot, Lize C; Panman, Jessica L; van Asseldonk, Lauren; Franzen, Sanne; Meeter, Lieke H H; Donker Kaat, Laura; van der Ende, Emma L; Dopper, Elise G P; Timman, Reinier; van Minkelen, Rick; van Swieten, John C; van den Berg, Esther; Papma, Janne M

2018-06-01

We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD). Presymptomatic MAPT (n = 15) and GRN mutation carriers (n = 31), and healthy controls (n = 39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression. MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p < 0.05). Cognitive decline in ScreeLing phonology (p = 0.046) and letter fluency (p = 0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p = 0.025) for an underlying MAPT mutation. Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD.

Combined fulminant frontotemporal dementia and amyotrophic lateral sclerosis associated with an I113T SOD1 mutation.

PubMed

Katz, Jonathan S; Katzberg, Hans D; Woolley, Susan C; Marklund, Stefan L; Andersen, Peter M

2012-10-01

Mutations in the gene for superoxide dismutase type 1 cause amyotrophic lateral sclerosis (ALS), but are not thought to be associated with frontotemporal dementia (FTD). A lack of detailed case reports is one reason, among others, for this skepticism. This case report comments on a patient with familial ALS caused by I113T mutation in the SOD1 gene presenting with progressive cognitive and behavioral decline two years before developing progressive motor degeneration. In conclusion, this case provides evidence that SOD1 mutations can be associated with FTD.

Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease Regardless of Amnesia?

PubMed

Bertoux, Maxime; de Souza, Leonardo Cruz; O'Callaghan, Claire; Greve, Andrea; Sarazin, Marie; Dubois, Bruno; Hornberger, Michael

2016-01-01

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.

Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features

PubMed Central

Mahoney, Colin J.; Beck, Jon; Rohrer, Jonathan D.; Lashley, Tammaryn; Mok, Kin; Shakespeare, Tim; Yeatman, Tom; Warrington, Elizabeth K.; Schott, Jonathan M.; Fox, Nick C.; Rossor, Martin N.; Hardy, John; Collinge, John; Revesz, Tamas; Mead, Simon

2012-01-01

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases

Spatio-temporal and kinematic gait analysis in patients with Frontotemporal dementia and Alzheimer's disease through 3D motion capture.

PubMed

Rucco, Rosaria; Agosti, Valeria; Jacini, Francesca; Sorrentino, Pierpaolo; Varriale, Pasquale; De Stefano, Manuela; Milan, Graziella; Montella, Patrizia; Sorrentino, Giuseppe

2017-02-01

Alzheimer's disease (AD) and behavioral variant of Frontotemporal Dementia (bvFTD) are characterized respectively by atrophy in the medial temporal lobe with memory loss and prefrontal and anterior temporal degeneration with dysexecutive syndrome. In this study, we hypothesized that specific gait patterns are induced by either frontal or temporal degeneration. To test this hypothesis, we studied the gait pattern in bvFTD (23) and AD (22) patients in single and dual task ("motor" and "cognitive") conditions. To detect subtle alterations, we performed motion analysis estimating both spatio-temporal parameters and joint excursions. In the single task condition, the bvFTD group was more unstable and slower compared to healthy subjects, while only two stability parameters were compromised in the AD group. During the motor dual task, both velocity and stability parameters worsened further in the bvFTD group. In the same experimental conditions, AD patients showed a significantly lower speed and stride length than healthy subjects. During the cognitive dual task, a further impairment of velocity and stability parameters was observed in the bvFTD group. Interestingly, during the cognitive dual task, the gait performance of the AD group markedly deteriorated, as documented by the impairment of more indices of velocity and stability. Finally, the kinematic data of thigh, knee, and ankle were more helpful in revealing gait impairment than the spatio-temporal parameters alone. In conclusion, our data showed that the dysexecutive syndrome induces specific gait alterations. Furthermore, our results suggest that the gait worsens in the AD patients when the cognitive resources are stressed. Copyright © 2016 Elsevier B.V. All rights reserved.

Self-Awareness and Self-Monitoring of Cognitive and Behavioral Deficits in Behavioral Variant Frontotemporal Dementia, Primary Progressive Aphasia and Probable Alzheimer’s Disease

PubMed Central

Banks, Sarah; Weintraub, Sandra

2008-01-01

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. Different components of insight, self-awareness and self-monitoring, are also often considered separate phenomena. The current study compared insight in patients with PPA, bvFTD, and probable Alzheimer’s disease (PrAD) and a group of cognitively intact control subjects. Additionally, differences in insight for the domains primarily affected by the three types of dementia, namely, Behavior, Naming, and Memory, were assessed, and self-awareness and self-monitoring were compared. A total of 55 participants were enrolled. Participants were asked to complete self-estimate scales demonstrating their perceived ability immediately prior to, and immediately following a test in each domain of interest. Results indicated that PPA and normal control groups performed very similarly on control (Weight and Eyesight) and cognitive domains, whereas bvFTD and PrAD patients were unable to accurately assess Memory. All three diagnostic groups failed to accurately assess their behavioral symptoms, suggesting that this domain is vulnerable to loss of insight across diagnoses. Naming ability, in contrast, was either accurately assessed or underestimated in all groups. Finally, there were no notable differences between self-awareness and self-monitoring, potential explanations for this are examined. PMID:18194832

Alzheimer Disease and Behavioral Variant Frontotemporal Dementia: Automatic Classification Based on Cortical Atrophy for Single-Subject Diagnosis.

PubMed

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

2016-06-01

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

Prospective evaluation of behavioral scales in the behavioral variant of frontotemporal dementia.

PubMed

Boutoleau-Bretonnière, Claire; Lebouvier, Thibaud; Volteau, Christelle; Jaulin, Philippe; Lacomblez, Lucette; Damier, Philippe; Thomas-Anterion, Catherine; Vercelletto, Martine

2012-01-01

The Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI) are widely used in patients with the behavioral variant of frontotemporal dementia (bvFTD). Yet, few data are available on the long-term relevance of these scales. Based on a bvFTD population that participated in the Memantine Clinical Trial (NCT00200538), we studied the evolution and correlation between scores obtained on behavioral scales (NPI and FBI), cognitive scales [Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS)] and a burden scale [Zarit Burden Inventory (ZBI)]. The assessments were performed at 1 year in 41 patients and at 2 years in 23 patients who agreed to participate in this open-label study. The 2-year scores obtained on the FBI were significantly higher than the scores at inclusion while those obtained on the NPI did not change. There were significant correlations between the FBI, and the MDRS and MMSE, especially regarding the negative items. The ZBI correlated with behavioral scales at all stages for positive items. This study based on a large population shows that the FBI is a better tool than the NPI for the long-term assessment of bvFTD patients. Moreover, the FBI allows a distinction to be made between behavioral disturbances that involve cognitive functions from those which have an important impact on caregiver burden. Copyright © 2012 S. Karger AG, Basel.

Use of antidementia drugs in frontotemporal lobar degeneration.

PubMed

López-Pousa, Secundino; Calvó-Perxas, Laia; Lejarreta, Saioa; Cullell, Marta; Meléndez, Rosa; Hernández, Erélido; Bisbe, Josep; Perkal, Héctor; Manzano, Anna; Roig, Anna Maria; Turró-Garriga, Oriol; Vilalta-Franch, Joan; Garre-Olmo, Josep

2012-06-01

Clinical evidence indicates that acetylcholinesterase inhibitors (AChEIs) are not efficacious to treat frontotemporal lobar degeneration (FTLD). The British Association for Psychopharmacology recommends avoiding the use of AChEI and memantine in patients with FTLD. Cross-sectional design using 1092 cases with Alzheimer's disease (AD) and 64 cases with FTLD registered by the Registry of Dementias of Girona. Bivariate analyses were performed, and binary logistic regressions were used to detect variables associated with antidementia drugs consumption. The AChEIs were consumed by 57.6% and 42.2% of the patients with AD and FTLD, respectively. Memantine was used by 17.2% and 10.9% of patients with AD and FTLD, respectively. Binary logistic regressions yielded no associations with antidementia drugs consumption. There is a discrepancy regarding clinical practice and the recommendations based upon clinical evidence. The increased central nervous system drug use detected in FTLD requires multicentric studies aiming at finding the best means to treat these patients.

[Neuroepigenetics: Desoxyribonucleic acid methylation in Alzheimer's disease and other dementias].

PubMed

Mendioroz Iriarte, Maite; Pulido Fontes, Laura; Méndez-López, Iván

2015-05-21

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. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia.

PubMed

Dermody, Nadene; Wong, Stephanie; Ahmed, Rebekah; Piguet, Olivier; Hodges, John R; Irish, Muireann

2016-05-30

Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

Behavioral and Neuroimaging Evidence for Facial Emotion Recognition in Elderly Korean Adults with Mild Cognitive Impairment, Alzheimer’s Disease, and Frontotemporal Dementia

PubMed Central

Park, Soowon; Kim, Taehoon; Shin, Seong A; Kim, Yu Kyeong; Sohn, Bo Kyung; Park, Hyeon-Ju; Youn, Jung-Hae; Lee, Jun-Young

2017-01-01

Background: Facial emotion recognition (FER) is impaired in individuals with frontotemporal dementia (FTD) and Alzheimer’s disease (AD) when compared to healthy older adults. Since deficits in emotion recognition are closely related to caregiver burden or social interactions, researchers have fundamental interest in FER performance in patients with dementia. Purpose: The purpose of this study was to identify the performance profiles of six facial emotions (i.e., fear, anger, disgust, sadness, surprise, and happiness) and neutral faces measured among Korean healthy control (HCs), and those with mild cognitive impairment (MCI), AD, and FTD. Additionally, the neuroanatomical correlates of facial emotions were investigated. Methods: A total of 110 (33 HC, 32 MCI, 32 AD, 13 FTD) older adult participants were recruited from two different medical centers in metropolitan areas of South Korea. These individuals underwent an FER test that was used to assess the recognition of emotions or absence of emotion (neutral) in 35 facial stimuli. Repeated measures two-way analyses of variance were used to examine the distinct profiles of emotional recognition among the four groups. We also performed brain imaging and voxel-based morphometry (VBM) on the participants to examine the associations between FER scores and gray matter volume. Results: The mean score of negative emotion recognition (i.e., fear, anger, disgust, and sadness) clearly discriminated FTD participants from individuals with MCI and AD and HC [F(3,106) = 10.829, p < 0.001, η2 = 0.235], whereas the mean score of positive emotion recognition (i.e., surprise and happiness) did not. A VBM analysis showed negative emotions were correlated with gray matter volume of anterior temporal regions, whereas positive emotions were related to gray matter volume of fronto-parietal regions. Conclusion: Impairment of negative FER in patients with FTD is cross-cultural. The discrete neural correlates of FER indicate that emotional

Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia

PubMed Central

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.

2016-01-01

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

The frontal-anatomic specificity of design fluency repetitions and their diagnostic relevance for behavioral variant frontotemporal dementia.

PubMed

Possin, Katherine L; Chester, Serana K; Laluz, Victor; Bostrom, Alan; Rosen, Howard J; Miller, Bruce L; Kramer, Joel H

2012-09-01

On tests of design fluency, an examinee draws as many different designs as possible in a specified time limit while avoiding repetition. The neuroanatomical substrates and diagnostic group differences of design fluency repetition errors and total correct scores were examined in 110 individuals diagnosed with dementia, 53 with mild cognitive impairment (MCI), and 37 neurologically healthy controls. The errors correlated significantly with volumes in the right and left orbitofrontal cortex (OFC), the right and left superior frontal gyrus, the right inferior frontal gyrus, and the right striatum, but did not correlate with volumes in any parietal or temporal lobe regions. Regression analyses indicated that the lateral OFC may be particularly crucial for preventing these errors, even after excluding patients with behavioral variant frontotemporal dementia (bvFTD) from the analysis. Total correct correlated more diffusely with volumes in the right and left frontal and parietal cortex, the right temporal cortex, and the right striatum and thalamus. Patients diagnosed with bvFTD made significantly more repetition errors than patients diagnosed with MCI, Alzheimer's disease, semantic dementia, progressive supranuclear palsy, or corticobasal syndrome. In contrast, total correct design scores did not differentiate the dementia patients. These results highlight the frontal-anatomic specificity of design fluency repetitions. In addition, the results indicate that the propensity to make these errors supports the diagnosis of bvFTD. (JINS, 2012, 18, 1-11).

Neurocognitive similarities between severe chronic schizophrenia and behavioural variant frontotemporal dementia.

PubMed

Chan, Hui-Minn; Stolwyk, Rene; Neath, Joanna; Kelso, Wendy; Walterfang, Mark; Mocellin, Ramon; Pantelis, Christos; Velakoulis, Dennis

2015-02-28

This study focuses on a group of patients with chronic schizophrenia who have a more severe form of the disorder, as indicated by socio-functional decline, treatment resistance, and recurrent hospitalisation. Previous research has suggested that the pattern and severity of cognitive deficits in people with severe chronic schizophrenia is similar to that observed in behavioural variant frontotemporal dementia (bvFTD). In the current study, we compared neurocognitive performance in 16 cognitive domains in 7 inpatients with severe chronic schizophrenia, 13 community-dwelling outpatients with chronic schizophrenia, 12 patients with bvFTD, and 18 healthy controls. Our findings revealed more similar cognitive profiles between the schizophrenia inpatient and bvFTD groups compared to the schizophrenia outpatient group, who outperformed the former groups. The current results provide preliminary evidence for a distinct schizophrenia subgroup, distinguishable from other chronic schizophrenia patients by poorer clinical and functional status, who have levels of cognitive impairment comparable to those seen in bvFTD patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

PubMed Central

Shahheydari, Hamideh; Ragagnin, Audrey; Walker, Adam K.; Toth, Reka P.; Vidal, Marta; Jagaraj, Cyril J.; Perri, Emma R.; Konopka, Anna; Sultana, Jessica M.; Atkin, Julie D.

2017-01-01

Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials. PMID:28539871

TREM2 mutations are rare in a French cohort of patients with frontotemporal dementia.

PubMed

Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Dayan, Sarah; Godard, Chloé; Van Bortel, Inge; De Septenville, Anne; Ciura, Sorana; Brice, Alexis; Kabashi, Edor

2013-10-01

Homozygous mutations in TREM2 have been recently identified by exome sequencing in families presenting with frontotemporal dementia (FTD)-like phenotype. No study has evaluated the exact frequency of TREM2 mutations in cohorts of FTD patients so far. We sequenced TREM2 in 175 patients with pure FTD, mostly French, to test whether mutations could be implicated in the pathogenesis of the disease. No disease-causing mutation was identified in 175 individuals from the French cohort of FTD patients. We did not identify the polymorphism p.R47H (rs75932628), strongly associated with an increased risk of developing Alzheimer's disease. We conclude that TREM2 mutations are extremely rare in patients with pure FTD, although further investigation in larger populations is needed. Copyright © 2013 Elsevier Inc. All rights reserved.

Stereotypic behaviors in degenerative dementias.

PubMed

Prioni, S; Fetoni, V; Barocco, F; Redaelli, V; Falcone, C; Soliveri, P; Tagliavini, F; Scaglioni, A; Caffarra, P; Concari, L; Gardini, S; Girotti, F

2012-11-01

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.

Diagnostic Accuracy of Cerebrospinal Fluid Amyloid-β Isoforms for Early and Differential Dementia Diagnosis.

PubMed

Struyfs, Hanne; Van Broeck, Bianca; Timmers, Maarten; Fransen, Erik; Sleegers, Kristel; Van Broeckhoven, Christine; De Deyn, Peter P; Streffer, Johannes R; Mercken, Marc; Engelborghs, Sebastiaan

2015-01-01

Overlapping cerebrospinal fluid biomarkers (CSF) levels between Alzheimer's disease (AD) and non-AD patients decrease differential diagnostic accuracy of the AD core CSF biomarkers. Amyloid-β (Aβ) isoforms might improve the AD versus non-AD differential diagnosis. To determine the added diagnostic value of Aβ isoforms, Aβ(1-37), Aβ(1-38), and Aβ(1-40), as compared to the AD CSF biomarkers Aβ(1-42), T-tau, and P-tau(181P). CSF from patients with dementia due to AD (n = 50), non-AD dementias (n = 50), mild cognitive impairment due to AD (n = 50) and non-demented controls (n = 50) was analyzed with a prototype multiplex assay using MSD detection technology. The non-AD group consisted of frontotemporal dementia (FTD; n = 17), dementia with Lewy bodies (DLB; n = 17), and vascular dementia (n = 16). Aβ(1-37) and Aβ(1-38) increased accuracy to differentiate AD from FTD or DLB. Aβ(1-37), Aβ(1-38), and Aβ(1-40) levels correlated with Mini-Mental State Examination scores and disease duration in dementia due to AD. The Aβ(1-42)/Aβ(1-40) ratio improved diagnostic performance of Aβ(1-42) in most differential diagnostic situations. Aβ(1-42) levels were lower in APOE ε4 carriers compared to non-carriers. Aβ isoforms help to differentiate AD from FTD and DLB. Aβ isoforms increase diagnostic performance of Aβ(1-42). In contrast to Aβ1-42, Aβ isoforms seem to be correlated with disease severity in AD. Adding the Aβ isoforms to the current biomarker panel could enhance diagnostic accuracy.

Rich club network analysis shows distinct patterns of disruption in frontotemporal dementia and Alzheimer’s disease

PubMed Central

Daianu, Madelaine; Jahanshad, Neda; Villalon-Reina, Julio E.; Mendez, Mario F.; Bartzokis, George; Jimenez, Elvira E.; Joshi, Aditi; Barsuglia, Joseph; Thompson, Paul M.

2015-01-01

Diffusion imaging and brain connectivity analyses can reveal the underlying organizational patterns of the human brain, described as complex networks of densely interlinked regions. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants – 15 patients with behavioral variant frontotemporal (bvFTD) dementia, 19 with early-onset Alzheimer’s disease (EOAD), and 30 healthy elderly controls. Based on whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We examined how bvFTD and EOAD disrupt the weighted ‘rich club’ – a network property where high-degree network nodes are more interconnected than expected by chance. bvFTD disrupts both the nodal and global organization of the network in both low- and high-degree regions of the brain. EOAD targets the global connectivity of the brain, mainly affecting the fiber density of high-degree (highly connected) regions that form the rich club network. These rich club analyses suggest distinct patterns of disruptions among different forms of dementia. PMID:26161050

Comparing the driving behaviours of individuals with frontotemporal lobar degeneration and those with Alzheimer's disease.

PubMed

Fujito, Ryoko; Kamimura, Naoto; Ikeda, Manabu; Koyama, Asuka; Shimodera, Shinji; Morinobu, Shigeru; Inoue, Shimpei

2016-01-01

Assessing driving aptitude in dementia patients is critically important for both patient and public safety. However, there have been only a few reports on the driving behaviours and accident risk of patients with dementia, especially frontotemporal lobar degeneration (FTLD). Therefore, we compared the characteristics of driving behaviours in patients with FTLD and those with Alzheimer's disease (AD). The subjects were 28 FTLD and 67 AD patients who visited the Department of Psychiatry, Kochi Medical School Hospital. We conducted semi-structured interviews with their families and caregivers about traffic accident history and changes in patient driving behaviours after dementia onset and then compared the findings between the two groups. Overall changes in driving behaviours were reported in 89% (25/28) and 76% (51/67) of the FTLD and AD patients, respectively (P = 0.17). In the FTLD group, difficulty in judging inter-vehicle distances, ignoring road signs and traffic signals, and distraction were reported in 50% (14/28), 61% (17/28), and 50% (14/28) of patients, respectively, and 75% (21/28) patients had caused a traffic accident after dementia onset. The risk of causing an accident was higher in the FTLD group than in the AD group (odds ratio = 10.4, 95% confidence interval = 3.7-29.1). In addition, the mean duration between dementia onset and a traffic accident was 1.35 years in the FTLD group compared with 3.0 years in the AD group (P < 0.01). Patients with FTLD were more likely to show dangerous driving behaviours than those with AD, and the risk of causing a traffic accident may be higher in patients with FTLD from an early disease stage. © 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.

Financial errors in dementia: Testing a neuroeconomic conceptual framework

PubMed Central

Chiong, Winston; Hsu, Ming; Wudka, Danny; Miller, Bruce L.; Rosen, Howard J.

2013-01-01

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. PMID:23550884

Functional neuroimaging and presenting psychiatric features in frontotemporal dementia

PubMed Central

Mendez, M F; McMurtray, A; Chen, A K; Shapira, J S; Mishkin, F; Miller, B L

2006-01-01

Background Frontotemporal dementia (FTD) is a behavioural syndrome caused by degeneration of the frontal and anterior temporal lobes. Behavioural disturbances include psychiatric features. Whether patients with FTD present with psychiatric features varies with the initial neuroanatomical variability of FTD. Objective To identify presenting psychiatric changes not part of diagnostic criteria of FTD and contrast them with the degree of hemispheric asymmetry and frontal and temporal hypoperfusion on single photon emission computed tomography (SPECT) imaging. Methods 74 patients who met consensus criteria for FTD were evaluated at a two year follow up. All had brain SPECT on initial presentation. Results of an FTD psychiatric checklist were contrasted with ratings of regional hypoperfusion. Results The regions of predominant hypoperfusion did not correlate with differences on FTD demographic variables but were associated with presenting psychiatric features. Dysthymia and anxiety were associated with right temporal hypoperfusion. “Moria” or frivolous behaviour also occurred with temporal lobe changes, especially on the right. The only significant frontal lobe feature was the presence of a peculiar physical bearing in association with right frontal hypoperfusion. Conclusions Patients with FTD may present with psychiatric changes distinct from the behavioural diagnostic criteria for this disorder. Early temporal involvement is associated with frivolous behaviour and right temporal involvement is associated with emotional disturbances. In contrast, those with right frontal disease may present with alterations in non‐verbal behaviour. PMID:16043457

Dyslexia susceptibility genes influence brain atrophy in frontotemporal dementia.

PubMed

Paternicó, Donata; Premi, Enrico; Alberici, Antonella; Archetti, Silvana; Bonomi, Elisa; Gualeni, Vera; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara

2015-10-01

In this study, we evaluated whether variations within genes specifically associated with dyslexia, namely KIAA0319, DCDC2, and CNTNAP2, were associated with greater damage of language-related regions in patients with frontotemporal dementia (FTD) and primary progressive aphasia (PPA) in particular. A total of 118 patients with FTD, 84 with the behavioral variant of FTD (bvFTD) and 34 with PPA, underwent neuropsychological examination, genetic analyses, and brain MRI. KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G, and CNTNAP2 rs17236239 A/G genetic variations were assessed. Patients were grouped according to clinical phenotype and genotype status (GA/AA or GG). Gray matter (GM) and white matter (WM) differences were assessed by voxel-based morphometry and structural intercorrelation pattern analyses. Patients carrying KIAA0319 A* (GA or AA) showed greater GM and WM atrophy in the left middle and inferior temporal gyri, as compared with KIAA0319 GG (p < 0.001). The effect of KIAA0319 polymorphism was mainly reported in patients with PPA. In patients with PPA carrying at-risk polymorphism, temporal damage led to loss of interhemispheric and intrahemispheric GM and WM structural association. No effect of DCDC2 and CNTNAP2 was found. Genes involved in dyslexia susceptibility, such as KIAA0319, result in language network vulnerability in FTD, and in PPA in particular.

Biomarkers of aggression in dementia.

PubMed

Gotovac, Kristina; Nikolac Perković, Matea; Pivac, Nela; Borovečki, Fran

2016-08-01

Dementia is a clinical syndrome defined by progressive global impairment of acquired cognitive abilities. It can be caused by a number of underlying conditions. The most common types of dementia are Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular cognitive impairment (VCI) and dementia with Lewy bodies (DLB). Despite the fact that cognitive impairment is central to the dementia, noncognitive symptoms, most commonly described nowadays as neuropsychiatric symptoms (NPS) exist almost always at certain point of the illness. Aggression as one of the NPS represents danger both for patients and caregivers and the rate of aggression correlates with the loss of independence, cognitive decline and poor outcome. Therefore, biomarkers of aggression in dementia patients would be of a great importance. Studies have shown that different genetic factors, including monoamine signaling and processing, can be associated with various NPS including aggression. There have been significant and multiple neurotransmitter changes identified in the brains of patients with dementia and some of these changes have been involved in the etiology of NPS. Aggression specific changes have also been observed in neuropathological studies. The current consensus is that the best approach for development of such biomarkers may be incorporation of genetics (polymorphisms), neurobiology (neurotransmitters and neuropathology) and neuroimaging techniques. Copyright © 2016 Elsevier Inc. All rights reserved.

Diagnosis of Dementia in the Specialist Setting: A Comparison Between the Swedish Dementia Registry (SveDem) and the Registry of Dementias of Girona (ReDeGi)

PubMed Central

Garre-Olmo, Josep; Garcia-Ptacek, Sara; Calvó-Perxas, Laia; Turró-Garriga, Oriol; López-Pousa, Secundino; Eriksdotter, Maria

2016-01-01

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

Distinct Clinical Features and Outcomes in Motor Neuron Disease Associated with Behavioural Variant Frontotemporal Dementia.

PubMed

Cortés-Vicente, Elena; Turon-Sans, Janina; Gelpi, Ellen; Clarimón, Jordi; Borrego-Écija, Sergi; Dols-Icardo, Oriol; Illán-Gala, Ignacio; Lleó, Alberto; Illa, Isabel; Blesa, Rafael; Al-Chalabi, Ammar; Rojas-García, Ricard

2018-06-08

To determine the motor phenotype and outcome in a clinically ascertained group of patients with motor neuron disease (MND) and frontotemporal dementia (FTD). This is an observational retrospective clinical study of patients fulfilling the clinical criteria for MND-FTD. A contemporary series of patients with amyotrophic lateral sclerosis (ALS) without dementia were included for comparison. Demographic, clinical, genetic, and neuropathological data were collected. A descriptive and comparative data analysis was performed. We identified 22 patients with MND-FTD. Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients - in 15 of them associated with severe dysphagia. Aspiration pneumonia was the most common cause of death (12/19; 63%) despite gastrostomy. One-third of the patients did not develop upper motor neuron dysfunction. When compared to classic ALS without dementia (n = 162), these features were significantly different. A neuro-pathological examination was performed on 7 patients, and it confirmed the presence of MND with TDP43 protein aggregates in all patients. The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research. © 2018 S. Karger AG, Basel.

Gene Therapy Models of Alzheimer’s Disease and Other Dementias

PubMed Central

Combs, Benjamin; Kneynsberg, Andrew; Kanaan, Nicholas M.

2016-01-01

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

Montreal Cognitive Assessment (MoCA): validation study for frontotemporal dementia.

PubMed

Freitas, Sandra; Simões, Mário R; Alves, Lara; Duro, Diana; Santana, Isabel

2012-09-01

The Montreal Cognitive Assessment (MoCA) is a brief instrument developed for the screening of milder forms of cognitive impairment, having surpassed the well-known limitations of the Mini-Mental State Examination (MMSE). The aim of the present study was to validate the MoCA as a cognitive screening test for behavioral-variant frontotemporal dementia (bv-FTD) by examining its psychometric properties and diagnostic accuracy. Three matched subgroups of participants were considered: bv-FTD (n = 50), Alzheimer disease (n = 50), and a control group of healthy adults (n = 50). Compared with the MMSE, the MoCA demonstrated consistently superior psychometric properties and discriminant capacity, providing comprehensive information about the patients' cognitive profiles. The diagnostic accuracy of MoCA for bv-FTD was extremely high (area under the curve AUC [MoCA] = 0.934, 95% confidence interval [CI] = 0.866-.974; AUC [MMSE] = 0.772, 95% CI = 0.677-0.850). With a cutoff below 17 points, the MoCA results for sensitivity, specificity, positive predictive value, negative predictive value, and classification accuracy were significantly superior to those of the MMSE. The MoCA is a sensitive and accurate instrument for screening the patients with bv-FTD and represents a better option than the MMSE.

Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

PubMed Central

Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta

2017-01-01

Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Lewy body dementia (LBD). We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression. PMID:29249935

Homozygous TREM2 mutation in a family with atypical frontotemporal dementia.

PubMed

Le Ber, Isabelle; De Septenville, Anne; Guerreiro, Rita; Bras, José; Camuzat, Agnès; Caroppo, Paola; Lattante, Serena; Couarch, Philippe; Kabashi, Edor; Bouya-Ahmed, Kawtar; Dubois, Bruno; Brice, Alexis

2014-10-01

TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20-50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging. Copyright © 2014 Elsevier Inc. All rights reserved.

Homozygous TREM2 mutation in a family with atypical frontotemporal dementia

PubMed Central

Bras, José; Camuzat, Agnès; Caroppo, Paola; Lattante, Serena; Couarch, Philippe; Kabashi, Edor; Bouya-Ahmed, Kawtar; Dubois, Bruno; Brice, Alexis

2014-01-01

TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20–50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging. PMID:24910390

Frontotemporal Lobar Degeneration

PubMed Central

Rabinovici, Gil D.; Miller, Bruce L.

2010-01-01

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

Dementia

PubMed Central

McGuinness, B; Herron, B; Passmore, AP

2015-01-01

Dementia is a clinical diagnosis requiring new functional dependence on the basis of progressive cognitive decline. It is estimated that 1.3% of the entire UK population, or 7.1% of those aged 65 or over, have dementia. Applying these to 2013 population estimates gives an estimated number of 19,765 people living with dementia in Northern Ireland. The clinical syndrome of dementia can be due to a variety of underlying pathophysiological processes. The most common of these is Alzheimer's disease (50-75%) followed by vascular dementia (20%), dementia with Lewy bodies (5%) and frontotemporal lobar dementia (5%). The clinical symptoms and pathophysiological processes of these diseases overlap significantly. Biomarkers to aid diagnosis and prognosis are emerging. Acetylcholinesterase inhibitors and memantine are the only medications currently licensed for the treatment of dementia. The nature of symptoms mean people with dementia are more dependent and vulnerable, both socially and in terms of physical and mental health, presenting evolving challenges to society and to our healthcare systems. PMID:26170481

The usefulness of monitoring sleep talking for the diagnosis of Dementia with Lewy bodies.

PubMed

Honda, Kazuki; Hashimoto, Mamoru; Yatabe, Yusuke; Kaneda, Keiichiro; Yuki, Seiji; Ogawa, Yusuke; Matsuzaki, Shiho; Tsuyuguchi, Atsuko; Tanaka, Hibiki; Kashiwagi, Hiroko; Hasegawa, Noriko; Ishikawa, Tomohisa; Ikeda, Manabu

2013-05-01

Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia. It is frequently difficult to differentiate DLB from Alzheimer's disease (AD) and other types of dementia. This study examined the usefulness of monitoring sleep talking for the diagnosis of DLB. A total of 317 patients with dementia were selected from a consecutive series at the Dementia Clinic of Kumamoto University Hospital. Diagnostic categories consisted of probable DLB (n = 55), probable AD (n = 191), frontotemporal lobar degeneration (FTLD) (n = 16), vascular dementia (VaD) (n = 18), and other/unspecified dementia (n = 37). We evaluated sleep talking in all dementia patients and normal elderly subjects (n = 32) using an originally designed sleep talking questionnaire. Sleep talking occurred most frequently in the DLB group (61.8%), followed by the VaD group (33.3%), other/unspecified dementia group (27.0%), AD group (18.8%), FTLD group (12.5%), and normal elderly subjects group (6.3%). The prevalence of sleep talking in the DLB group was significantly higher than in other groups, except in the VaD group. The sleep talking yielded high specificity (81.2%) and some sensitivity (61.8%) for the differential diagnosis of DLB from AD. Furthermore, loud sleep talking may improve the specificity (96.9%). For the differentiation of DLB from all other dementia types, the specificity of sleep talking and loud sleep talking was also high (79.4% and 95.8% respectively). Assessing sleep talking, especially the volume of sleep talking, may be useful in the clinical discrimination of DLB from not only AD but also from all other types of dementia.

Differential Hemispheric Predilection of Microstructural White Matter and Functional Connectivity Abnormalities between Respectively Semantic and Behavioral Variant Frontotemporal Dementia.

PubMed

Meijboom, Rozanna; Steketee, Rebecca M E; Ham, Leontine S; van der Lugt, Aad; van Swieten, John C; Smits, Marion

2017-01-01

Semantic dementia (SD) and behavioral variant frontotemporal dementia (bvFTD), subtypes of frontotemporal dementia, are characterized by distinct clinical symptoms and neuroimaging features, with predominant left temporal grey matter (GM) atrophy in SD and bilateral or right frontal GM atrophy in bvFTD. Such differential hemispheric predilection may also be reflected by other neuroimaging features, such as brain connectivity. This study investigated white matter (WM) microstructure and functional connectivity differences between SD and bvFTD, focusing on the hemispheric predilection of these differences. Eight SD and 12 bvFTD patients, and 17 controls underwent diffusion tensor imaging and resting state functional MRI at 3T. Whole-brain WM microstructure was assessed to determine distinct WM tracts affected in SD and bvFTD. For these tracts, diffusivity measures and lateralization indices were calculated. Functional connectivity was established for GM regions affected in early stage SD or bvFTD. Results of a direct comparison between SD and bvFTD are reported. Whole-brain WM microstructure abnormalities were more pronounced in the left hemisphere in SD and bilaterally- with a slight predilection for the right- in bvFTD. Lateralization of tract-specific abnormalities was seen in SD only, toward the left hemisphere. Functional connectivity of disease-specific regions was mainly decreased bilaterally in SD and in the right hemisphere in bvFTD. SD and bvFTD show WM microstructure and functional connectivity abnormalities in different regions, that are respectively more pronounced in the left hemisphere in SD and in the right hemisphere in bvFTD. This indicates differential hemispheric predilection of brain connectivity abnormalities between SD and bvFTD.

Natural Phytochemicals in the Treatment and Prevention of Dementia: An Overview.

PubMed

Libro, Rosaliana; Giacoppo, Sabrina; Soundara Rajan, Thangavelu; Bramanti, Placido; Mazzon, Emanuela

2016-04-21

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.

Social influence on associative learning: double dissociation in high-functioning autism, early-stage behavioural variant frontotemporal dementia and Alzheimer's disease.

PubMed

Kéri, Szabolcs

2014-05-01

Most of our learning activity takes place in a social context. I examined how social interactions influence associative learning in neurodegenerative diseases and atypical neurodevelopmental conditions primarily characterised by social cognitive and memory dysfunctions. Participants were individuals with high-functioning autism (HFA, n = 18), early-stage behavioural variant frontotemporal dementia (bvFTD, n = 16) and Alzheimer's disease (AD, n = 20). The leading symptoms in HFA and bvFTD were social and behavioural dysfunctions, whereas AD was characterised by memory deficits. Participants received three versions of a paired associates learning task. In the game with boxes test, objects were hidden in six candy boxes placed in different locations on the computer screen. In the game with faces, each box was labelled by a photo of a person. In the real-life version of the game, participants played with real persons. Individuals with HFA and bvFTD performed well in the computer games, but failed on the task including real persons. In contrast, in patients with early-stage AD, social interactions boosted paired associates learning up to the level of healthy control volunteers. Worse performance in the real life game was associated with less successful recognition of complex emotions and mental states in the Reading the Mind in the Eyes Test. Spatial span did not affect the results. When social cognition is impaired, but memory systems are less compromised (HFA and bvFTD), real-life interactions disrupt associative learning; when disease process impairs memory systems but social cognition is relatively intact (early-stage AD), social interactions have a beneficial effect on learning and memory. Copyright © 2014 Elsevier Ltd. All rights reserved.

Trajectories of Behavioural Disturbances Across Dementia Types.

PubMed

Linds, Alexandra B; Kirstein, Alana B; Freedman, Morris; Verhoeff, Nicolaas P L G; Wolf, Uri; Chow, Tiffany W

2015-11-01

To replicate a previous finding that the trajectory of the Neuropsychiatric Inventory (NPI) shifts in the sixth year of behavioural variant frontotemporal dementia (bvFTD). We evaluated longitudinal tracking with both the Frontal Behavioural Inventory (FBI) and NPI, comparing bvFTD against other dementias. Chart reviews over two to five years for patients with bvFTD (n=30), primary progressive aphasia (PPA, n=13) and Alzheimer's disease (AD, n=118) at an urban Canadian tertiary clinic specializing in dementia. Linear regressions of the longitudinal data tested predictors of annualized rates of change (ROC) in NPI and FBI total and subscales for apathy and disinhibition among dementia groups. The mode of the overall sample for the most advanced duration of illness observed was 5 years, with the median at 7 years. We did not find a crescendo-decrescendo pattern in scores although, for bvFTD and AD, high initial scores correlated with ensuing downward ROCs on the NPI and FBI. Educational level showed an influence on disinhibition ROCs. The FBI was no more revealing than the NPI for apathy and disinhibition scores in these dementias. A cognitive reserve effect on behavioural disturbance was supported but it may take longer than our 4 years of observing the clinical sample to record inflection points in the behavioural and psychiatric symptoms seen in bvFTD. The current data only imply that both apathy and disinhibition will diminish over the course of dementia.

Frontotemporal dementia and its subtypes: a genome-wide association study

PubMed Central

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

2014-01-01

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

Word list and story recall elicit different patterns of memory deficit in patients with Alzheimer's disease, frontotemporal dementia, subcortical ischemic vascular disease, and Lewy body dementia.

PubMed

Perri, Roberta; Fadda, Lucia; Caltagirone, Carlo; Carlesimo, Giovanni Augusto

2013-01-01

Different roles have been attributed to mesio-temporal areas and frontal lobes in declarative memory functioning, and qualitative differences have been observed in the amnesic symptoms due to pathological damage of these two portions of the central nervous system. The aim of the present study was to look for memory profiles related to pathological involvement in the temporal and frontal structures in patients with different dementia syndromes on word-list and prose memory tasks. 20 patients with Alzheimer's disease (AD), 20 with frontal variant of FTD (fvFTD), 20 with subcortical ischemic vascular dementia (SIVD), and 20 with Lewy body dementia (LBD) and 34 healthy subjects (NCs) were submitted to word-list and prose memory tasks. All groups performed similarly on both the immediate and delayed recall of the word-list. Conversely, AD patients performed worse than all the other dementia groups on the immediate prose recall. On delayed prose recall, AD patients performed worse than fvFTD and SIVD patients but similar to LBD patients. Differential scores between word-list and prose tests were minimal in the AD group and very pronounced in fvFTD and SIVD groups. The combined use of the prose and word-list tasks evidenced a "mesio-temporal" memory profile in AD patients as opposed to a "frontal" one in fvFTD and SIVD patients and a mixed profile in the LBD patients. In particular, a differential score between the two tests can be useful in differentiating AD patients from patients with other forms of dementia.

Humour processing in frontotemporal lobar degeneration: A behavioural and neuroanatomical analysis

PubMed Central

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.

2015-01-01

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

Decision-making in frontotemporal dementia: clinical, theoretical and legal implications.

PubMed

Manes, Facundo; Torralva, Teresa; Ibáñez, Agustín; Roca, María; Bekinschtein, Tristán; Gleichgerrcht, Ezequiel

2011-01-01

The behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive changes in personality and social interaction, loss of empathy, disinhibition and impulsivity, most of which generally precede the onset of cognitive deficits. In this study, we investigated decision-making cognition in a group of patients with an early bvFTD diagnosis whose standard neuropsychological performance was within normal range for all variables. The Iowa Gambling Task was administered to this group of early bvFTD patients, to a group of early bvFTD patients who had shown impaired performance on the classical neuropsychological battery and to healthy controls. Decision-making was impaired in both bvFTD patient groups, whether they had shown impaired or normal performance in the classical neuropsychological evaluation. Patients with early bvFTD may perform normally on standard cognitive tests, and yet develop severe deficits in judgment and decision-making. In many current legal systems, early bvFTD patients showing preserved cognitive functioning who commit unlawful acts run the risk of not being able to plead insane or not guilty on the grounds of diminished responsibility beyond reasonable doubt. This represents a unique legal and ethical dilemma. Our findings have important implications for medicolegal decisions relating to capacity and culpability, and regarding the philosophical concept of 'free will'. 2011 S. Karger AG, Basel.

A single center study: Aβ42/p-Tau181 CSF ratio to discriminate AD from FTD in clinical setting.

PubMed

Vergallo, Andrea; Carlesi, Cecilia; Pagni, Cristina; Giorgi, Filippo Sean; Baldacci, Filippo; Petrozzi, Lucia; Ceravolo, Roberto; Tognoni, Gloria; Siciliano, Gabriele; Bonuccelli, Ubaldo

2017-10-01

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau 181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice.

Added Diagnostic Value of Cerebrospinal Fluid Biomarkers for Differential Dementia Diagnosis in an Autopsy-Confirmed Cohort.

PubMed

Niemantsverdriet, Ellis; Feyen, Bart F E; Le Bastard, Nathalie; Martin, Jean-Jacques; Goeman, Johan; De Deyn, Peter Paul; Bjerke, Maria; Engelborghs, Sebastiaan

2018-01-01

Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt. Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis. Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42, T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses. Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively. AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses.

Comparison of QOL between patients with different degenerative dementias, focusing especially on positive and negative affect.

PubMed

Kurisu, Kairi; Terada, Seishi; Oshima, Etsuko; Horiuchi, Makiko; Imai, Nao; Yabe, Mayumi; Yokota, Osamu; Ishihara, Takeshi; Yamada, Norihito

2016-08-01

Quality of life (QOL) has become an important outcome measure in the care of dementia patients. However, there have been few studies focusing on the difference in QOL between different dementias. Two-hundred seventy-nine consecutive outpatients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD) were recruited. The QOL was evaluated objectively using the QOL Questionnaire for Dementia (QOL-D).The QOL-D comprises six domains: positive affect, negative affect and actions, communication, restlessness, attachment to others, and spontaneity. General cognition, daily activities, and behavioral and psychological symptoms of dementia were also evaluated. The scores of positive affect of QOL-D of AD patients were significantly higher than those of patients with DLB or FTD (AD 3.1 ± 0.8, DLB 2.6 ± 0.9, FTD 2.6 ± 0.7). The scores of negative affect and action of QOL-D of FTD patients were significantly higher than those of patients with AD or DLB (FTD 2.0 ± 0.8, AD 1.4 ± 0.5, DLB 1.5 ± 0.6). The apathy scores of FTD and DLB patients were significantly higher than those of patients with AD. The disinhibition scores of FTD patients were significantly higher than those of patients with AD or DLB. The apathy of FTD and DLB patients and depression of DLB patients might affect the lower positive affect of FTD and DLB patients compared to AD patients. The disinhibition of FTD patients might affect the abundance of negative affect & actions in FTD patients compared to AD and DLB patients.

Disrupted rich club network in behavioral variant frontotemporal dementia and early-onset Alzheimer's disease

PubMed Central

Daianu, Madelaine; Mezher, Adam; Mendez, Mario F.; Jahanshad, Neda; Jimenez, Elvira E.; Thompson, Paul M.

2016-01-01

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

Facial Emotion Recognition Performance Differentiates Between Behavioral Variant Frontotemporal Dementia and Major Depressive Disorder.

PubMed

Chiu, Isabelle; Piguet, Olivier; Diehl-Schmid, Janine; Riedl, Lina; Beck, Johannes; Leyhe, Thomas; Holsboer-Trachsler, Edith; Kressig, Reto W; Berres, Manfred; Monsch, Andreas U; Sollberger, Marc

Misdiagnosis of early behavioral variant frontotemporal dementia (bvFTD) with major depressive disorder (MDD) is not uncommon due to overlapping symptoms. The aim of this study was to improve the discrimination between these disorders using a novel facial emotion perception task. In this prospective cohort study (July 2013-March 2016), we compared 25 patients meeting Rascovsky diagnostic criteria for bvFTD, 20 patients meeting DSM-IV criteria for MDD, 21 patients meeting McKhann diagnostic criteria for Alzheimer's disease dementia, and 31 healthy participants on a novel emotion intensity rating task comprising morphed low-intensity facial stimuli. Participants were asked to rate the intensity of morphed faces on the congruent basic emotion (eg, rating on sadness when sad face is shown) and on the 5 incongruent basic emotions (eg, rating on each of the other basic emotions when sad face is shown). While bvFTD patients underrated congruent emotions (P < .01), they also overrated incongruent emotions (P < .001), resulting in confusion of facial emotions. In contrast, MDD patients overrated congruent negative facial emotions (P < .001), but not incongruent facial emotions. Accordingly, ratings of congruent and incongruent emotions highly discriminated between bvFTD and MDD patients, ranging from area under the curve (AUC) = 93% to AUC = 98%. Further, an almost complete discrimination (AUC = 99%) was achieved by contrasting the 2 rating types. In contrast, Alzheimer's disease dementia patients perceived emotions similarly to healthy participants, indicating no impact of cognitive impairment on rating scores. Our congruent and incongruent facial emotion intensity rating task allows a detailed assessment of facial emotion perception in patient populations. By using this simple task, we achieved an almost complete discrimination between bvFTD and MDD, potentially helping improve the diagnostic certainty in early bvFTD. © Copyright 2018 Physicians Postgraduate Press, Inc.

C9ORF72 G4C2-repeat expansion and frontotemporal dementia first reported case in Argentina.

PubMed

Fernández Suarez, M; Surace, Ezequiel; Harris, P; Tapajoz, F; Sevlever, G; Allegri, R; Russo, G N

2016-06-01

We present a female patient aged 51 who developed behavioral disorders followed by cognitive impairment over 3 years. Neuropsychological, neuropsychiatric, and radiological features suggested a probable behavioral variant of frontotemporal dementia (bvFTD). A family history of amyotrophic lateral sclerosis and parkinsonism suggested the hexanucleotide repeat expansion G4C2 in C9ORF72 . We set up a two-step genotyping algorithm for the detection of the expansion using fragment-length analysis polymerase chain reaction (PCR) and repeat-primed PCR with fluorescent primers. We confirmed the presence of an expanded G4C2 allele in the patient. This represents the first documented case of bvFTD due to a C9ORF72 expansion in Argentina.

Impaired recognition of body expressions in the behavioral variant of frontotemporal dementia.

PubMed

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

2015-08-01

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Decline in Literacy and Incident AD Dementia Among Community-Dwelling Older Persons.

PubMed

Yu, Lei; Wilson, Robert S; Han, S Duke; Leurgans, Sue; Bennett, David A; Boyle, Patricia A

2017-06-01

To quantify longitudinal change in financial and health literacy and examine the associations of declining literacy with incident Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Data came from 799 participants of an ongoing cohort study. Literacy was measured using a battery of 32 questions. Clinical diagnoses were made annually following uniform structured procedures. The associations of declining literacy with incident AD dementia and MCI were tested using a joint model for longitudinal and time-to-event data. We observed an overall decline in total literacy score over up to 6 years of follow-up ( p < .001). Faster decline in literacy was associated with higher risks for incident AD dementia (hazard ratio = 4.526, 95% confidence interval = [2.993, 6.843], p < .001) and incident MCI (hazard ratio = 2.971, 95% confidence interval = [1.509, 5.849], p = .002). Declining literacy among community-dwelling older persons predicts adverse cognitive outcomes and serves as an early indicator of impending dementia.

Behavioral variant frontotemporal dementia: advanced disease stages and death. A step to palliative care.

PubMed

Diehl-Schmid, J; Richard-Devantoy, S; Grimmer, T; Förstl, H; Jox, R

2017-08-01

The aim of the present study was to gain insight into the living and care situation in advanced behavioral variant frontotemporal dementia (bvFTD), to describe symptoms and findings in advanced bvFTD, and to evaluate somatic comorbidities and circumstances of death. Standardized interviews were conducted with family caregivers of 83 patients with bvFTD. Forty-four percent of the patients were already deceased at the time of the interview. At the time of the interview or death, respectively, 47% of the patients lived in a nursing home. The median time between symptom onset and nursing home admission was 5.0 ± 5.5 years. In moderate and severe dementia stages almost all patients suffered from severe disabilities including impairment of language, gait, swallowing, and of the ability to care for themselves. Sixteen percent of the patients had got enteral tube feeding. Comorbid somatic diseases were diagnosed in 46% of the patients. Twenty-three percent of the deceased patients had been admitted into a hospital before death. Cardiovascular disease and respiratory disease, mostly pneumonia, were the most frequent causes of death. Advanced bvFTD is characterized by severe cognitive impairment and physical disabilities. BvFTD leads to a premature death. Our findings stress the importance of strategies that maximize patient comfort in advanced disease stages and allow for a peaceful death. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Semi-quantitative analysis of perfusion of Brodmann areas in the differential diagnosis of cognitive impairment in Alzheimer's disease, fronto-temporal dementia and mild cognitive impairment.

PubMed

Tranfaglia, Cristina; Palumbo, Barbara; Siepi, Donatella; Sinzinger, Helmut; Parnetti, Lucilla

2009-01-01

Different perfusion defects reflect neurological damage characteristics of different kinds of dementia. Our aim was to investigate the role of brain single photon emission tomography (SPET) with semiquantitative analysis of Brodmann areas in dementia, by technetium-99m - hexamethyl-propylenamine- oxime ((99m)Tc-HMPAO) brain SPET with semiquantitative analysis of Brodmann areas in patients with Alzheimer's disease (AD), frontotemporal dementia (FTD) and mild cognitive impairment (MCI). We studied 75 patients, 25 with AD (NiNCDS ADRDA criteria), 25 with FTD (Lund and Manchester criteria), 25 with MCI (EADC criteria). After i.v. injection of 740MBq of (99m)Tc-HMPAO, each patient underwent brain SPET. A software application was used able to map the SPET brain image to a stereotaxic atlas (Talairach), providing an affine co-registration by blocks of data defined in the Talairach space. A normal database calculating voxel by voxel the mean and the standard deviation of the measured values was built. Functional SPET data of 3D regions of interest (ROI) of predefined Brodmann's area templates were compared with those of a database of healthy subjects of the same age and gender. Mean values obtained in the Brodmann area ROI in the different groups of patients studied were evaluated. Our results showed that different Brodmann areas were significantly impaired in the different categories of dementia subjects. Both areas 37 (temporal gyrus) and 39 (angular gyrus) of AD patients (mean+/-SD: 37L= -1.6+/-1.0; 37R= -1.5+/-1.1; 39L= -2.3+/-1.3; 39R= -1.9+/-1.2) showed significant hypoperfusion (P<0.05) versus MCI (37L= -0.9 +/-0.7; 37R= -1.1+/-0.9; 39L= -1.4+/-1.1; 39R= -1.6+/-1.6.) and FTD (37L= -1.1+/-0.8; 37R= -1.0+/-0.9; 39L= -1.4+/-1.0; 39R= -1.2+/-1.2) subjects. AD patients showed significantly (P<0.01) decreased perfusion in areas 40 (supramarginal gyrus) (40L= -2.6+/-1.0; 40R= -2.3+/-1.1) with respect to MCI patients (40L= -1.8+/-0.9; 40R= -1.7+/-1.2). Finally, FTD patients

Establishing robust cognitive dimensions for characterization and differentiation of patients with Alzheimer's disease, mild cognitive impairment, frontotemporal dementia and depression.

PubMed

Beck, Irene R; Schmid, Nicole S; Berres, Manfred; Monsch, Andreas U

2014-06-01

The diagnosis of mild cognitive impairment (MCI) and dementia requires detailed neuropsychological examinations. These examinations typically yield a large number of outcome variables, which may complicate the interpretation and communication of results. The purposes of this study were the following: (i) to reduce a large data set of interrelated neuropsychological variables to a smaller number of cognitive dimensions; (ii) to create a common metric for these dimensions (z-scores); and (iii) to study the ability of the cognitive dimensions to distinguish between groups of patients with different types of cognitive impairment. We tested 1646 patients with different forms of dementia or with a major depression with a standard (n = 632) or, if cognitively less affected, a challenging neuropsychological battery (n = 1014). To identify the underlying cognitive dimensions of the two test batteries, maximum likelihood factor analyses with a promax rotation were conducted. To interpret the sum scores of the factors as standard scores, we divided them by the standard deviation of a cognitively healthy sample (n = 1145). The factor analyses yielded seven factors for each test battery. The cognitive dimensions in both test batteries distinguished patients with different forms of dementia (MCI, Alzheimer's dementia or frontotemporal dementia) and patients with major depression. Furthermore, patients with stable MCI could be separated from patients with progressing MCI. Discriminant analyses with an independent new sample of patients (n = 306) revealed that the new dimension scores distinguished new samples of patients with MCI from patients with Alzheimer's dementia with high accuracy. These findings suggest that these cognitive dimensions may benefit neuropsychological diagnostics. © 2013 The Authors International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

Establishing robust cognitive dimensions for characterization and differentiation of patients with Alzheimer's disease, mild cognitive impairment, frontotemporal dementia and depression

PubMed Central

Beck, Irene R; Schmid, Nicole S; Berres, Manfred; Monsch, Andreas U

2014-01-01

Objective The diagnosis of mild cognitive impairment (MCI) and dementia requires detailed neuropsychological examinations. These examinations typically yield a large number of outcome variables, which may complicate the interpretation and communication of results. The purposes of this study were the following: (i) to reduce a large data set of interrelated neuropsychological variables to a smaller number of cognitive dimensions; (ii) to create a common metric for these dimensions (z-scores); and (iii) to study the ability of the cognitive dimensions to distinguish between groups of patients with different types of cognitive impairment. Methods We tested 1646 patients with different forms of dementia or with a major depression with a standard (n = 632) or, if cognitively less affected, a challenging neuropsychological battery (n = 1014). To identify the underlying cognitive dimensions of the two test batteries, maximum likelihood factor analyses with a promax rotation were conducted. To interpret the sum scores of the factors as standard scores, we divided them by the standard deviation of a cognitively healthy sample (n = 1145). Results The factor analyses yielded seven factors for each test battery. The cognitive dimensions in both test batteries distinguished patients with different forms of dementia (MCI, Alzheimer's dementia or frontotemporal dementia) and patients with major depression. Furthermore, patients with stable MCI could be separated from patients with progressing MCI. Discriminant analyses with an independent new sample of patients (n = 306) revealed that the new dimension scores distinguished new samples of patients with MCI from patients with Alzheimer's dementia with high accuracy. Conclusion These findings suggest that these cognitive dimensions may benefit neuropsychological diagnostics. PMID:24227657

Is blue light, cryptochrome in the eye, and magnetite in the brain involved in the development of frontotemporal dementia and other diseases?

PubMed

Størmer, Fredrik C

2015-04-01

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

Art and the brain: a view from dementia.

PubMed

Gretton, Cosima; ffytche, Dominic H

2014-02-01

Art making encompasses a range of perceptual and cognitive functions involving widely distributed brain systems. The dementias impact on these systems in different ways, raising the possibility that each dementia has a unique artistic signature. Here we use a review of the visual art of 14 artists with dementia (five Alzheimer's disease, seven fronto-temporal dementia and two dementia with Lewy bodies) to further our understanding of the neurobiological constituents of art production and higher artistic function. Artists with Alzheimer's disease had prominent changes in spatial aspects of their art and attributes of colour and contrast. These qualities were preserved in the art of fronto-temporal dementia, which was characterised by perseverative themes and a shift towards realistic representation. The art of dementia with Lewy Bodies was characterised by simple, bizarre content. The limitations of using visual aspects of individual artworks to infer the impact of dementia on art production are discussed with the need for a wider perspective encompassing changes in cognition, emotion, creativity and artistic personality. A novel classificatory scheme is presented to help characterise neural mechanisms of higher artistic functions in future studies. Copyright © 2013 John Wiley & Sons, Ltd.

Differential diagnosis of degenerative dementias using basic neuropsychological tests: multivariable logistic regression analysis of 301 patients.

PubMed

Jiménez-Huete, Adolfo; Riva, Elena; Toledano, Rafael; Campo, Pablo; Esteban, Jesús; Barrio, Antonio Del; Franch, Oriol

2014-12-01

The validity of neuropsychological tests for the differential diagnosis of degenerative dementias may depend on the clinical context. We constructed a series of logistic models taking into account this factor. We retrospectively analyzed the demographic and neuropsychological data of 301 patients with probable Alzheimer's disease (AD), frontotemporal degeneration (FTLD), or dementia with Lewy bodies (DLB). Nine models were constructed taking into account the diagnostic question (eg, AD vs DLB) and subpopulation (incident vs prevalent). The AD versus DLB model for all patients, including memory recovery and phonological fluency, was highly accurate (area under the curve = 0.919, sensitivity = 90%, and specificity = 80%). The results were comparable in incident and prevalent cases. The FTLD versus AD and DLB versus FTLD models were both inaccurate. The models constructed from basic neuropsychological variables allowed an accurate differential diagnosis of AD versus DLB but not of FTLD versus AD or DLB. © The Author(s) 2014.

Progranulin mutation causes frontotemporal dementia in the Swedish Karolinska family.

PubMed

Chiang, Huei-Hsin; Rosvall, Lina; Brohede, Jesper; Axelman, Karin; Björk, Behnosh F; Nennesmo, Inger; Robins, Tiina; Graff, Caroline

2008-11-01

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by cognitive impairment, language dysfunction, and/or changes in personality. Recently it has been shown that progranulin (GRN) mutations can cause FTD as well as other neurodegenerative phenotypes. DNA from 30 family members, of whom seven were diagnosed with FTD, in the Karolinska family was available for GRN sequencing. Fibroblast cell mRNA from one affected family member and six control individuals was available for relative quantitative real-time polymerase chain reaction to investigate the effect of the mutation. Furthermore, the cDNA of an affected individual was sequenced. Clinical and neuropathologic findings of a previously undescribed family branch are presented. A frameshift mutation in GRN (g.102delC) was detected in all affected family members and absent in four unaffected family members older than 70 years. Real-time polymerase chain reaction data showed an approximately 50% reduction of GRN fibroblast mRNA in an affected individual. The mutated mRNA transcripts were undetectable by cDNA sequencing. Segregation and RNA analyses showed that the g.102delC mutation, previously reported, causes FTD in the Karolinska family. Our findings add further support to the significance of GRN in FTD etiology and the presence of modifying genes, which emphasize the need for further studies into the mechanisms of clinical heterogeneity. However, the results already call for attention to the complexity of predictive genetic testing of GRN mutations.

Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging.

PubMed

Ghetti, B; Oblak, A L; Boeve, B F; Johnson, K A; Dickerson, B C; Goedert, M

2015-02-01

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. © 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Dementias show differential physiological responses to salient sounds.

PubMed

Fletcher, Phillip D; Nicholas, Jennifer M; Shakespeare, Timothy J; Downey, Laura E; Golden, Hannah L; Agustus, Jennifer L; Clark, Camilla N; Mummery, Catherine J; Schott, Jonathan M; Crutch, Sebastian J; Warren, Jason D

2015-01-01

Abnormal responsiveness to salient sensory signals is often a prominent feature of dementia diseases, particularly the frontotemporal lobar degenerations, but has been little studied. Here we assessed processing of one important class of salient signals, looming sounds, in canonical dementia syndromes. We manipulated tones using intensity cues to create percepts of salient approaching ("looming") or less salient withdrawing sounds. Pupil dilatation responses and behavioral rating responses to these stimuli were compared in patients fulfilling consensus criteria for dementia syndromes (semantic dementia, n = 10; behavioral variant frontotemporal dementia, n = 16, progressive nonfluent aphasia, n = 12; amnestic Alzheimer's disease, n = 10) and a cohort of 26 healthy age-matched individuals. Approaching sounds were rated as more salient than withdrawing sounds by healthy older individuals but this behavioral response to salience did not differentiate healthy individuals from patients with dementia syndromes. Pupil responses to approaching sounds were greater than responses to withdrawing sounds in healthy older individuals and in patients with semantic dementia: this differential pupil response was reduced in patients with progressive nonfluent aphasia and Alzheimer's disease relative both to the healthy control and semantic dementia groups, and did not correlate with nonverbal auditory semantic function. Autonomic responses to auditory salience are differentially affected by dementias and may constitute a novel biomarker of these diseases.

ALS and Frontotemporal Dysfunction: A Review

PubMed Central

Achi, Eugene Y.; Rudnicki, Stacy A.

2012-01-01

Though once believed to be a disease that was limited to the motor system, it is now apparent that amyotrophic lateral sclerosis (ALS) may be associated with cognitive changes in some patients. Changes are consistent with frontotemporal dysfunction, and may range from mild abnormalities only recognized with formal neuropsychological testing, to profound frontotemporal dementia (FTD). Executive function, behavior, and language are the most likely areas to be involved. Screening helpful in detecting abnormalities includes verbal or categorical fluency, behavioral inventories filled out by the caregiver, and evaluation for the presence of depression and pseudobulbar affect. Patients with cognitive dysfunction have shortened survival and may be less compliant with recommendations regarding use of feeding tubes and noninvasive ventilation. Evolving knowledge of genetic and pathological links between ALS and FTD has allowed us to better understand the overlapping spectrum of ALS and FTD. PMID:22919484

A longitudinal study of behavior in frontotemporal dementia and primary progressive aphasia.

PubMed

Marczinski, Cecile A; Davidson, Wilda; Kertesz, Andrew

2004-12-01

To evaluate the construct validity of the Frontal Behavioral Inventory (FBI) and to describe the evolution of the behavioral abnormalities of the behavioral and aphasic presentations of frontotemporal dementia (FTD) by means of a 3-year longitudinal study. The FBI is a standardized behavioral questionnaire useful in the diagnosis and quantification of the personality and behavior disorder FTD. Patients who had three consecutive yearly assessments with the FBI were selected, 12 with the behavioral variant of FTD (FTD-bv) and 14 with Primary Progressive Aphasia (PPA). FBI scores rose as the disease progressed in both the FTD-bv and PPA groups over the 3 years of testing. Initial mean FBI scores of the FTD-bv group were above the cutoff for FTD as established for this diagnosis with previous standardization. By the third year, the mean FBI score of PPA patients was also above the established cutoff for FTD. The outcome of the study demonstrates that the FBI is sensitive to changes in behavior and personality in both variants of FTD. The FBI can be used to describe the evolution of symptoms and the course of the illness of Pick complex patients who present initially with FTD-bv or who present with PPA and subsequently develop the behavioral disorder.

Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.

PubMed

Filiano, Anthony J; Martens, Lauren Herl; Young, Allen H; Warmus, Brian A; Zhou, Ping; Diaz-Ramirez, Grisell; Jiao, Jian; Zhang, Zhijun; Huang, Eric J; Gao, Fen-Biao; Farese, Robert V; Roberson, Erik D

2013-03-20

Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knock-out (Grn(-/-)) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn(+/-)) mice, which model progranulin haploinsufficiency. We found that Grn(+/-) mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn(-/-) mice, behavioral deficits in Grn(+/-) mice occurred in the absence of gliosis or increased expression of tumor necrosis factor-α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn(+/-) mice. Our findings indicate that FTD-related deficits resulting from progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.

[An autopsied case of senile onset frontotemporal lobar degeneration].

PubMed

Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Deguchi, Akira; Yoshida, Mari

2011-06-01

A Japanese male with no family history of neurological disease or dementia showed behavioral abnormalities including egocentric and antisocial behavior at the age of 80. Over the next few years, other psychiatric symptoms such as allotriophagy and stereotypical behavior were also observed and his abnormal behavior became a social problem. Neurological examination revealed no apparent motor abnormalities, pyramidal and extrapyramidal signs, or ataxia. Aphasia, including semantic dementia was not apparent. The severity of memory disturbance was relatively milder than his psychiatric symptoms. Daily living activities and conversational ability were relatively maintained until shortly before his death at the age of 86. The clinical diagnosis was Alzheimer disease. Autopsy revealed that the brain weighed 950 g; frontotemporal atrophy with lateral ventricular dilatation was apparent. Neuron loss, gliosis, and tissue rarefaction were recognized in the frontotemporal cortex, subiculum, transentorhinal cortex, amygdala, and insular cortex and were particularly noticeable in the superficial layer of the cortex. Many ubiquitin-positive/TDP-43 positive but tau-negative dystrophic neurites with a few neuronal cytoplasmic inclusions were widely observed. Neuronal cytoplasmic inclusions were also observed in the dentate gyrus of the hippocampus. Although the spinal cord was not investigated, there was no apparent involvement of the motor neuron system. Small numbers of neurofibrillary tangles and senile plaques were observed, corresponding to Braak stage II and CERAD stage B, respectively. Argyrophilic grains, Lewy bodies and Pick bodies were not observed. The patient was pathologically diagnosed with frontotemporal lobar degeneration with ubiquitin-positive/TDP-43-positive inclusions (FTLD-TDP) and without motor neuron disease. No mutation was found in the TDP-43 gene. We considered the psychiatric symptoms and head CT findings of the present patient to be important observations

Using the revised diagnostic criteria for frontotemporal dementia in India: evidence of an advanced and florid disease.

PubMed

Ghosh, Amitabha; Dutt, Aparna; Ghosh, Madhura; Bhargava, Pallavi; Rao, Sulakshana

2013-01-01

The International Consortium (FTDC) that revised the diagnostic criteria for behavioural variant frontotemporal dementia (bvFTD) did not have an Asian representation. Whether the revised criteria are equally useful in the early detection of Asian bvFTD patients therefore remains largely unexplored. Earlier studies have indicated differences in clinical manifestations in Indian and other Asian bvFTD patients when compared to western groups. There is an urgent need for clarification, given the projected exponential rise in dementia in these countries and the imminent clinical trials on bvFTD. To assess how Indian bvFTD patients fulfil the FTDC criteria, hypothesizing that our patients might present differently early in the illness. In a hospital-based retrospective observational study, we assessed 48 probable bvFTD patients, diagnosed according to the FTDC criteria, for the speed with which these criteria were fulfilled, the frequency of individual symptoms and their order of appearance during the illness. Most of our patients presented with moderate to severe dementia, in spite of having relatively short onset to diagnosis times. Patients on average took 1.4 years from onset to meet the FTDC criteria, with 90% of them presenting with four or more symptoms at diagnosis. Disinhibition was the commonest symptom and the first symptom in most patients. With most patients presenting with advanced and florid disease, the FTDC criteria have little additional impact in early identification of bvFTD in India. Modifying the criteria further could allow detection of Indian patients early enough for their inclusion in future clinical trials.

Auditory hedonic phenotypes in dementia: A behavioural and neuroanatomical analysis

PubMed Central

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.

2015-01-01

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

Music models aberrant rule decoding and reward valuation in dementia

PubMed Central

Clark, Camilla N; Golden, Hannah L; McCallion, Oliver; Nicholas, Jennifer M; Cohen, Miriam H; Slattery, Catherine F; Paterson, Ross W; Fletcher, Phillip D; Mummery, Catherine J; Rohrer, Jonathan D; Crutch, Sebastian J; Warren, Jason D

2018-01-01

Abstract Aberrant rule- and reward-based processes underpin abnormalities of socio-emotional behaviour in major dementias. However, these processes remain poorly characterized. Here we used music to probe rule decoding and reward valuation in patients with frontotemporal dementia (FTD) syndromes and Alzheimer’s disease (AD) relative to healthy age-matched individuals. We created short melodies that were either harmonically resolved (‘finished’) or unresolved (‘unfinished’); the task was to classify each melody as finished or unfinished (rule processing) and rate its subjective pleasantness (reward valuation). Results were adjusted for elementary pitch and executive processing; neuroanatomical correlates were assessed using voxel-based morphometry. Relative to healthy older controls, patients with behavioural variant FTD showed impairments of both musical rule decoding and reward valuation, while patients with semantic dementia showed impaired reward valuation but intact rule decoding, patients with AD showed impaired rule decoding but intact reward valuation and patients with progressive non-fluent aphasia performed comparably to healthy controls. Grey matter associations with task performance were identified in anterior temporal, medial and lateral orbitofrontal cortices, previously implicated in computing diverse biological and non-biological rules and rewards. The processing of musical rules and reward distils cognitive and neuroanatomical mechanisms relevant to complex socio-emotional dysfunction in major dementias. PMID:29186630

Family history of frontotemporal lobar degeneration in Asia--an international multi-center research.

PubMed

Fukuhara, Ryuji; Ghosh, Amitabha; Fuh, Jong-Ling; Dominguez, Jacqueline; Ong, Paulus Anam; Dutt, Aparna; Liu, Yi-Chien; Tanaka, Hibiki; Ikeda, Manabu

2014-12-01

Previous studies in western countries have shown that about 30%-50% of patients with frontotemporal lobar degeneration (FTLD) have a positive family history, whereas the few epidemiological studies on FTLD done in Asia reported much lower frequencies. It is not clear the reason why the frequencies of FTLD with positive family history were lower in Asia. Furthermore, these findings were not from studies focused on family history. Therefore, it is necessary to conduct further studies on the family history of FTLD in Asia. This international multi-center research aims to investigate the family histories in patients with FTLD and related neurodegenerative diseases such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and motor neuron diseases in a larger Asian cohort. Participants were collected from five countries: India, Indonesia, Japan, Taiwan, and Philippines. All patients were diagnosed with behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive non-fluent aphasia (PA), frontotemporal dementia with motor neuron disease (FTD/MND), PSP, and corticobasal degeneration (CBD) according to international consensus criteria. Family histories of FTLD and related neurodegenerative diseases were investigated in each patient. Ninety-one patients were included in this study. Forty-two patients were diagnosed to have bvFTD, two patients had FTD/MND, 22 had SD, 15 had PA, one had PA/CBS, five had CBS and four patients had PSP. Family history of any FTLD spectrum disorder was reported in 9.5% in bvFTD patients but in none of the SD or PA. In contrast to patients of the western countries, few Asian FTLD patients have positive family histories of dementia.

The Determinants of Quality of Life of Nursing Home Residents with Young-Onset Dementia and the Differences between Dementia Subtypes.

PubMed

Appelhof, Britt; Bakker, Christian; Van Duinen-van den Ijssel, Jeannette C L; Zwijsen, Sandra A; Smalbrugge, Martin; Verhey, Frans R J; de Vugt, Marjolein E; Zuidema, Sytse U; Koopmans, Raymond T C M

2017-01-01

The aims of this study are to (1) explore the determinants of quality of life (QoL) in nursing home residents with young-onset dementia (YOD), (2) investigate whether there are differences between dementia subtypes (Alzheimer dementia, vascular/mixed dementia, frontotemporal dementia, other) regarding these determinants, and (3) compare QoL profiles of YOD nursing home residents across dementia subtypes. This cross-sectional study included 207 nursing home residents. Multilevel modeling was used to determine the relationships between QoL and neuropsychiatric symptoms (NPS), dementia severity, psychotropic drug use (PDU), dementia subtype, age, and gender. Additional multilevel models were used to compare aspects of QoL between dementia subtypes. Residents' QoL was negatively associated with advanced dementia, PDU, and NPS. In general, the relationships between the determinants and QoL were similar across the dementia subtypes. Aspects of QoL differed by dementia subtype. Residents with frontotemporal dementia showed less negative emotions, accepted more help and experienced better quality of relationships with professional caregivers, had a more positive self-image, felt more comfortable in the nursing home environment, and experienced lower quality of social relationships. Considering the high rates of NPS and PDU in YOD residents and their negative associations with QoL, we recommend emphasizing services to manage and reduce NPS and PDU in nursing home residents with YOD. Furthermore, our findings suggest accounting for differences in aspects of QoL by dementia subtype to address specific needs and thereby improve QoL. © 2017 The Author(s) Published by S. Karger AG, Basel.

Co-Occurrence of Language and Behavioural Change in Frontotemporal Lobar Degeneration.

PubMed

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

2016-01-01

We aimed to evaluate the co-occurrence of language and behavioural impairment in patients with frontotemporal lobar degeneration (FTLD) spectrum pathology. 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. 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. 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.

Argentinian/Chilean validation of the Spanish-language version of Addenbrooke's Cognitive Examination III for diagnosing dementia.

PubMed

Bruno, D; Slachevsky, A; Fiorentino, N; Rueda, D S; Bruno, G; Tagle, A R; Olavarria, L; Flores, P; Lillo, P; Roca, M; Torralva, T

2017-08-30

The Addenbrooke's Cognitive Examination III (ACE-III), an adaptation of the ACE cognitive screening test, has been demonstrated to have high sensitivity and specificity in detecting cognitive impairment in patients with dementia and other neurological and psychiatric disorders. Although the Spanish-language version of the ACE-III has already been validated in Spain, it is yet to be validated in Latin America. The aim of this study was to validate the ACE-III test in an Argentinean and Chilean population. ACE-III was administered to 70 patients with Alzheimer disease, 31 patients with behavioural variant frontotemporal dementia, and a control group of 139 healthy volunteers. Participants were recruited at centres in both countries. The Spanish-language version of ACE-III was found to have good internal consistency (Cronbach's alpha=0.87). We found significant differences in total ACE-III scores between patients with Alzheimer disease and controls (p< .05) and between patients with Alzheimer disease and bvFTD (p< .05). With a cut-off point of 86, 98.6% of AD patients, 83.9% of behavioural variant frontotemporal dementia patients, and 84.2% of controls were correctly classified. This study shows that the Spanish-language version of ACE-III continues to be an effective tool for detecting cognitive dysfunction in patients with dementia. Copyright © 2017. Publicado por Elsevier España, S.L.U.

Dementias show differential physiological responses to salient sounds

PubMed Central

Fletcher, Phillip D.; Nicholas, Jennifer M.; Shakespeare, Timothy J.; Downey, Laura E.; Golden, Hannah L.; Agustus, Jennifer L.; Clark, Camilla N.; Mummery, Catherine J.; Schott, Jonathan M.; Crutch, Sebastian J.; Warren, Jason D.

2015-01-01

Abnormal responsiveness to salient sensory signals is often a prominent feature of dementia diseases, particularly the frontotemporal lobar degenerations, but has been little studied. Here we assessed processing of one important class of salient signals, looming sounds, in canonical dementia syndromes. We manipulated tones using intensity cues to create percepts of salient approaching (“looming”) or less salient withdrawing sounds. Pupil dilatation responses and behavioral rating responses to these stimuli were compared in patients fulfilling consensus criteria for dementia syndromes (semantic dementia, n = 10; behavioral variant frontotemporal dementia, n = 16, progressive nonfluent aphasia, n = 12; amnestic Alzheimer's disease, n = 10) and a cohort of 26 healthy age-matched individuals. Approaching sounds were rated as more salient than withdrawing sounds by healthy older individuals but this behavioral response to salience did not differentiate healthy individuals from patients with dementia syndromes. Pupil responses to approaching sounds were greater than responses to withdrawing sounds in healthy older individuals and in patients with semantic dementia: this differential pupil response was reduced in patients with progressive nonfluent aphasia and Alzheimer's disease relative both to the healthy control and semantic dementia groups, and did not correlate with nonverbal auditory semantic function. Autonomic responses to auditory salience are differentially affected by dementias and may constitute a novel biomarker of these diseases. PMID:25859194

Imaging of neurodegenerative cognitive and behavioral disorders: practical considerations for dementia clinical practice.

PubMed

Atri, Alireza

2016-01-01

This chapter reviews clinical applications and imaging findings useful in medical practice relating to neurodegenerative cognitive/dementing disorders. The preponderance of evidence and consensus guidelines support an essential role of multitiered neuroimaging in the evaluation and management of neurodegenerative cognitive/dementia syndrome that range in severity from mild impairments to frank dementia. Additionally, imaging features are incorporated in updated clinical and research diagnostic criteria for most dementias, including Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal Lobar Degenerations/Frontotemporal Dementia (FTD), and Vascular Cognitive Impairment (VCI). Best clinical practices dictate that structural imaging, preferably with magnetic resonance imaging (MRI) when possible and computed tomography when not, be obtained as a first-tier approach during the course of a thorough clinical evaluation to improve diagnostic confidence and assess for nonneurodegenerative treatable conditions that may cause or substantially contribute to cognitive/behavioral symptoms or which may dictate a substantial change in management. These conditions include less common structural (e.g., mass lesions such as tumors and hematomas; normal-pressure hydrocephalus), inflammatory, autoimmune and infectious conditions, and more common comorbid contributing conditions (e.g., vascular cerebral injury causing leukoaraiosis, infarcts, or microhemorrhages) that can produce a mixed dementia syndrome. When, after appropriate clinical, cognitive/neuropsychologic, and structural neuroimaging assessment, a dementia specialist remains in doubt regarding etiology and appropriate management, second-tier imaging with molecular methods, preferably with fluorodexoyglucose positron emission tomography (PET) (or single-photon emission computed tomography if PET is unavailable) can provide more diagnostic specificity (e.g., help differentiate between atypical AD and FTD as

Anatomical Correlates of Non-Verbal Perception in Dementia Patients.

PubMed

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

2016-01-01

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. 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. 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. 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.

Screening for the C9ORF72 repeat expansion in a greek frontotemporal dementia cohort.

PubMed

Kartanou, Chrisoula; Karadima, Georgia; Koutsis, Georgios; Breza, Marianthi; Papageorgiou, Sokratis G; Paraskevas, George P; Kapaki, Elisabeth; Panas, Marios

2018-02-01

The C9orf72 repeat expansion is a common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in European populations. A previous study has reported a high frequency of the expansion in Greek ALS. However, no data have been reported on the frequency of the expansion in Greek FTD. Currently, we investigated the frequency of the C9orfF72 expansion in a well-characterized cohort of 64 Greek FTD patients. We detected the C9orf72 repeat expansion in 9.3% of cases. Overall, 27.7% of familial and 2.2% of sporadic cases were expansion-positive. Five out of 6 cases had a diagnosis of behavioral variant FTD. All expansion-positive cases had fairly typical FTD presentations. Clinical features included motor neuron disease, Parkinsonism and hallucinations. We conclude that the overall frequency of C9orf72-positive cases in Greek FTD is high, comparable to Greek ALS, similar to some Western European, but significantly higher than some Mediterranean FTD populations.

Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

PubMed Central

Almeida, Sandra; Zhang, Zhijun; Coppola, Giovanni; Mao, Wenjie; Futai, Kensuke; Karydas, Anna; Geschwind, Michael D.; Tartaglia, M. Carmela; Gao, Fuying; Gianni, Davide; Sena-Esteves, Miguel; Geschwind, Daniel H.; Miller, Bruce L.; Farese, Robert V.; Gao, Fen-Biao

2012-01-01

SUMMARY The pathogenic mechanisms of frontotemporal dementia (FTD) remain poorly understood. Here we generated multiple induced pluripotent stem cell (iPSC) lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel GRN mutation (PGRN S116X). In neurons and microglia differentiated from PGRN S116X iPSCs, the levels of intracellular and secreted progranulin were reduced, establishing patient-specific cellular models of progranulin haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the PI3K and MAPK pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by progranulin expression. Our findings identify cell-autonomous, reversible defects in patient neurons with progranulin deficiency and provide a new model for studying progranulin-dependent pathogenic mechanisms and testing potential therapies. PMID:23063362

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis

PubMed Central

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.

2015-01-01

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

Psychiatric Aspects of Dementia

PubMed Central

Onyike, Chiadi U.

2016-01-01

Purpose of Review: The psychiatric aspects of dementia are increasingly recognized as significant contributors to distress, disability, and care burden, and, thus, are of increasing interest to practicing neurologists. This article examines how psychiatric disorders are entwined with dementia and describes the predictive, diagnostic, and therapeutic implications of the psychiatric symptoms of dementia. Recent Findings: Psychiatric disorders, particularly depression and schizophrenia, are associated with higher risk for late-life dementia. Psychiatric phenomena also define phenotypes such as frontotemporal dementia and dementia with Lewy bodies, cause distress, and amplify dementia-related disabilities. Management requires a multidisciplinary team, a problem-solving stance, programs of care, and pharmacologic management. Recent innovations include model programs that provide structured problem-solving interventions and tailored in-home care. Summary: There is new appreciation of the complexity of the relationship between psychiatric disorders and dementia as well as the significance of this relationship for treatment, community services, and research. PMID:27042910

Frontotemporal brain sagging syndrome

PubMed Central

Wicklund, M.R.; Mokri, B.; Drubach, D.A.; Boeve, B.F.; Parisi, J.E.

2011-01-01

Background: Behavioral variant frontotemporal dementia (bvFTD) is a relatively well-defined clinical syndrome. It is associated with frontal and temporal lobe structural/metabolic changes and pathologic findings of a neurodegenerative disease. We have been evaluating patients with clinical and imaging features partially consistent with bvFTD but with evidence also suggestive of brain sagging, which we refer to as frontotemporal brain sagging syndrome (FBSS). Methods: Retrospective medical chart review to identify all patients seen at our institution between 1996 and 2010, who had a clinical diagnosis of FTD and imaging evidence of brain sag. Results: Eight patients, 7 male and 1 female, were diagnosed with FBSS. The median age at symptom onset was 53 years. All patients had insidious onset and slow progression of behavioral and cognitive dysfunction accompanied by daytime somnolence and headache. Of the 5 patients with functional imaging, all showed evidence of hypometabolism of the frontotemporal regions. On brain MRI, all patients had evidence of brain sagging with distortion of the brainstem; 3 patients had diffuse pachymeningeal enhancement. CSF opening pressure was varied and CSF protein was mildly elevated. A definite site of CSF leak was not identified by myelogram or cisternography, except in one patient with a site highly suggestive of leak who subsequently underwent surgery confirming a CSF leak. In 2 patients with a neuropathologic examination, there was no evidence of a neurodegenerative disease. Conclusions: This case series demonstrates that FBSS may mimic typical bvFTD but should be recognized as an unusual presentation that is potentially treatable. PMID:21502595

Anatomical Correlates of Non-Verbal Perception in Dementia Patients

PubMed Central

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

2016-01-01

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

Motor speech signature of behavioral variant frontotemporal dementia: Refining the phenotype.

PubMed

Vogel, Adam P; Poole, Matthew L; Pemberton, Hugh; Caverlé, Marja W J; Boonstra, Frederique M C; Low, Essie; Darby, David; Brodtmann, Amy

2017-08-22

To provide a comprehensive description of motor speech function in behavioral variant frontotemporal dementia (bvFTD). Forty-eight individuals (24 bvFTD and 24 age- and sex-matched healthy controls) provided speech samples. These varied in complexity and thus cognitive demand. Their language was assessed using the Progressive Aphasia Language Scale and verbal fluency tasks. Speech was analyzed perceptually to describe the nature of deficits and acoustically to quantify differences between patients with bvFTD and healthy controls. Cortical thickness and subcortical volume derived from MRI scans were correlated with speech outcomes in patients with bvFTD. Speech of affected individuals was significantly different from that of healthy controls. The speech signature of patients with bvFTD is characterized by a reduced rate (75%) and accuracy (65%) on alternating syllable production tasks, and prosodic deficits including reduced speech rate (45%), prolonged intervals (54%), and use of short phrases (41%). Groups differed on acoustic measures derived from the reading, unprepared monologue, and diadochokinetic tasks but not the days of the week or sustained vowel tasks. Variability of silence length was associated with cortical thickness of the inferior frontal gyrus and insula and speech rate with the precentral gyrus. One in 8 patients presented with moderate speech timing deficits with a further two-thirds rated as mild or subclinical. Subtle but measurable deficits in prosody are common in bvFTD and should be considered during disease management. Language function correlated with speech timing measures derived from the unprepared monologue only. © 2017 American Academy of Neurology.

Alzheimer's Disease-Related Dementias Summit 2016: National research priorities.

PubMed

Corriveau, Roderick A; Koroshetz, Walter J; Gladman, Jordan T; Jeon, Sophia; Babcock, Debra; Bennett, David A; Carmichael, S Thomas; Dickinson, Susan L-J; Dickson, Dennis W; Emr, Marian; Fillit, Howard; Greenberg, Steven M; Hutton, Michael L; Knopman, David S; Manly, Jennifer J; Marder, Karen S; Moy, Claudia S; Phelps, Creighton H; Scott, Paul A; Seeley, William W; Sieber, Beth-Anne; Silverberg, Nina B; Sutherland, Margaret L; Taylor, Angela; Torborg, Christine L; Waddy, Salina P; Gubitz, Amelie K; Holtzman, David M

2017-12-05

Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature. © 2017 American Academy of Neurology.

Usefulness of 3-dimensional stereotactic surface projection FDG PET images for the diagnosis of dementia

PubMed Central

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

2016-01-01

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

When one loses empathy: its effect on carers of patients with dementia.

PubMed

Hsieh, Sharpley; Irish, Muireann; Daveson, Naomi; Hodges, John R; Piguet, Olivier

2013-09-01

The effects of empathy loss in frontotemporal dementia (FTD) and Alzheimer disease (AD) on carer symptomatology were investigated. Carers of patients with 2 clinical subtypes of FTD (behavioral-variant FTD [bvFTD] = 18; semantic dementia [SD] = 14) and AD (n = 18) completed the Interpersonal Reactivity Index (IRI), a standardized questionnaire of empathy as well as a measure of perceived burden (Zarit Burden Interview) and the quality of the marital relationship (Intimate Bond Measure). Patient ratings were also obtained on the IRI. Loss of empathy was most striking in the bvFTD group with a marked discrepancy observed between carer and patient ratings for change in emotional warmth and the ability to take the perspective of others. Empathy loss in bvFTD was associated with a loss of a caring marital relationship. Empathic deficits in SD were milder by comparison to bvFTD and correlated with disease severity and increased perceived carer burden. The behavioral pattern observed in AD differed from the FTD syndromes; deficits were observed only for measures of personal distress with carers reporting that patients were less able to handle emotionally evocative situations. Results highlight that changes in aspects of empathy differ across dementia syndromes and are associated with differing carer and clinical variables. These findings might be explained by the progression of atrophy in regions that are known to be critical for empathy and social behavior and has implications for the delivery and planning of services in dementia.

The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia.

PubMed

Radford, Rowan A; Morsch, Marco; Rayner, Stephanie L; Cole, Nicholas J; Pountney, Dean L; Chung, Roger S

2015-01-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.

The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia

PubMed Central

Radford, Rowan A.; Morsch, Marco; Rayner, Stephanie L.; Cole, Nicholas J.; Pountney, Dean L.; Chung, Roger S.

2015-01-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future. PMID:26578880

Judgments about moral responsibility and determinism in patients with behavioural variant of frontotemporal dementia: still compatibilists.

PubMed

Cova, Florian; Bertoux, Maxime; Bourgeois-Gironde, Sacha; Dubois, Bruno

2012-06-01

Do laypeople think that moral responsibility is compatible with determinism? Recently, philosophers and psychologists trying to answer this question have found contradictory results: while some experiments reveal people to have compatibilist intuitions, others suggest that people could in fact be incompatibilist. To account for this contradictory answers, Nichols and Knobe (2007) have advanced a 'performance error model' according to which people are genuine incompatibilist that are sometimes biased to give compatibilist answers by emotional reactions. To test for this hypothesis, we investigated intuitions about determinism and moral responsibility in patients suffering from behavioural frontotemporal dementia. Patients suffering from bvFTD have impoverished emotional reaction. Thus, the 'performance error model' should predict that bvFTD patients will give less compatibilist answers. However, we found that bvFTD patients give answers quite similar to subjects in control group and were mostly compatibilist. Thus, we conclude that the 'performance error model' should be abandoned in favour of other available model that best fit our data. Copyright © 2012 Elsevier Inc. All rights reserved.

Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis.

PubMed

Arrant, Andrew E; Onyilo, Vincent C; Unger, Daniel E; Roberson, Erik D

2018-02-28

Loss-of-function mutations in progranulin, a lysosomal glycoprotein, cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency causes CLN11 neuronal ceroid lipofuscinosis (NCL). Progranulin replacement is a rational therapeutic strategy for these disorders, but there are critical unresolved mechanistic questions about a progranulin gene therapy approach, including its potential to reverse existing pathology. Here, we address these issues using an AAV vector (AAV- Grn ) to deliver progranulin in Grn -/- mice (both male and female), which model aspects of NCL and FTD pathology, developing lysosomal dysfunction, lipofuscinosis, and microgliosis. We first tested whether AAV- Grn could improve preexisting pathology. Even with treatment after onset of pathology, AAV- Grn reduced lipofuscinosis in several brain regions of Grn -/- mice. AAV- Grn also reduced microgliosis in brain regions distant from the injection site. AAV-expressed progranulin was only detected in neurons, not in microglia, indicating that the microglial activation in progranulin deficiency can be improved by targeting neurons and thus may be driven at least in part by neuronal dysfunction. Even areas with sparse transduction and almost undetectable progranulin showed improvement, indicating that low-level replacement may be sufficiently effective. The beneficial effects of AAV- Grn did not require progranulin binding to sortilin. Finally, we tested whether AAV- Grn improved lysosomal function. AAV-derived progranulin was delivered to the lysosome, ameliorated the accumulation of LAMP-1 in Grn -/- mice, and corrected abnormal cathepsin D activity. These data shed light on progranulin biology and support progranulin-boosting therapies for NCL and FTD due to GRN mutations. SIGNIFICANCE STATEMENT Heterozygous loss-of-function progranulin ( GRN ) mutations cause frontotemporal dementia (FTD) and homozygous mutations cause neuronal

Neuropsychological assessment and differential diagnosis in young-onset dementias.

PubMed

Sitek, Emilia J; Barczak, Anna; Harciarek, Michał

2015-06-01

Although Alzheimer's disease is the most common cause of dementia in the elderly, there are several conditions (ie, frontotemporal dementia or Huntington's disease) associated with a relatively earlier onset. This article provides arguments in favor of a comprehensive neuropsychological assessment in the differential diagnosis of young-onset dementia, as episodic memory impairment is not observed early in the course of most types of young-onset dementia that predominantly affect the domains of behavior, executive, language, and/or motor function. Copyright © 2015 Elsevier Inc. All rights reserved.

Trichotillomania Ranging from “Ritual to Illness” and as a Rare Clinical Manifestation of Frontotemporal Dementia: Review of Literature and Case Report

PubMed Central

Issac, Thomas Gregor; Telang, Ashay Vivek; Chandra, Sadanandavalli Retnaswami

2018-01-01

Frontotemporal dementia (FTD) is the most common form of dementia in the younger age group and often exists with comorbid obsessions and compulsions in up to 80% of the patients. Trichotillomania or compulsive “hair-pulling” disorder is a rare manifestation of FTD and is a poorly evaluated symptom in this condition. The release of “grooming functions” due to frontal disinhibition is often attributed to the evolutionary perspective; however, recent findings also implicate the role of neurotransmitter dysfunction. Trichotillomania is currently classified under obsessive and compulsive behavioral spectrum disorders and is often encountered in the younger population with research evidence of response to selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and newer drugs such as N-acetyl cysteine. The role of behavioral therapy also has robust evidence in trichotillomania. We herewith report the case of a middle-aged male patient who presented with features of personality change and behavioral problems in terms of anger, agitation, and disinhibitory behavior who on detailed clinical evaluation and radiological assessment had features consistent with behavioral variant of FTD along with compulsive “hair plucking” behavior which responded minimally with SSRIs. FTD can have features of trichotillomania which is an often overlooked and relatively uncommon manifestation of dementias. Treatment options such as N-acetyl cysteine and behavioral therapy could have potential utility in this degenerative condition hitherto at an earlier stage. PMID:29769783

Motor Speech Phenotypes of Frontotemporal Dementia, Primary Progressive Aphasia, and Progressive Apraxia of Speech.

PubMed

Poole, Matthew L; Brodtmann, Amy; Darby, David; Vogel, Adam P

2017-04-14

Our purpose was to create a comprehensive review of speech impairment in frontotemporal dementia (FTD), primary progressive aphasia (PPA), and progressive apraxia of speech in order to identify the most effective measures for diagnosis and monitoring, and to elucidate associations between speech and neuroimaging. Speech and neuroimaging data described in studies of FTD and PPA were systematically reviewed. A meta-analysis was conducted for speech measures that were used consistently in multiple studies. The methods and nomenclature used to describe speech in these disorders varied between studies. Our meta-analysis identified 3 speech measures which differentiate variants or healthy control-group participants (e.g., nonfluent and logopenic variants of PPA from all other groups, behavioral-variant FTD from a control group). Deficits within the frontal-lobe speech networks are linked to motor speech profiles of the nonfluent variant of PPA and progressive apraxia of speech. Motor speech impairment is rarely reported in semantic and logopenic variants of PPA. Limited data are available on motor speech impairment in the behavioral variant of FTD. Our review identified several measures of speech which may assist with diagnosis and classification, and consolidated the brain-behavior associations relating to speech in FTD, PPA, and progressive apraxia of speech.

Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay

PubMed Central

Nguyen, Thi A.; Zhang, Jiasheng; Devireddy, Swathi; Zhou, Ping; Karydas, Anna M.; Xu, Xialian; Miller, Bruce L.; Rigo, Frank; Ferguson, Shawn M.; Walther, Tobias C.; Farese, Robert V.

2018-01-01

Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized GrnR493X knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous GrnR493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP-43 accumulation, reduced synaptic density, lipofuscinosis, hyperinflammatory macrophages, excessive grooming behavior, and reduced survival. Inhibition of nonsense-mediated mRNA decay (NMD) by genetic, pharmacological, or antisense oligonucleotide-based approaches showed that NMD contributes to the reduced mRNA levels in GrnR493X mice and cell lines and in fibroblasts from patients containing the GRNR493X mutation. Moreover, the expressed truncated R493X mutant protein was functional in several assays in progranulin-deficient cells. Together, these findings establish a murine model for in vivo testing of NMD inhibition or other therapies as potential approaches for treating progranulin deficiency caused by the R493X mutation. PMID:29511098

Color perception differentiates Alzheimer's Disease (AD) from Vascular Dementia (VaD) patients.

PubMed

Arnaoutoglou, N A; Arnaoutoglou, M; Nemtsas, P; Costa, V; Baloyannis, S J; Ebmeier, K P

2017-08-01

Alzheimer's Disease (AD) and Vascular Dementia (VaD) are the most common causes of dementia in older people. Both diseases appear to have similar clinical symptoms, such as deficits in attention and executive function, but specific cognitive domains are affected. Current cohort studies have shown a close relationship between αβ deposits and age-related macular degeneration (Johnson et al., 2002; Ratnayaka et al., 2015). Additionally, a close link between the thinning of the retinal nerve fiber (RNFL) and AD patients has been described, while it has been proposed that AD patients suffer from a non-specific type of color blindness (Pache et al., 2003). Our study included 103 individuals divided into three groups: A healthy control group (n = 35), AD (n = 32) according to DSM-IV-TR, NINCDS-ADRDA criteria, and VaD (n = 36) based on ΝΙΝDS-AIREN, as well as Magnetic Resonance Imaging (MRI) results. The severity of patient's cognitive impairment, was measured with the Mini-Mental State Examination (MMSE) and was classified according to the Reisberg global deterioration scale (GDS). Visual perception was examined using the Ishihara plates: "Ishihara Color Vision Test - 38 Plate." The three groups were not statistically different for demographic data (age, gender, and education). The Ishihara color blindness test has a sensitivity of 80.6% and a specificity of 87.5% to discriminate AD and VaD patients when an optimal (32.5) cut-off value of performance is used. Ishihara Color Vision Test - 38 Plate is a promising potential method as an easy and not time-consuming screening test for the differential diagnosis of dementia between AD and VaD.

Behavioral correlates of cerebrospinal fluid amino acid and biogenic amine neurotransmitter alterations in dementia.

PubMed

Vermeiren, Yannick; Le Bastard, Nathalie; Van Hemelrijck, An; Drinkenburg, Wilhelmus H; Engelborghs, Sebastiaan; De Deyn, Peter P

2013-09-01

Behavioral and psychological signs and symptoms of dementia (BPSD) are a heterogeneous group of behavioral and psychiatric disturbances occurring in dementia patients of any etiology. Research suggests that altered activities of dopaminergic, serotonergic, (nor)adrenergic, as well as amino acid neurotransmitter systems play a role in the etiopathogenesis of BPSD. In this study we attempted to identify cerebrospinal fluid (CSF) neurochemical correlates of BPSD to provide further insight into its underlying neurochemical pathophysiological mechanisms. Patients with probable Alzheimer's disease (AD; n = 202), probable AD with cerebrovascular disease (n = 37), probable frontotemporal dementia (FTD; n = 32), and probable dementia with Lewy bodies (DLB; n = 26) underwent behavioral assessment and lumbar puncture. CSF levels of six amino acids and several biogenic amines and metabolites were analyzed using ultraperformance liquid chromatography with fluorescence detection and reversed-phase high-performance liquid chromatography with fluorescence detection. In the AD patients, CSF homovanillic acid/5-hydroxyindoleacetic acid (HVA/5HIAA) ratios correlated positively with anxieties/phobias, whereas CSF levels of taurine correlated negatively with depression and behavioral disturbances in general. In FTD patients, CSF levels of glutamate correlated negatively with verbally agitated behavior. In DLB patients, CSF levels of HVA correlated negatively with hallucinations. Several neurotransmitter systems can be linked to one specific behavioral syndrome depending on the dementia subtype. In addition to biogenic amines and metabolites, amino acids seem to play a major role in the neurochemical etiology of BPSD as well. Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia.

PubMed

Meijboom, R; Steketee, R M E; de Koning, I; Osse, R J; Jiskoot, L C; de Jong, F J; van der Lugt, A; van Swieten, J C; Smits, M

2017-04-01

Phenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD. Seven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups. PhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes. Our findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD. • PhFTD shows brain abnormalities that are similar to bvFTD. • PhFTD shows increased functional connectivity in the parietal default mode network. • PhFTD shows microstructural white matter abnormalities in the frontal lobe. • We hypothesise phFTD and bvFTD may belong to the same disease spectrum.

Creativity and dementia: a review.

PubMed

Palmiero, Massimiliano; Di Giacomo, Dina; Passafiume, Domenico

2012-08-01

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.

Music Recognition in Frontotemporal Lobar Degeneration and Alzheimer Disease

PubMed Central

Johnson, Julene K; Chang, Chiung-Chih; Brambati, Simona M; Migliaccio, Raffaella; Gorno-Tempini, Maria Luisa; Miller, Bruce L; Janata, Petr

2013-01-01

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

Atypical, slowly progressive behavioral variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion

PubMed Central

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.

2012-01-01

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

Difficulties in detecting behavioral symptoms of frontotemporal lobar degeneration across cultures.

PubMed

Papatriantafyllou, John D; Viskontas, Indre V; Papageorgiou, Sokratis G; Miller, Bruce L; Pavlic, Danijela; Bingol, Ayse; Yener, Gorsev

2009-01-01

Cross-cultural studies of neurodegenerative disorders are especially important when the disease in question is difficult to diagnose, particularly if symptoms of the illness include behavioral disturbances that may be interpreted differently in different cultures. One such disease is frontotemporal lobar degeneration (FTLD), an early-age-of-onset dementia that disproportionately affects social behavior. We report the demographic and neuropsychologic characteristics of more than 300 patients diagnosed with FTLD in the United States, Greece, and Turkey. We find that patients with the frontal variant of frontotemporal dementia (FTD) are diagnosed at an earlier age and report earlier symptom onset in the United States than in Greece or Turkey. Furthermore, neuropsychologic measures indicate that at diagnosis, FTD patients in the United States are less impaired than patients in Greece and Turkey. Patients with FTD in Greece and Turkey are diagnosed later in the disease, presumably because their behavioral symptoms are not easily detected by the medical system in these countries. Our study underscores the need to create culturally appropriate indices of the behavioral symptoms of FTLD, so that patients may be diagnosed and treated at an earlier stage.

Apathy and impulsivity in frontotemporal lobar degeneration syndromes

PubMed Central

Coyle-Gilchrist, Ian T. S.; Jones, P. Simon; Vázquez Rodríguez, Patricia; Wilcox, Alicia; Wehmann, Eileen; Dick, Katrina M.; Robbins, Trevor W.; Rowe, James B.

2017-01-01

Abstract Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck’s disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal

Right Limbic FDG-PET Hypometabolism Correlates with Emotion Recognition and Attribution in Probable Behavioral Variant of Frontotemporal Dementia Patients

PubMed Central

Cerami, Chiara; Dodich, Alessandra; Iannaccone, Sandro; Marcone, Alessandra; Lettieri, Giada; Crespi, Chiara; Gianolli, Luigi; Cappa, Stefano F.; Perani, Daniela

2015-01-01

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

Understanding Emotions in Frontotemporal Dementia: The Explicit and Implicit Emotional Cue Mismatch.

PubMed

Balconi, Michela; Cotelli, Maria; Brambilla, Michela; Manenti, Rosa; Cosseddu, Maura; Premi, Enrico; Gasparotti, Roberto; Zanetti, Orazio; Padovani, Alessandro; Borroni, Barbara

2015-01-01

Previous studies have reported significant deficits in emotion recognition among individuals along the frontotemporal dementia (FTD) spectrum. The basis of emotional impairment is still poorly understood and explicit (emotion appraisal) and implicit (autonomic system activity) responses have not been carefully evaluated. We investigated explicit evaluation of emotions by testing valence and arousal using self-report measures and we also assessed automatic responses to emotional cues, using autonomic measures (skin conductance response and heart rate). 16 behavioral variant FTD and 12 agrammatic variants of primary progressive aphasia patients were included. The performance of these patients was compared to a group of 14 patients with Alzheimer's disease and 20 healthy controls. Each subject was required to observe and evaluate affective pictures while autonomic parameters were recorded. FTD patients preserved a functional general competency in terms of valence (correct positive versus negative attribution) and arousal (correct dichotomy between high versus low arousal category) distinction. These patients showed significant changes in autonomic implicit response compared to the other groups. The mismatch between explicit and implicit responsiveness to emotional cues was found both in behavioral variant FTD and in agrammatic variants of primary progressive aphasia. Emotional responsiveness was related to the severity of behavioral abnormalities as measured by the Frontal Behavioral Inventory and associated with atrophy of the left putamen. The present findings indicate that FTD patients are able to explicitly "appraise" the emotion, but they cannot implicitly "feel" the emotion. This mismatch between the two levels may help explain the general emotional behavior impairment found in these patients.

Clinical utility of FDG-PET for the differential diagnosis among the main forms of dementia.

PubMed

Nestor, Peter J; Altomare, Daniele; Festari, Cristina; Drzezga, Alexander; Rivolta, Jasmine; Walker, Zuzana; Bouwman, Femke; Orini, Stefania; Law, Ian; Agosta, Federica; Arbizu, Javier; Boccardi, Marina; Nobili, Flavio; Frisoni, Giovanni Battista

2018-05-07

To assess the clinical utility of FDG-PET as a diagnostic aid for differentiating Alzheimer's disease (AD; both typical and atypical forms), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD), vascular dementia (VaD) and non-degenerative pseudodementia. A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted on six different diagnostic scenarios using the Delphi method. The level of empirical study evidence for the use of FDG-PET was considered good for the discrimination of DLB and AD; fair for discriminating FTLD from AD; poor for atypical AD; and lacking for discriminating DLB from FTLD, AD from VaD, and for pseudodementia. Delphi voting led to consensus in all scenarios within two iterations. Panellists supported the use of FDG-PET for all PICOs-including those where study evidence was poor or lacking-based on its negative predictive value and on the assistance it provides when typical patterns of hypometabolism for a given diagnosis are observed. Although there is an overall lack of evidence on which to base strong recommendations, it was generally concluded that FDG-PET has a diagnostic role in all scenarios. Prospective studies targeting diagnostically uncertain patients for assessing the added value of FDG-PET would be highly desirable.

Developing a dementia-specific health state classification system for a new preference-based instrument AD-5D.

PubMed

Nguyen, Kim-Huong; Mulhern, Brendan; Kularatna, Sanjeewa; Byrnes, Joshua; Moyle, Wendy; Comans, Tracy

2017-01-25

With an ageing population, the number of people with dementia is rising. The economic impact on the health care system is considerable and new treatment methods and approaches to dementia care must be cost effective. Economic evaluation requires valid patient reported outcome measures, and this study aims to develop a dementia-specific health state classification system based on the Quality of Life for Alzheimer's disease (QOL-AD) instrument (nursing home version). This classification system will subsequently be valued to generate a preference-based measure for use in the economic evaluation of interventions for people with dementia. We assessed the dimensionality of the QOL-AD to develop a new classification system. This was done using exploratory and confirmatory factor analysis and further assessment of the structure of the measure to ensure coverage of the key areas of quality of life. Secondly, we used Rasch analysis to test the psychometric performance of the items, and select item(s) to describe each dimension. This was done on 13 items of the QOL-AD (excluding two general health items) using a sample of 284 residents living in long-term care facilities in Australia who had a diagnosis of dementia. A five dimension classification system is proposed resulting from the three factor structure (defined as 'interpersonal environment', 'physical health' and 'self-functioning') derived from the factor analysis and two factors ('memory' and 'mood') from the accompanying review. For the first three dimensions, Rasch analysis selected three questions of the QOL-AD ('living situation', 'physical health', and 'do fun things') with memory and mood questions representing their own dimensions. The resulting classification system (AD-5D) includes many of the health-related quality of life dimensions considered important to people with dementia, including mood, global function and skill in daily living. The development of the AD-5D classification system is an important step

Autobiographical memory and patterns of brain atrophy in frontotemporal lobar degeneration.

PubMed

McKinnon, Margaret C; Nica, Elena I; Sengdy, Pheth; Kovacevic, Natasa; Moscovitch, Morris; Freedman, Morris; Miller, Bruce L; Black, Sandra E; Levine, Brian

2008-10-01

Autobiographical memory paradigms have been increasingly used to study the behavioral and neuroanatomical correlates of human remote memory. Although there are numerous functional neuroimaging studies on this topic, relatively few studies of patient samples exist, with heterogeneity of results owing to methodological variability. In this study, fronto-temporal lobar degeneration (FTLD), a form of dementia affecting regions crucial to autobiographical memory, was used as a model of autobiographical memory loss. We emphasized the separation of episodic (recollection of specific event, perceptual, and mental state information) from semantic (factual information unspecific in time and place) autobiographical memory, derived from a reliable method for scoring transcribed autobiographical protocols, the Autobiographical Interview [Levine, B., Svoboda, E., Hay, J., Winocur, G., & Moscovitch, M. Aging and autobiographical memory: Dissociating episodic from semantic retrieval. Psychology and Aging, 17, 677-689, 2002]. Patients with the fronto-temporal dementia (FTD) and mixed fronto-temporal and semantic dementia (FTD/SD) variants of FTLD were impaired at reconstructing episodically rich autobiographical memories across the lifespan, with FTD/SD patients generating an excess of generic semantic autobiographical information. Patients with progressive nonfluent aphasia were mildly impaired for episodic autobiographical memory, but this impairment was eliminated with the provision of structured cueing, likely reflecting relatively intact medial-temporal lobe function, whereas the same cueing failed to bolster the FTD and FTD/SD patients' performance relative to that of matched comparison subjects. The pattern of episodic, but not semantic, autobiographical impairment was enhanced with disease progression on 1- to 2-year follow-up testing in a subset of patients, supplementing the cross-sectional evidence for specificity of episodic autobiographical impairment with longitudinal

Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psychiatric Disorders

PubMed Central

Zanardini, Roberta; Ciani, Miriam; Benussi, Luisa; Ghidoni, Roberta

2016-01-01

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

CSF neurofilament concentration reflects disease severity in frontotemporal degeneration

PubMed Central

Scherling, Carole S.; Hall, Tracey; Berisha, Flora; Klepac, Kristen; Karydas, Anna; Coppola, Giovanni; Kramer, Joel H.; Rabinovici, Gil; Ahlijanian, Michael; Miller, Bruce L.; Seeley, William; Grinberg, Lea T.; Rosen, Howard; Meredith, Jere; Boxer, Adam L.

2014-01-01

Objective Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD. Methods CSF NfL, amyloid-β42 (Aβ42), tau and phosphorylated tau (ptau) concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer’s disease, 6 Parkinson’s disease and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural MR images determined the relationship between brain volume and CSF NfL. Results Mean CSF NfL concentrations were higher in bvFTD, SD and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, and not in other diagnostic groups. Analyses in two independent FTD cohorts and a group of autopsy verified or biomarker enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with highest NfL levels exhibited the most atrophy. Interpretation CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted. PMID:24242746

Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients.

PubMed

Almeida, Sandra; Gao, Fuying; Coppola, Giovanni; Gao, Fen-Biao

2016-06-01

Mutations in the granulin (GRN) gene cause frontotemporal dementia (FTD) due to progranulin haploinsufficiency. Compounds that can increase progranulin production and secretion may be considered as potential therapeutic drugs; however, very few of them have been directly tested on human cortical neurons. To this end, we differentiated 9 induced pluripotent stem cell lines derived from a control subject, a sporadic FTD case and an FTD patient with progranulin S116X mutation. Treatment with 1 μM suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased the production of progranulin in cortical neurons of all subjects at both the mRNA and protein levels without affecting their viability. Microarray analysis revealed that SAHA treatment not only reversed some gene expression changes caused by progranulin haploinsufficiency but also caused massive alterations in the overall transcriptome. Thus, histone deacetylase inhibitors may be considered as therapeutic drugs for GRN mutation carriers. However, this class of drugs also causes drastic changes in overall gene expression in human cortical neurons and their side effects and potential impacts on other pathways should be carefully evaluated. Copyright © 2016 Elsevier Inc. All rights reserved.

Executive and social-cognitive determinants of environmental dependency syndrome in behavioral frontotemporal dementia.

PubMed

Flanagan, Emma C; Lagarde, Julien; Hahn, Valérie; Guichart-Gomez, Elodie; Sarazin, Marie; Hornberger, Michael; Bertoux, Maxime

2018-05-01

Environmental dependency syndrome (EDS), including utilization (UB) and imitation (IB) behaviors, is often reported in behavioral variant frontotemporal dementia (bvFTD). These behaviors are commonly attributed to executive dysfunction. However, inconsistent associations between EDS and poor executive performance has led to an alternative "social hypothesis," instead implicating patients' misinterpretation of the examiner's intention. We investigated the possible explanatory cognitive mechanisms of EDS in bvFTD by relating UB and IB to performance on tests of executive functioning and theory of mind (ToM). This study analyzed retrospective data of 32 bvFTD patients. Data included scores of UB and IB, various executive measures, and ToM assessment using the faux pas test, from which we extracted a mental attribution score. Of the patients, 15.6% and 40.6% exhibited UB and IB, respectively. We conducted an automatic linear modeling analysis with executive and mental attribution measures as predictor variables, and UB and IB sequentially considered as target variables. ToM mental attribution score, visual abstraction and flexibility measures from the Wisconsin Card Sorting Test, and motor sequence performance significantly (corrected ps < .05) predicted IB. No executive or ToM measures significantly predicted UB. These findings reveal a complex interaction between executive dysfunction and mental attribution deficits influencing the prevalence of EDS in bvFTD. Further investigation is required to improve our understanding of the mechanisms underlying these behaviors. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Frontotemporal dementia and its subtypes: a genome-wide association study.

PubMed

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; St George-Hyslop, Peter; Rossi, Giacomina; Tagliavini, Fabrizio; Giaccone, Giorgio; Rowe, James B; Schlachetzki, Johannes C M; Uphill, James; Collinge, John; Mead, Simon; Danek, Adrian; Van Deerlin, Vivianna M; Grossman, Murray; Trojanowski, 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 A L; Scheltens, Philip; Logroscino, Giancarlo; Capozzo, Rosa; Novelli, Valeria; Puca, Annibale A; Franceschi, Massimo; 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

2014-07-01

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. We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of 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)) single-nucleotide polymorphisms. We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data

Pain in dementia: prevalence and associated factors: protocol of a multidisciplinary study.

PubMed

van Kooten, Janine; Delwel, Suzanne; Binnekade, Tarik T; Smalbrugge, Martin; van der Wouden, Johannes C; Perez, Roberto S G M; Rhebergen, Didi; Zuurmond, Wouter W A; Stek, Max L; Lobbezoo, Frank; Hertogh, Cees M P M; Scherder, Erik J A

2015-03-21

Pain is a common problem in people with dementia, however the exact prevalence of pain in dementia subtypes, e.g. Alzheimer's Disease (AD), Vascular Dementia (VaD), Frontotemporal Dementia (FTD) and dementia with Lewy Bodies (DLB), is unknown, as is the relation between pain and the different subtypes of dementia. In this study, the prevalence of pain in people with dementia will be investigated per dementia subtype and the relationship between the various subtypes of dementia and the presence of specific types of pain (i.e. musculoskeletal pain, neuropathic pain and orofacial pain) will be examined. Secondly, associations between various types of pain, cognitive functioning, neuropsychiatric symptoms and quality of life in people with dementia will be examined. A third purpose is to study the value of the assessment of autonomic responses in assessing pain in people with dementia. Finally, the effect of feedback to the attending physician on the presence of pain, based on examination by investigators with backgrounds in neuropsychology, geriatric dentistry and elderly care medicine, will be evaluated. A cross-sectional, partially longitudinal observational study in 400 participants with dementia, aged 60 years and older. Participants will be recruited from an outpatient memory clinic and dementia special care units. All participants will be examined by an elderly care medicine trainee, a dentist with experience in geriatric dentistry, and a neuropsychologist. The primary outcome is presence of pain. Secondary outcomes will include oral health, autonomic responses to pain stimulus, vital sensibility and gnostic sensibility, musculoskeletal examination, cognitive functioning, neuropsychiatric symptoms, and quality of life. This study will help to enhance our knowledge regarding the prevalence of different types of pain in different dementia subtypes i.e. AD, VaD, FTD and DLB. This study also aims to contribute to a better understanding of oral health status in

Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria.

PubMed

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

2017-05-01

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).

Impairment of prosocial sentiments is associated with frontopolar and septal damage in frontotemporal dementia.

PubMed

Moll, Jorge; Zahn, Roland; de Oliveira-Souza, Ricardo; Bramati, Ivanei E; Krueger, Frank; Tura, Bernardo; Cavanagh, Alyson L; Grafman, Jordan

2011-01-15

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. Published by Elsevier Inc.

Impairment of prosocial sentiments is associated with frontopolar and septal damage in frontotemporal dementia

PubMed Central

Moll, Jorge; Zahn, Roland; de Oliveira-Souza, Ricardo; Bramati, Ivanei E.; Krueger, Frank; Tura, Bernardo; Cavanagh, Alyson L.; Grafman, Jordan

2010-01-01

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

Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay.

PubMed

Nguyen, Andrew D; Nguyen, Thi A; Zhang, Jiasheng; Devireddy, Swathi; Zhou, Ping; Karydas, Anna M; Xu, Xialian; Miller, Bruce L; Rigo, Frank; Ferguson, Shawn M; Huang, Eric J; Walther, Tobias C; Farese, Robert V

2018-03-20

Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized Grn R493X knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous Grn R493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP-43 accumulation, reduced synaptic density, lipofuscinosis, hyperinflammatory macrophages, excessive grooming behavior, and reduced survival. Inhibition of nonsense-mediated mRNA decay (NMD) by genetic, pharmacological, or antisense oligonucleotide-based approaches showed that NMD contributes to the reduced mRNA levels in Grn R493X mice and cell lines and in fibroblasts from patients containing the GRN R493X mutation. Moreover, the expressed truncated R493X mutant protein was functional in several assays in progranulin-deficient cells. Together, these findings establish a murine model for in vivo testing of NMD inhibition or other therapies as potential approaches for treating progranulin deficiency caused by the R493X mutation. Copyright © 2018 the Author(s). Published by PNAS.

The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine.

PubMed

Hedges, Erin C; Mehler, Vera J; Nishimura, Agnes L

2016-01-01

In recent years several genes have linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as a spectrum disease; however little is known about what triggers their onset. With the ability to generate patient specific stem cell lines from somatic cells, it is possible to model disease without the need to transfect cells with exogenous DNA. These pluripotent stem cells have opened new avenues for identification of disease phenotypes and their relation to specific molecular pathways. Thus, as never before, compounds with potential applications for regenerative medicine can be specifically tailored in patient derived cultures. In this review, we discuss how patient specific induced pluripotent stem cells (iPSCs) have been used to model ALS and FTD and the most recent drug screening targets for these diseases. We also discuss how an iPSC bank would improve the quality of the available cell lines and how it would increase knowledge about the ALS/FTD disease spectrum.

[Artistic creativity and dementia].

PubMed

Sellal, François; Musacchio, Mariano

2008-03-01

Artistic creativity can be defined as the ability to produce both innovative and esthetic works. Though most dementias result in a loss of instrumental functions and a deterioration in artistic production, for some established artists, dementia, most often Alzheimer's disease, changed their style and technique but preserved their creativity and prolific artistic drive. Moreover, in some cases, mainly frontotemporal dementia, Parkinson's disease, and very occasionally strokes, the disease may favour the emergence of de novo artistic talent. This phenomenon has been conceptualized as a paradoxical facilitation, a disinhibition of brain areas devoted to visuospatial processing, greater freedom in a patient who becomes less bound by social conventions, enhancement of motivation and pleasure, etc. These neurological cases provide an opportunity to shed some light on the roots of artistic creation.

Psychiatric symptoms in preclinical behavioural-variant frontotemporal dementia in MAPT mutation carriers.

PubMed

Cheran, Gayathri; Silverman, Hannah; Manoochehri, Masood; Goldman, Jill; Lee, Seonjoo; Wu, Liwen; Cines, Sarah; Fallon, Emer; Kelly, Brendan Desmond; Olszewska, Diana Angelika; Heidebrink, Judith; Shair, Sarah; Campbell, Stephen; Paulson, Henry; Lynch, Timothy; Cosentino, Stephanie; Huey, Edward D

2018-05-01

To characterise psychiatric symptoms in preclinical and early behavioural-variant frontotemporal dementia (bvFTD), a neurodegenerative disorder whose symptoms overlap with and are often mistaken for psychiatric illness. The present study reports findings from a systematic, global, prospective evaluation of psychiatric symptoms in 12 preclinical carriers of pathogenic MAPT mutations, not yet meeting bvFTD diagnostic criteria, and 46 familial non-carrier controls. Current psychiatric symptoms, informant-reported symptoms and lifetime prevalence of psychiatric disorders were assessed with The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the Neuropsychiatric Inventory Questionnaire. Fisher exact test was used to compare carriers and non-carriers' lifetime prevalence of six DSM-IV disorders: major depressive disorder, panic attacks, alcohol abuse, generalised anxiety disorder, panic disorder, and depressive disorder not otherwise specified. Other DSM-IV disorders had insufficient prevalence across our sample for between-group comparisons, but are reported. Non-carriers had greater prevalence of mood and anxiety disorders than has been reported for a general reference population. Preclinical carriers had lower lifetime prevalence of mood and anxiety disorders than non-carriers, except for depressive disorder not otherwise specified, an atypical syndrome comprising clinically significant depressive symptoms which fail to meet criteria for major depressive disorder. Findings suggest that early psychiatric symptoms of emergent bvFTD may manifest as emotional blunting or mood changes not cleanly conforming to criteria for a DSM-defined mood disorder. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia

PubMed Central

Yokoyama, Jennifer S.; Karch, Celeste M.; Fan, Chun C.; Bonham, Luke W.; Kouri, Naomi; Ross, Owen A.; Rademakers, Rosa; Kim, Jungsu; Wang, Yunpeng; Höglinger, Günter U.; Muller, Ulrich; Ferrari, Raffaele; Hardy, John; Momeni, Parastoo; Sugrue, Leo P.; Hess, Christopher P.; Barkovich, A. James; Boxer, Adam L.; Seeley, William W.; Rabinovici, Gil D.; Rosen, Howard J.; Miller, Bruce L.; Schmansky, Nicholas J.; Fischl, Bruce; Hyman, Bradley T.; Dickson, Dennis W.; Schellenberg, Gerard D.; Andreassen, Ole A.; Dale, Anders M.; Desikan, Rahul S.

2017-01-01

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p-values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p < 2.0 × 10−16). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: i) novel genetic overlap between CBD and PSP beyond the MAPT locus; ii) strong ties between CBD and FTD through the MAPT clade, and; iii) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies. PMID:28271184

Family caregivers of individuals with frontotemporal dementia: examining the relationship between coping and caregiver physical and mental health.

PubMed

Wong, Cindy C; Wallhagen, Margaret I

2014-01-01

To identify strategies to assist family caregivers of individuals with frontotemporal dementia (FTD) in dealing with their caregiving demands, nurses must understand these family members' unique needs and how they currently deal with their demands. The purpose of this study was to examine the relationship between coping and caregiver physical and mental health among FTD family caregivers. Participants were primary caregivers of individuals with FTD (with behavioral symptoms) living at home (N = 61). A small positive association was noted between problem-focused coping and caregiver physical health (r = 0.29, p < 0.05), and a small but nonsignificant positive correlation was noted between emotion-focused coping and caregiver mental health (r = 0.21, p = 0.10). However, multiple regression analysis showed that emotion-focused coping (β = 0.46, p < 0.05) made a statistically significant, unique contribution to caregiver mental health and explained approximately 14% of its variance. These findings support the potential value of emotion-focused coping strategies when dealing with behavioral symptoms manifested by individuals with FTD. Copyright 2014, SLACK Incorporated.

Face shape and face identity processing in behavioral variant fronto-temporal dementia: A specific deficit for familiarity and name recognition of famous faces.

PubMed

De Winter, François-Laurent; Timmers, Dorien; de Gelder, Beatrice; Van Orshoven, Marc; Vieren, Marleen; Bouckaert, Miriam; Cypers, Gert; Caekebeke, Jo; Van de Vliet, Laura; Goffin, Karolien; Van Laere, Koen; Sunaert, Stefan; Vandenberghe, Rik; Vandenbulcke, Mathieu; Van den Stock, Jan

2016-01-01

Deficits in face processing have been described in the behavioral variant of fronto-temporal dementia (bvFTD), primarily regarding the recognition of facial expressions. Less is known about face shape and face identity processing. Here we used a hierarchical strategy targeting face shape and face identity recognition in bvFTD and matched healthy controls. Participants performed 3 psychophysical experiments targeting face shape detection (Experiment 1), unfamiliar face identity matching (Experiment 2), familiarity categorization and famous face-name matching (Experiment 3). The results revealed group differences only in Experiment 3, with a deficit in the bvFTD group for both familiarity categorization and famous face-name matching. Voxel-based morphometry regression analyses in the bvFTD group revealed an association between grey matter volume of the left ventral anterior temporal lobe and familiarity recognition, while face-name matching correlated with grey matter volume of the bilateral ventral anterior temporal lobes. Subsequently, we quantified familiarity-specific and name-specific recognition deficits as the sum of the celebrities of which respectively only the name or only the familiarity was accurately recognized. Both indices were associated with grey matter volume of the bilateral anterior temporal cortices. These findings extent previous results by documenting the involvement of the left anterior temporal lobe (ATL) in familiarity detection and the right ATL in name recognition deficits in fronto-temporal lobar degeneration.

Should I trust you? Learning and memory of social interactions in dementia.

PubMed

Wong, Stephanie; Irish, Muireann; O'Callaghan, Claire; Kumfor, Fiona; Savage, Greg; Hodges, John R; Piguet, Olivier; Hornberger, Michael

2017-09-01

Social relevance has an enhancing effect on learning and subsequent memory retrieval. The ability to learn from and remember social interactions may impact on susceptibility to financial exploitation, which is elevated in individuals with dementia. The current study aimed to investigate learning and memory of social interactions, the relationship between performance and financial vulnerability and the neural substrates underpinning performance in 14 Alzheimer's disease (AD) and 20 behavioural-variant frontotemporal dementia (bvFTD) patients and 20 age-matched healthy controls. On a "trust game" task, participants invested virtual money with counterparts who acted either in a trustworthy or untrustworthy manner over repeated interactions. A non-social "lottery" condition was also included. Participants' learning of trust/distrust responses and subsequent memory for the counterparts and nature of the interactions was assessed. Carer-rated profiles of financial vulnerability were also collected. Relative to controls, both patient groups showed attenuated learning of trust/distrust responses, and lower overall memory for social interactions. Despite poor learning performance, both AD and bvFTD patients showed better memory of social compared to non-social interactions. Importantly, better memory for social interactions was associated with lower financial vulnerability in AD, but not bvFTD. Learning and memory of social interactions was associated with medial temporal and temporoparietal atrophy in AD, whereas a wider network of frontostriatal, insular, fusiform and medial temporal regions was implicated in bvFTD. Our findings suggest that although social relevance influences memory to an extent in both AD and bvFTD, this is associated with vulnerability to financial exploitation in AD only, and is underpinned by changes to different neural substrates. Theoretically, these findings provide novel insights into potential mechanisms that give rise to vulnerability in

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

PubMed

Shiarli, A-M; Jennings, R; Shi, J; Bailey, K; Davidson, Y; Tian, J; Bigio, E H; Ghetti, B; Murrell, J R; Delisle, M B; Mirra, S; Crain, B; Zolo, P; Arima, K; Iseki, E; Murayama, S; Kretzschmar, H; Neumann, M; Lippa, C; Halliday, G; Mackenzie, J; Khan, N; Ravid, R; Dickson, D; Wszolek, Z; Iwatsubo, T; Pickering-Brown, S M; Mann, D M A

2006-08-01

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

The Relationship between Subclinical Asperger's Syndrome and Frontotemporal Lobar Degeneration

PubMed Central

Midorikawa, Akira; Kawamura, Mitsuru

2012-01-01

Background/Aims The existence of the behavioral variant of frontotemporal dementia (bv-FTD), including senile Asperger's syndrome (AS), has been proposed. However, there are no empirical case reports to support the proposal. In this report, we present 3 patients who showed symptoms of bv-FTD and demonstrated signs of autistic spectrum disorder, especially AS. Methods We evaluated 3 subjects using the diagnostic criteria for bv-FTD, and their caregivers retrospectively provided data to calculate the Autism-Spectrum Quotient, Japanese version [Wakabayashi et al.: Shinrigaku Kenkyu 2004;75:78–84]. We also compared these data with those obtained from 3 individuals with Alzheimer's disease. Results All 3 patients met the criteria for bv-FTD and had a higher Autism-Spectrum Quotient score than did comparable Alzheimer's disease subjects. Conclusion It is possible that some senile persons with frontotemporal lobar degeneration-like maladaptive behavior may suffer from subclinical AS. PMID:22719743

Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

PubMed

Bonanni, L; Bontempo, G; Borrelli, I; Bifolchetti, S; Buongarzone, M P; Carlesi, N; Carolei, A; Ciccocioppo, F; Colangelo, U; Colonna, G; Desiderio, M; Ferretti, S; Fiorelli, L; D'Alessio, O; D'Amico, A; D'Amico, M C; De Lucia, R; Del Re, L; Di Blasio, F; Di Giacomo, R; Di Iorio, A; Di Santo, E; Di Giuseppe, M; Felice, N; Litterio, P; Gabriele, A; Mancino, E; Manzoli, L; Maruotti, V; Mearelli, S; Molino, G; Monaco, D; Nuccetelli, F; Onofrj, M; Perfetti, B; Sacchet, C; Sensi, F; Sensi, S; Sucapane, P; Taylor, J P; Thomas, A; Viola, P; Viola, S; Zito, M; Zhuzhuni, H

2013-06-01

Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. The results

Integration of Intention and Outcome for Moral Judgment in Frontotemporal Dementia: Brain Structural Signatures.

PubMed

Baez, Sandra; Kanske, Philipp; Matallana, Diana; Montañes, Patricia; Reyes, Pablo; Slachevsky, Andrea; Matus, Cristian; Vigliecca, Nora Silvana; Torralva, Teresa; Manes, Facundo; Ibanez, Agustin

2016-01-01

Moral judgment has been proposed to rely on a distributed brain network. This function is impaired in behavioral variant frontotemporal dementia (bvFTD), a condition involving damage to some regions of this network. However, no studies have investigated moral judgment in bvFTD via structural neuroimaging. We compared the performance of 21 bvFTD patients and 19 controls on a moral judgment task involving scenarios that discriminate between the contributions of intentions and outcomes. Voxel-based morphometry was used to assess (a) the atrophy pattern in bvFTD patients, (b) associations between gray matter (GM) volume and moral judgments, and (c) structural differences between bvFTD subgroups (patients with relatively preserved moral judgment and patients with severer moral judgment impairments). Patients judged attempted harm as more permissible and accidental harm as less permissible than controls. The groups' performance on accidental harm was associated with GM volume in the precuneus. In controls, it was al- so associated with the ventromedial prefrontal cortex (VMPFC). Also, both groups' performance on attempted harm was associated with GM volume in the temporoparietal junction. Patients exhibiting worse performance displayed smaller GM volumes in the precuneus and temporal pole. Results suggest that moral judgment abnormalities in bvFTD are associated with impaired integration of intentions and outcomes, which depends on an extended brain network. In bvFTD, moral judgment seems to critically depend on areas beyond the VMPFC. © 2016 S. Karger AG, Basel.

TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD

PubMed Central

Yu, Lei; Wilson, Robert S.; Chen, Er-Yun; Bennett, David A.; Schneider, Julie A.

2017-01-01

Objective: To investigate the association of TAR DNA-binding protein 43 (TDP-43) pathology with memory, other cognitive domains, and dementia in community-dwelling elders without pathologic diagnoses of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). Methods: Of 1,058 autopsied participants, 343 (32.4%) did not have pathologic diagnoses of AD or FTLD. Diagnosis of dementia was based on clinical evaluation and cognitive performance tests, which were used to create summary measures of global cognition and of 5 cognitive domains. TDP-43 pathology evaluated in 6 brain regions by immunohistochemistry was converted into a summary measure of TDP-43 severity. Results: Of 343 participants, 135 (39.4%) had TDP-43 pathology with a mean TDP-43 severity score of 0.394 (SD 0.490). TDP-43 inclusions were confined to the amygdala (stage 1) in 43.7% of participants, 40% showed additional involvement of the hippocampus or entorhinal cortex (stages 2), while fewer (16.3%) showed additional TDP-43 pathology in the temporal and frontal cortices (stage 3). Severity of TDP-43 pathology was independently related to lower function in global cognition and episodic and semantic memory while increased odds of dementia was only a trend. When participants with hippocampal sclerosis (HS) were excluded from the models, TDP-43 pathology remained associated with lower episodic memory but relationships with global cognition, semantic memory, and dementia were attenuated. Conclusions: TDP-43 pathology in elders, without pathologic diagnoses of AD or FTLD, is common and independently associated with lower function in episodic memory, while its associations with global cognitive impairment and dementia are difficult to separate from HS. PMID:28087828

Communication of brain network core connections altered in behavioral variant frontotemporal dementia but possibly preserved in early-onset Alzheimer's disease

NASA Astrophysics Data System (ADS)

Daianu, Madelaine; Jahanshad, Neda; Mendez, Mario F.; Bartzokis, George; Jimenez, Elvira E.; Thompson, Paul M.

2015-03-01

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.

Delayed help seeking behavior in dementia care: preliminary findings from the Clinical Pathway for Alzheimer's Disease in China (CPAD) study.

PubMed

Zhao, Mei; Lv, Xiaozhen; Tuerxun, Maimaitirexiati; He, Jincai; Luo, Benyan; Chen, Wei; Wang, Kai; Gu, Ping; Kuang, Weihong; Zhou, Yuying; Qu, Qiumin; He, Jianhua; Zhang, Nan; Feng, Yongping; Wang, Yanping; Yu, Xin; Wang, Huali

2016-02-01

The prevalence and factors associated with delays in help seeking for people with dementia in China are unknown. Within 1,010 consecutively registered participants in the Clinical Pathway for Alzheimer's Disease in China (CPAD) study (NCT01779310), 576 persons with dementia (PWDs) and their informants reported the estimated time from symptom onset to first medical visit seeking diagnosis. Univariate analysis of general linear model was used to examine the potential factors associated with the delayed diagnosis seeking. The median duration from the first noticeable symptom to the first visit seeking diagnosis or treatment was 1.77 years. Individuals with a positive family history of dementia had longer duration (p = 0.05). Compared with other types of dementia, people with vascular dementia (VaD) were referred for diagnosis earliest, and the sequence for such delays was: VaD < Alzheimer's disease (AD) < frontotemporal dementia (FTD) (p < 0.001). Subtypes of dementia (p < 0.001), family history (p = 0.01), and education level (p = 0.03) were associated with the increased delay in help seeking. In China, seeking diagnosis for PWDs is delayed for approximately 2 years, even in well-established memory clinics. Clinical features, family history, and less education may impede help seeking in dementia care.

The structural neuroanatomy of music emotion recognition: Evidence from frontotemporal lobar degeneration

PubMed Central

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.

2011-01-01

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. PMID:21385617

Structural MRI in Frontotemporal Dementia: Comparisons between Hippocampal Volumetry, Tensor-Based Morphometry and Voxel-Based Morphometry

PubMed Central

Muñoz-Ruiz, Miguel Ángel; Hartikainen, Päivi; Koikkalainen, Juha; Wolz, Robin; Julkunen, Valtteri; Niskanen, Eini; Herukka, Sanna-Kaisa; Kivipelto, Miia; Vanninen, Ritva; Rueckert, Daniel; Liu, Yawu; Lötjönen, Jyrki; Soininen, Hilkka

2012-01-01

Background MRI is an important clinical tool for diagnosing dementia-like diseases such as Frontemporal Dementia (FTD). However there is a need to develop more accurate and standardized MRI analysis methods. Objective To compare FTD with Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) with three automatic MRI analysis methods - Hippocampal Volumetry (HV), Tensor-based Morphometry (TBM) and Voxel-based Morphometry (VBM), in specific regions of interest in order to determine the highest classification accuracy. Methods Thirty-seven patients with FTD, 46 patients with AD, 26 control subjects, 16 patients with progressive MCI (PMCI) and 48 patients with stable MCI (SMCI) were examined with HV, TBM for shape change, and VBM for gray matter density. We calculated the Correct Classification Rate (CCR), sensitivity (SS) and specificity (SP) between the study groups. Results We found unequivocal results differentiating controls from FTD with HV (hippocampus left side) (CCR = 0.83; SS = 0.84; SP = 0.80), with TBM (hippocampus and amygdala (CCR = 0.80/SS = 0.71/SP = 0.94), and with VBM (all the regions studied, especially in lateral ventricle frontal horn, central part and occipital horn) (CCR = 0.87/SS = 0.81/SP = 0.96). VBM achieved the highest accuracy in differentiating AD and FTD (CCR = 0.72/SS = 0.67/SP = 0.76), particularly in lateral ventricle (frontal horn, central part and occipital horn) (CCR = 0.73), whereas TBM in superior frontal gyrus also achieved a high accuracy (CCR = 0.71/SS = 0.68/SP = 0.73). TBM resulted in low accuracy (CCR = 0.62) in the differentiation of AD from FTD using all regions of interest, with similar results for HV (CCR = 0.55). Conclusion Hippocampal atrophy is present not only in AD but also in FTD. Of the methods used, VBM achieved the highest accuracy in its ability to differentiate between FTD and AD. PMID:23285078

Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias?

PubMed Central

2014-01-01

Introduction Two methods of non-invasive brain stimulation, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have demonstrable positive effects on cognition and can ameliorate neuropsychiatric symptoms such as depression. Less is known about the efficacy of these approaches in common neurodegenerative diseases. In this review, we evaluate the effects of TMS and tDCS upon cognitive and neuropsychiatric symptoms in the major dementias, including Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and frontotemporal dementia (FTD), as well as the potential pre-dementia states of Mild Cognitive Impairment (MCI) and Parkinson’s disease (PD). Methods PubMed (until 7 February 2014) and PsycINFO (from 1967 to January Week 3 2014) databases were searched in a semi-systematic manner in order to identify relevant treatment studies. A total of 762 studies were identified and 32 studies (18 in the dementias and 14 in PD populations) were included. Results No studies were identified in patients with PDD, FTD or VaD. Of the dementias, 13 studies were conducted in patients with AD, one in DLB, and four in MCI. A total of 16 of the 18 studies showed improvements in at least one cognitive or neuropsychiatric outcome measure. Cognitive or neuropsychiatric improvements were observed in 12 of the 14 studies conducted in patients with PD. Conclusions Both TMS and tDCS may have potential as interventions for the treatment of symptoms associated with dementia and PD. These results are promising; however, available data were limited, particularly within VaD, PDD and FTD, and major challenges exist in order to maximise the efficacy and clinical utility of both techniques. In particular, stimulation parameters vary considerably between studies and are likely to subsequently impact upon treatment efficacy. PMID:25478032

Developing a dementia-specific preference--based quality of life measure (AD-5D) in Australia: a valuation study protocol.

PubMed

Comans, Tracy A; Nguyen, Kim-Huong; Mulhern, Brendan; Corlis, Megan; Li, Li; Welch, Alyssa; Kurrle, Susan E; Rowen, Donna; Moyle, Wendy; Kularatna, Sanjeewa; Ratcliffe, Julie

2018-01-21

Generic instruments for assessing health-related quality of life may lack the sensitivity to detect changes in health specific to certain conditions, such as dementia. The Quality of Life in Alzheimer's Disease (QOL-AD) is a widely used and well-validated condition-specific instrument for assessing health-related quality of life for people living with dementia, but it does not enable the calculation of quality-adjusted life years, the basis of cost utility analysis. This study will generate a preference-based scoring algorithm for a health state classification system -the Alzheimer's Disease Five Dimensions (AD-5D) derived from the QOL-AD. Discrete choice experiments with duration (DCE TTO ) and best-worst scaling health state valuation tasks will be administered to a representative sample of 2000 members of the Australian general population via an online survey and to 250 dementia dyads (250 people with dementia and their carers) via face-to-face interview. A multinomial (conditional) logistic framework will be used to analyse responses and produce the utility algorithm for the AD-5D. The algorithms developed will enable prospective and retrospective economic evaluation of any treatment or intervention targeting people with dementia where the QOL-AD has been administered and will be available online. Results will be disseminated through journals that publish health economics articles and through professional conferences. This study has ethical approval. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations.

PubMed

de la Torre, Jack C

2017-01-01

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.

Dementia with Lewy bodies

PubMed Central

McKeith, Ian

2004-01-01

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people, accounting for 10% to 15% of all cases, it occupies part of a spectrum that includes Parkinson's disease and primary autonomic failure. All these diseases share a neuritic pathology based upon abnormal aggregation of the synaptic protein α-synuciein. It is important to identify DLB patients accurately because they have specific symptoms, impairments, and functional disabilities thai differ from other common dementia syndromes such as Alzheimer's disease, vascular cognitive impairment, and frontotemporal dementia. Clinical diagnostic criteria for DLB have been validated against autopsy, but fail to detect a substantial minority of cases with atypical presentations that are often due to the presence of mixed pathology. DLB patients frequently have severe neuroleptic sensitivity reactions, which are associated with significantly increased morbidity and mortality. Cholinesterase inhibitor treatment is usually well tolerated and substantially improves cognitive and neuropsychiatrie symptoms. Although virtually unrecognized 20 years ago, DLB could within this decade become one of the most treatable neurodegenerative disorders of late life. PMID:22033743

Souvenaid reduces behavioral deficits and improves social cognition skills in frontotemporal dementia: a proof-of-concept study.

PubMed

Pardini, Matteo; Serrati, Carlo; Guida, Silvia; Mattei, Chiara; Abate, Lucia; Massucco, Davide; Sassos, Davide; Amore, Mario; Krueger, Frank; Cocito, Leonardo; Emberti Gialloreti, Leonardo

2015-01-01

Souvenaid™ is a nutraceutical compound thought to positively enhance synaptic function. In line with this mechanism of action, Souvenaid™ has been shown to improve cognitive function in subjects with mild Alzheimer's disease in randomized clinical trials. To date, however, the potential of Souvenaid™ to improve cognitive functioning in subjects with other neurodegenerative conditions also characterized by synaptic loss has not been explored. To evaluate the impact of Souvenaid™ on executive functions, social cognition and behavioral disturbances in subjects with the behavioral variant of frontotemporal dementia (bv-FTD). Twenty-six subjects with bv-FTD were enrolled in the study and randomized to Souvenaid™ (125 ml/day) or placebo groups. After 12 weeks, subjects were switched between the two groups. All subjects, blinded to treatment, underwent clinical and cognitive evaluations at enrollment, after 12 weeks and after 24 weeks. Treatment with Souvenaid™ was associated with a significant reduction of behavioral symptoms and an increase in Theory of Mind skills compared to placebo, which both returned to baseline when Souvenaid™ was discontinued. Souvenaid™ did not have an effect on executive functions. Our results provide evidence of the potential of Souvenaid™ therapy for the treatment of behavioral disturbances and social cognition skills in FTD. © 2015 S. Karger AG, Basel.

Developing a dementia-specific preference-­based quality of life measure (AD-5D) in Australia: a valuation study protocol

PubMed Central

Comans, Tracy A; Nguyen, Kim-Huong; Mulhern, Brendan; Corlis, Megan; Li, Li; Welch, Alyssa; Kurrle, Susan E; Rowen, Donna; Moyle, Wendy; Kularatna, Sanjeewa; Ratcliffe, Julie

2018-01-01

Introduction Generic instruments for assessing health-related quality of life may lack the sensitivity to detect changes in health specific to certain conditions, such as dementia. The Quality of Life in Alzheimer’s Disease (QOL-AD) is a widely used and well-validated condition-specific instrument for assessing health-related quality of life for people living with dementia, but it does not enable the calculation of quality-adjusted life years, the basis of cost utility analysis. This study will generate a preference-based scoring algorithm for a health state classification system -the Alzheimer’s Disease Five Dimensions (AD-5D) derived from the QOL-AD. Methods and analysis Discrete choice experiments with duration (DCETTO) and best–worst scaling health state valuation tasks will be administered to a representative sample of 2000 members of the Australian general population via an online survey and to 250 dementia dyads (250 people with dementia and their carers) via face-to-face interview. A multinomial (conditional) logistic framework will be used to analyse responses and produce the utility algorithm for the AD-5D. Ethics and dissemination The algorithms developed will enable prospective and retrospective economic evaluation of any treatment or intervention targeting people with dementia where the QOL-AD has been administered and will be available online. Results will be disseminated through journals that publish health economics articles and through professional conferences. This study has ethical approval. PMID:29358437

Pathological Heterogeneity of Frontotemporal Lobar Degeneration with Ubiquitin-Positive Inclusions Delineated by Ubiquitin Immunohistochemistry and Novel Monoclonal Antibodies

PubMed Central

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.

2006-01-01

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 α-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 α-synucleinopathies. Therefore, ubiquitin immunohistochemistry and the immunostaining properties of the novel mAbs generated here suggest that FTLD-U is pathologically he-terogeneous. Identification of the disease proteins recognized by these mAbs will further advance understanding of molecular substrates of FTLD-U neurodegenerative pathways. PMID:17003490

TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia.

PubMed

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

2016-07-15

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. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Regional cerebral blood flow single photon emission computed tomography for detection of Frontotemporal dementia in people with suspected dementia.

PubMed

Archer, Hilary A; Smailagic, Nadja; John, Christeena; Holmes, Robin B; Takwoingi, Yemisi; Coulthard, Elizabeth J; Cullum, Sarah

2015-06-23

In the UK, dementia affects 5% of the population aged over 65 years and 25% of those over 85 years. Frontotemporal dementia (FTD) represents one subtype and is thought to account for up to 16% of all degenerative dementias. Although the core of the diagnostic process in dementia rests firmly on clinical and cognitive assessments, a wide range of investigations are available to aid diagnosis.Regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) is an established clinical tool that uses an intravenously injected radiolabelled tracer to map blood flow in the brain. In FTD the characteristic pattern seen is hypoperfusion of the frontal and anterior temporal lobes. This pattern of blood flow is different to patterns seen in other subtypes of dementia and so can be used to differentiate FTD.It has been proposed that a diagnosis of FTD, (particularly early stage), should be made not only on the basis of clinical criteria but using a combination of other diagnostic findings, including rCBF SPECT. However, more extensive testing comes at a financial cost, and with a potential risk to patient safety and comfort. To determine the diagnostic accuracy of rCBF SPECT for diagnosing FTD in populations with suspected dementia in secondary/tertiary healthcare settings and in the differential diagnosis of FTD from other dementia subtypes. Our search strategy used two concepts: (a) the index test and (b) the condition of interest. We searched citation databases, including MEDLINE (Ovid SP), EMBASE (Ovid SP), BIOSIS (Ovid SP), Web of Science Core Collection (ISI Web of Science), PsycINFO (Ovid SP), CINAHL (EBSCOhost) and LILACS (Bireme), using structured search strategies appropriate for each database. In addition we searched specialised sources of diagnostic test accuracy studies and reviews including: MEDION (Universities of Maastricht and Leuven), DARE (Database of Abstracts of Reviews of Effects) and HTA (Health Technology Assessment) database

[Spanish translation and validation of an Executive Battery 25 (EB25) and its shortened version (ABE12) for executive dysfunction screening in dementia].

PubMed

Serrani Azcurra, D J L

2013-10-01

There is a need for clinically administered instruments capable of detecting executive dysfunction in dementia. The translation and validation of Executive Battery 25 (EB25) and a short version for screening of executive dysfunction in dementia. The original battery was translated and validated using convergent and divergent correlation in 66 mild dementia patients (CDR 1) matched with 66 controls. EB25 consists of 25 items which detect executive dysfunction. Convergent correlation was made with 7 tests assessing executive dysfunction, the Frontal Systems Behaviour Scale (FrSBe) and Disability Fast Assessment Scale. Patients had higher scores than controls and correlated with the Stroop Test, verbal fluency test and Frontal Behaviour Inventory. Only 12 out of 25 items were needed to separate both groups, which were used to build an abbreviated Executive Battery with equal psychometric properties and discriminative power. The cut-off point for EB25 was 12, and 7 for the abbreviated version. A cut-off point of 12 was able to discriminate between ¿Alzheimer's disease? (AD) and frontotemporal lobe dementia (FTLD). EB25 and AEB12 enable executive dysfunction to be detected in mild dementia. On the other hand, AEB12 exhibits better psychometric properties than the original battery, allowing discrimination between AD and FTLD and is completed in less time. Copyright © 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Dignity in people with frontotemporal dementia and similar disorders - a qualitative study of the perspective of family caregivers.

PubMed

Sagbakken, Mette; Nåden, Dagfinn; Ulstein, Ingun; Kvaal, Kari; Langhammer, Birgitta; Rognstad, May-Karin

2017-06-23

Frontotemporal dementia (FTD) constitutes on average 10-15% of dementia in younger persons (≤65 years old), but can also affect older people. These patients demonstrate a decline in social conduct, and/or language aphasias, apathy, and loss of insight that is gradual and progressive. Preservation of dignity seems to be highly relevant both before and after admission to different types of institutionalized care, but the research is scant. From the perspective of close relatives, this study aims to develop knowledge related to dignified or undignified care of patients with FTD and similar conditions. A qualitative, descriptive, and explorative design were employed to address the aims of this study. We interviewed nine relatives of people with FTD and similar conditions living in nursing homes, and two relatives of people living at home but attending day center 5 days a week. Relatives described the transition from being a close relative to someone who had little influence or knowledge of what constituted the care and the daily life of their loved ones. According to relatives' descriptions, patients are deprived of dignity in various ways: through limited interaction with peers and close relatives, limited confirmation of identity through staff who know them well, lack of possibilities for making autonomous decisions or entertaining meaningful roles or activities. Examples provided from the day care centres show how dignity is maintained through identity-strengthening activities conducted in different places, under various kinds of supervision and care, and together with people representing different roles and functions. Maintaining a link with the world outside the institution, through closer cooperation between the institution and family members, and/or by the use of day care centres, seems to facilitate prevention of many of the factors that may threaten dignified care.

Quantitative EEG and LORETA: valuable tools in discerning FTD from AD?

PubMed

Caso, Francesca; Cursi, Marco; Magnani, Giuseppe; Fanelli, Giovanna; Falautano, Monica; Comi, Giancarlo; Leocani, Letizia; Minicucci, Fabio

2012-10-01

Drawing a clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease (AD) is tricky, particularly at the early stages of disease. This study evaluates the possibility in differentiating 39 FTD, 39 AD, and 39 controls (CTR) by means of power spectral analysis and standardized low resolution brain electromagnetic tomography (sLORETA) within delta, theta, alpha 1 and 2, beta 1, 2, and 3 frequency bands. Both analyses revealed in AD patients, relative to CTR, higher expression of diffuse delta/theta and lower central/posterior fast frequency (from alpha1 to beta2) bands. FTD patients showed diffuse increased theta power compared with CTR and lower delta relative to AD patients. Compared with FTD, AD patients showed diffuse higher theta power at spectral analysis and, at sLORETA, decreased alpha2 and beta1 values in central/temporal regions. Spectral analysis and sLORETA provided complementary information that might help characterizing different patterns of electroencephalogram (EEG) oscillatory activity in AD and FTD. Nevertheless, this differentiation was possible only at the group level because single patients could not be discerned with sufficient accuracy. Copyright © 2012 Elsevier Inc. All rights reserved.

The structural neuroanatomy of music emotion recognition: evidence from frontotemporal lobar degeneration.

PubMed

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

2011-06-01

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. Copyright © 2011 Elsevier Inc. All rights reserved.

Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

PubMed Central

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.

2016-01-01

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

The Spectrum of Sociopathy in Dementia

PubMed Central

Mendez, Mario F.; Shapira, Jill S.; Saul, Ronald E.

2012-01-01

Although well-known from head trauma and acute strokes, sociopathic behavior from dementia is less known and understood. This study reviewed 33 dementia patients who had been in trouble with the law. They were divided into two groups: 22 who committed impulsive sociopathic acts and 11 who committed non-impulsive acts. The impulsive patients demonstrated nonviolent acts, such as dis-inhibited sexual behavior or pathological stealing, and had disproportionate frontal-caudate atrophy on neuroimaging. The majority of non-impulsive patients demonstrated agitation-paranoia, sometimes with reactive aggression, delusional beliefs, or aphasic paranoia, and had advanced memory and other cognitive impairment. The impulsive patients tended to have frontally predominant illnesses such as frontotemporal dementia or Huntington’s disease, whereas the non-impulsive group tended to have Alzheimer’s disease or prominent aphasia. Sociopathy has different causes in dementia. Two common mechanisms are disinhibition, with frontally predominant disease, and agitation-paranoia, with greater cognitive impairment. These forms of sociopathy differ significantly from the antisocial/ psychopathic personality. PMID:21677240

Screening of Early and Late Onset Alzheimer's Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy.

PubMed

Ferrari, Raffaele; Ferrara, Michela; Alinani, Anwar; Sutton, Roger Brian; Famà, Francesco; Picco, Agnese; Rodriguez, Guido; Nobili, Flavio; Momeni, Parastoo

2015-01-01

Cohorts from a defined geographical area enable ad hoc genotype-phenotype correlation studies providing novel and unique insight into disease. We analysed genetic risk factors associated with early and late onset Alzheimer's disease (EOAD and LOAD) in a population from Liguria (northern Italy), as part of an ongoing longitudinal study. We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer's and non-Alzheimer's forms of dementias in all dementia cases might be warranted. The analysis of the LOAD risk factors revealed no association with AD or AD + MCI status after Bonferroni correction. Lack of association with APOE is supported by previous studies in the Italian population. Our data also evidenced: 1) a potentially protective haplotype at the PSEN2 locus; 2) a nominal association with the GWAS-risk allele A for rs3818361 in CR1 and; 3) a threefold prevalence of AD in the female population compared to men.Our results will need to be further assessed and confirmed in larger cohorts from this area. 

What dementia reveals about proverb interpretation and its neuroanatomical correlates.

PubMed

Kaiser, Natalie C; Lee, Grace J; Lu, Po H; Mather, Michelle J; Shapira, Jill; Jimenez, Elvira; Thompson, Paul M; Mendez, Mario F

2013-08-01

Neuropsychologists frequently include proverb interpretation as a measure of executive abilities. A concrete interpretation of proverbs, however, may reflect semantic impairments from anterior temporal lobes, rather than executive dysfunction from frontal lobes. The investigation of proverb interpretation among patients with different dementias with varying degrees of temporal and frontal dysfunction may clarify the underlying brain-behavior mechanisms for abstraction from proverbs. We propose that patients with behavioral variant frontotemporal dementia (bvFTD), who are characteristically more impaired on proverb interpretation than those with Alzheimer's disease (AD), are disproportionately impaired because of anterior temporal-mediated semantic deficits. Eleven patients with bvFTD and 10 with AD completed the Delis-Kaplan Executive Function System (D-KEFS) Proverbs Test and a series of neuropsychological measures of executive and semantic functions. The analysis included both raw and age-adjusted normed data for multiple choice responses on the D-KEFS Proverbs Test using independent samples t-tests. Tensor-based morphometry (TBM) applied to 3D T1-weighted MRI scans mapped the association between regional brain volume and proverb performance. Computations of mean Jacobian values within select regions of interest provided a numeric summary of regional volume, and voxel-wise regression yielded 3D statistical maps of the association between tissue volume and proverb scores. The patients with bvFTD were significantly worse than those with AD in proverb interpretation. The worse performance of the bvFTD patients involved a greater number of concrete responses to common, familiar proverbs, but not to uncommon, unfamiliar ones. These concrete responses to common proverbs correlated with semantic measures, whereas concrete responses to uncommon proverbs correlated with executive functions. After controlling for dementia diagnosis, TBM analyses indicated significant

Sensitivity of the Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-II) to the neurocognitive deficits associated with the semantic dementia variant of frontotemporal lobar degeneration: A case study.

PubMed

Gontkovsky, Samuel T

2017-01-01

This case study of a 71-year-old woman illustrates the clinical utility of the Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-II) in assessing the neurocognitive sequelae of the semantic dementia variant of frontotemporal lobar degeneration. Obtained scores revealed a decline in estimated Full Scale IQ from the patient's expected premorbid level. Consistent with her initial onset of neuropathology in the left temporal lobe, the WASI-II yielded a difference of 53 standard score points between the Perceptual Reasoning and Verbal Comprehension composites, reflecting the patient's intact capabilities in visuospatial perception and construction in conjunction with marked disturbances of language. The similarities subtest was particularly sensitive to the patient's neurocognitive deficits. WASI-II scores corresponded well with the results obtained from other administered measures, in particular those from the Repeatable Battery for the Assessment of Neuropsychological Status. Findings provide support for use of the WASI-II in the clinical evaluation of semantic dementia and offer preliminary evidence that the test may be helpful in both lateralization and localization of brain lesions.

Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia.

PubMed

Wilke, Carlo; Gillardon, Frank; Deuschle, Christian; Hobert, Markus A; Jansen, Iris E; Metzger, Florian G; Heutink, Peter; Gasser, Thomas; Maetzler, Walter; Blauwendraat, Cornelis; Synofzik, Matthis

2017-01-01

Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations. © 2016 S. Karger AG, Basel.

Enhanced Positive Emotional Reactivity Undermines Empathy in Behavioral Variant Frontotemporal Dementia.

PubMed

Hua, Alice Y; Sible, Isabel J; Perry, David C; Rankin, Katherine P; Kramer, Joel H; Miller, Bruce L; Rosen, Howard J; Sturm, Virginia E

2018-01-01

Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterized by profound changes in emotions and empathy. Although most patients with bvFTD become less sensitive to negative emotional cues, some patients become more sensitive to positive emotional stimuli. We investigated whether dysregulated positive emotions in bvFTD undermine empathy by making it difficult for patients to share (emotional empathy), recognize (cognitive empathy), and respond (real-world empathy) to emotions in others. Fifty-one participants (26 patients with bvFTD and 25 healthy controls) viewed photographs of neutral, positive, negative, and self-conscious emotional faces and then identified the emotions displayed in the photographs. We used facial electromyography to measure automatic, sub-visible activity in two facial muscles during the task: Zygomaticus major ( ZM ), which is active during positive emotional reactions (i.e., smiling), and Corrugator supercilii ( CS ), which is active during negative emotional reactions (i.e., frowning). Participants rated their baseline positive and negative emotional experience before the task, and informants rated participants' real-world empathic behavior on the Interpersonal Reactivity Index. The majority of participants also underwent structural magnetic resonance imaging. A mixed effects model found a significant diagnosis X trial interaction: patients with bvFTD showed greater ZM reactivity to neutral, negative (disgust and surprise), self-conscious (proud), and positive (happy) faces than healthy controls. There was no main effect of diagnosis or diagnosis X trial interaction on CS reactivity. Compared to healthy controls, patients with bvFTD had impaired emotion recognition. Multiple regression analyses revealed that greater ZM reactivity predicted worse negative emotion recognition and worse real-world empathy. At baseline, positive emotional experience was higher in bvFTD than healthy controls and also predicted

A clinicopathological approach to the diagnosis of dementia

PubMed Central

Elahi, Fanny M.; Miller, Bruce L.

2018-01-01

The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes — Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases — with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms. PMID:28708131

A Novel MAPT Mutation, G55R, in a Frontotemporal Dementia Patient Leads to Altered Tau Function

PubMed Central

Guzman, Elmer; Barczak, Anna; Chodakowska-Żebrowska, Małgorzata; Barcikowska, Maria; Feinstein, Stuart

2013-01-01

Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment. PMID:24086739

Bilingualism, dementia, cognitive and neural reserve.

PubMed

Perani, Daniela; Abutalebi, Jubin

2015-12-01

We discuss the role of bilingualism as a source of cognitive reserve and we propose the putative neural mechanisms through which lifelong bilingualism leads to a neural reserve that delays the onset of dementia. Recent findings highlight that the use of more than one language affects the human brain in terms of anatomo-structural changes. It is noteworthy that recent evidence from different places and cultures throughout the world points to a significant delay of dementia onset in bilingual/multilingual individuals. This delay has been reported not only for Alzheimer's dementia and its prodromal mild cognitive impairment phase, but also for other dementias such as vascular and fronto-temporal dementia, and was found to be independent of literacy, education and immigrant status. Lifelong bilingualism represents a powerful cognitive reserve delaying the onset of dementia by approximately 4 years. As to the causal mechanism, because speaking more than one language heavily relies upon executive control and attention, brain systems handling these functions are more developed in bilinguals resulting in increases of gray and white matter densities that may help protect from dementia onset. These neurocognitive benefits are even more prominent when second language proficiency and exposure are kept high throughout life.

A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia

PubMed Central

Ferrari, Raffaele; Graziano, Francesca; Novelli, Valeria; Rossi, Giacomina; Galimberti, Daniela; Rainero, Innocenzo; Benussi, Luisa; Nacmias, Benedetta; Bruni, Amalia C.; Cusi, Daniele; Salvi, Erika; Borroni, Barbara; Grassi, Mario

2017-01-01

Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer’s disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies. PMID:29020091

The frontotemporal syndrome of ALS is associated with poor survival.

PubMed

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

2016-12-01

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.

A long-term longitudinal follow-up of depressed patients treated with ECT with special focus on development of dementia.

PubMed

Berggren, Åke; Gustafson, Lars; Höglund, Peter; Johanson, Aki

2016-08-01

In this study, the long term effects of ECT on patients with depression were investigated through repeated rCBF and EEG measures as well as clinical characteristics over several years. The aim of the investigation was to establish an association with the eventual development of dementia. A cohort of forty-nine patients (21 men and 28 women) with a mean age of 61 years underwent ECT. A subsequent evaluation from medical records and three rating-scales for diagnosis of Alzheimer´s disease (AD), fronto-temporal dementia (FTD), and for vascular dementia (VaD), revealed that 17 patients (8 men and 9 women), had developed dementia. These cases were compared to the 32 patients (13 men and 19 women), who had not developed dementia. Initially, the dementia group, compared to those without dementia, showed a lower hemispheric CBF (left side; p=.029, right side; p=.033), and a lower mean occipital EEG frequency (p=.048). After the first ECT-series, an increase in general disorientation (p=.015), personal disorientation (p=.009), and subsequently, spatial disorientation (p=.021), were seen in the dementia group. There were no differences in the clinical response or remissions after treatment in the groups. The small sample-size, which did not allow for the comparison of characteristics between different dementias. Depressed older patients who later developed dementia showed lower hemispheric mean level of CBF and EEG mean frequency before ECT and higher personal and spatial disorientation following ECT. Copyright © 2016 Elsevier B.V. All rights reserved.

Flavour identification in frontotemporal lobar degeneration.

PubMed

Omar, Rohani; Mahoney, Colin J; Buckley, Aisling H; Warren, Jason D

2013-01-01

Deficits of flavour processing may be clinically important in frontotemporal lobar degeneration (FTLD). To examine flavour processing in FTLD. We studied flavour identification prospectively in 25 patients with FTLD (12 with behavioural variant frontotemporal dementia (bvFTD), eight with semantic variant primary progressive aphasia (svPPA), five with non-fluent variant primary progressive aphasia (nfvPPA)) and 17 healthy control subjects, using a new test based on cross-modal matching of flavours to words and pictures. All subjects completed a general neuropsychological assessment, and odour identification was also assessed using a modified University of Pennsylvania Smell Identification Test. Brain MRI volumes from the patient cohort were analysed using voxel-based morphometry to identify regional grey matter associations of flavour identification. Relative to the healthy control group, the bvFTD and svPPA subgroups showed significant (p<0.05) deficits of flavour identification and all three FTLD subgroups showed deficits of odour identification. Flavour identification performance did not differ significantly between the FTLD syndromic subgroups. Flavour identification performance in the combined FTLD cohort was significantly (p<0.05 after multiple comparisons correction) associated with grey matter volume in the left entorhinal cortex, hippocampus, parahippocampal gyrus and temporal pole. Certain FTLD syndromes are associated with impaired flavour identification and this is underpinned by grey matter atrophy in an anteromedial temporal lobe network. These findings may have implications for our understanding of abnormal eating behaviour in these diseases.

Damage to Left Frontal Regulatory Circuits Produces Greater Positive Emotional Reactivity in Frontotemporal Dementia

PubMed Central

Sturm, Virginia E.; Yokoyama, Jennifer S.; Eckart, Janet A.; Zakrzewski, Jessica; Rosen, Howard J.; Miller, Bruce L.; Seeley, William W.; Levenson, Robert W.

2015-01-01

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, 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 analyses revealed that atrophy in predominantly left hemisphere fronto-striatal emotion regulation systems including left ventrolateral prefrontal cortex, orbitofrontal cortex, anterior insula, and striatum (pFWE < .05) was associated with greater happiness facial behavior during the film. 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 selective

SOME IS NOT ENOUGH: QUANTIFIER COMPREHENSION IN CORTICOBASAL SYNDROME AND BEHAVIORAL VARIANT FRONTOTEMPORAL DEMENTIA

PubMed Central

Morgan, Brianna; Gross, Rachel; Clark, Robin; Dreyfuss, Michael; Boller, Ashley; Camp, Emily; Liang, Tsao-Wei; Avants, Brian; McMillan, Corey; Grossman, Murray

2011-01-01

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 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. PMID:21930136

Face-Name Repetition Priming in Semantic Dementia: A Case Report

ERIC Educational Resources Information Center

Calabria, Marco; Miniussi, Carlo; Bisiacchi, Patricia S.; Zanetti, Orazio; Cotelli, Maria

2009-01-01

Repetition priming (RP) has been employed as a measure of implicit processing in patients suffering from a breakdown of semantic memory, as in the case of semantic dementia (SD), a subtype of frontotemporal lobar degeneration (FTLD). Here, we investigated face-name representation in a case of SD using a paradigm of within- and cross-domain…

Impaired imitation of gestures in mild dementia: comparison of dementia with Lewy bodies, Alzheimer's disease and vascular dementia.

PubMed

Nagahama, Yasuhiro; Okina, Tomoko; Suzuki, Norio

2015-11-01

To examine whether imitation of gestures provided useful information to diagnose early dementia in elderly patients. Imitation of finger and hand gestures was evaluated in patients with mild dementia; 74 patients had dementia with Lewy bodies (DLB), 100 with Alzheimer's disease (AD) and 52 with subcortical vascular dementia (SVaD). Significantly, more patients with DLB (32.4%) compared with patients with AD (5%) or SVaD (11.5%) had an impaired ability to imitate finger gestures bilaterally. Also, significantly, more patients with DLB (36.5%) compared with patients with AD (5%) or SVaD (15.4%) had lower mean scores of both hands. In contrast, impairment of the imitation of bimanual gestures was comparable among the three patient groups (DLB 50%, AD 42%, SVaD 42.3%). Our study revealed that imitation of bimanual gestures was impaired non-specifically in about half of the patients with mild dementia, whereas imitation of finger gestures was significantly more impaired in patients with early DLB than in those with AD or SVaD. Although the sensitivity was not high, the imitation tasks may provide additional information for diagnosis of mild dementia, especially for DLB. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Artistic creativity and dementia.

PubMed

Miller, Zachary A; Miller, Bruce L

2013-01-01

Artistic ability and creativity are defining characteristics of human behavior. Behavioral neurology, as a specialty, believes that even the most complex behaviors can be modeled and understood as the summation of smaller cognitive functions. Literature from individuals with specific brain lesions has helped to map out these smaller regions of cognitive abilities. More recently, models based on neurodegenerative conditions, especially from the frontotemporal dementias, have allowed for greater nuanced investigations into the various functional anatomies necessary for artistic behavior and possibly the underlying networks that promote creativity. © 2013 Elsevier B.V. All rights reserved.

[Reconciliating neurology and psychiatry: The prototypical case of frontotemporal dementia].

PubMed

Lagarde, J; Sarazin, M

2017-10-01

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

Inter-relation between "classic" motor neuron disease and frontotemporal dementia: neuropsychological and single photon emission computed tomography study.

PubMed Central

Talbot, P R; Goulding, P J; Lloyd, J J; Snowden, J S; Neary, D; Testa, H J

1995-01-01

The purpose of this study was to examine the possible association between "classic" motor neuron disease (cMND) and frontotemporal dementia (FTD), using neuropsychological evaluation and single photon emission computed tomography (SPECT). Psychological tests assessing language, perceptuospatial, memory, and "frontal lobe" functions were given to patients with cMND and test scores were compared with those of normal control subjects. 99mTc-HMPAO SPECT was performed on patients with cMND, FTD and motor neuron disease (FTD/MND), FTD alone, and normal control subjects. Regional cerebral blood flow indices (rCBFi) were determined in 36 cortical regions, and differences between grouped rCBFi data were investigated by canonical discriminant analysis. There were significant group differences in the scores of picture sequencing and token tests in patients with cMND compared with normal controls. Regional CBFi data showed frontal and anterior temporal reductions in patients with cMND compared with normal controls. A similar pattern of SPECT abnormality was seen in patients with FTD/MND and FTD alone, but to a more pronounced degree than in patients with cMND. Neuropsychological and SPECT findings in cMND, FTD/MND, and FTD showed a common pattern of cerebral involvement, most pronounced in the second two conditions. It is suggested that cMND, FTD/MND, and FTD represent a clinical range of a pathological continuum. Images PMID:7745399

Visual Versus Fully Automated Analyses of 18F-FDG and Amyloid PET for Prediction of Dementia Due to Alzheimer Disease in Mild Cognitive Impairment.

PubMed

Grimmer, Timo; Wutz, Carolin; Alexopoulos, Panagiotis; Drzezga, Alexander; Förster, Stefan; Förstl, Hans; Goldhardt, Oliver; Ortner, Marion; Sorg, Christian; Kurz, Alexander

2016-02-01

Biomarkers of Alzheimer disease (AD) can be imaged in vivo and can be used for diagnostic and prognostic purposes in people with cognitive decline and dementia. Indicators of amyloid deposition such as (11)C-Pittsburgh compound B ((11)C-PiB) PET are primarily used to identify or rule out brain diseases that are associated with amyloid pathology but have also been deployed to forecast the clinical course. Indicators of neuronal metabolism including (18)F-FDG PET demonstrate the localization and severity of neuronal dysfunction and are valuable for differential diagnosis and for predicting the progression from mild cognitive impairment (MCI) to dementia. It is a matter of debate whether to analyze these images visually or using automated techniques. Therefore, we compared the usefulness of both imaging methods and both analyzing strategies to predict dementia due to AD. In MCI participants, a baseline examination, including clinical and imaging assessments, and a clinical follow-up examination after a planned interval of 24 mo were performed. Of 28 MCI patients, 9 developed dementia due to AD, 2 developed frontotemporal dementia, and 1 developed moderate dementia of unknown etiology. The positive and negative predictive values and the accuracy of visual and fully automated analyses of (11)C-PiB for the prediction of progression to dementia due to AD were 0.50, 1.00, and 0.68, respectively, for the visual and 0.53, 1.00, and 0.71, respectively, for the automated analyses. Positive predictive value, negative predictive value, and accuracy of fully automated analyses of (18)F-FDG PET were 0.37, 0.78, and 0.50, respectively. Results of visual analyses were highly variable between raters but were superior to automated analyses. Both (18)F-FDG and (11)C-PiB imaging appear to be of limited use for predicting the progression from MCI to dementia due to AD in short-term follow-up, irrespective of the strategy of analysis. On the other hand, amyloid PET is extremely useful to

Conceptualizing neuropsychiatric diseases with multimodal data-driven meta-analyses – The case of behavioral variant frontotemporal dementia

PubMed Central

Schroeter, Matthias L.; Laird, Angela R.; Chwiesko, Caroline; Deuschl, Christine; Schneider, Else; Bzdok, Danilo; Eickhoff, Simon B.; Neumann, Jane

2014-01-01

Introduction Uniform coordinate systems in neuroimaging research have enabled comprehensive systematic and quantitative meta-analyses. Such approaches are particularly relevant for neuropsychiatric diseases, the understanding of their symptoms, prediction and treatment. Behavioral variant frontotemporal dementia (bvFTD), a common neurodegenerative syndrome, is characterized by deep alterations in behavior and personality. Investigating this ‘nexopathy’ elucidates the healthy social and emotional brain. Methods Here, we combine three multimodal meta-analyses approaches – anatomical & activation likelihood estimates and behavioral domain profiles – to identify neural correlates of bvFTD in 417 patients and 406 control subjects and to extract mental functions associated with this disease by meta-analyzing functional activation studies in the comprehensive probabilistic functional brain atlas of the BrainMap database. Results The analyses identify the frontomedian cortex, basal ganglia, anterior insulae and thalamus as most relevant hubs, with a regional dissociation between atrophy and hypometabolism. Neural networks affected by bvFTD were associated with emotion and reward processing, empathy and executive functions (mainly inhibition), suggesting these functions as core domains affected by the disease and finally leading to its clinical symptoms. In contrast, changes in theory of mind or mentalizing abilities seem to be secondary phenomena of executive dysfunctions. Conclusions The study creates a novel conceptual framework to understand neuropsychiatric diseases by powerful data-driven meta-analytic approaches that shall be extended to the whole neuropsychiatric spectrum in the future. PMID:24763126

Theory of mind and recognition of facial emotion in dementia: challenge to current concepts.

PubMed

Freedman, Morris; Binns, Malcolm A; Black, Sandra E; Murphy, Cara; Stuss, Donald T

2013-01-01

Current literature suggests that theory of mind (ToM) and recognition of facial emotion are impaired in behavioral variant frontotemporal dementia (bvFTD). In contrast, studies suggest that ToM is spared in Alzheimer disease (AD). However, there is controversy whether recognition of emotion in faces is impaired in AD. This study challenges the concepts that ToM is preserved in AD and that recognition of facial emotion is impaired in bvFTD. ToM, recognition of facial emotion, and identification of emotions associated with video vignettes were studied in bvFTD, AD, and normal controls. ToM was assessed using false-belief and visual perspective-taking tasks. Identification of facial emotion was tested using Ekman and Friesen's pictures of facial affect. After adjusting for relevant covariates, there were significant ToM deficits in bvFTD and AD compared with controls, whereas neither group was impaired in the identification of emotions associated with video vignettes. There was borderline impairment in recognizing angry faces in bvFTD. Patients with AD showed significant deficits on false belief and visual perspective taking, and bvFTD patients were impaired on second-order false belief. We report novel findings challenging the concepts that ToM is spared in AD and that recognition of facial emotion is impaired in bvFTD.

[Self-consciousness, consciousness of the other and dementias].

PubMed

Gil, Roger

2007-06-01

Studies of self-consciousness in dementia concern essentially anosognosia or the loss of insight. However, Self-consciousness is multifaceted: it includes awareness of the body, perceptions, one's own history, identity, and one's own projects. Self-consciousness is linked to consciousness of others i.e. to social cognition supported by identification of others, but also by comprehension of facial expression of emotions, comprehension and expression of emotional prosody, pragmatic abilities, ability to infer other's people's mental states, thoughts, and feelings (theory of mind and empathy), knowledge of social norms and rules, social reasoning. The subtypes of dementias (and namely Alzheimer's disease and frontotemporal dementia) affect heterogeneously the different aspects of the self-and other-consciousness. Further studies are needed for a better knowledge of the complex relationship between Self-consciousness, social cognition, decision making and neuropsychiatric symptoms and behavioral disturbances occurring in demented patients.

Semantic dementia Brazilian study of nineteen cases

PubMed Central

Senaha, Mirna Lie Hosogi; Caramelli, Paulo; Porto, Claudia Sellitto; Nitrini, Ricardo

2007-01-01

The term semantic dementia was devised by Snowden et al. in 1989 and nowadays, the semantic dementia syndrome is recognized as one of the clinical forms of frontotemporal lobar degeneration (FTLD) and is characterized by a language semantic disturbance associated to non-verbal semantic memory impairment. Objectives The aim of this study was to describe a Brazilian sample of 19 semantic dementia cases, emphasizing the clinical characteristics important for differential diagnosis of this syndrome. Methods Nineteen cases with semantic dementia were evaluated between 1999 and 2007. All patients were submitted to neurological evaluation, neuroimaging exams and cognitive, language and semantic memory evaluation. Results All patients presented fluent spontaneous speech, preservation of syntactic and phonological aspects of the language, word-finding difficulty, semantic paraphasias, word comprehension impairment, low performance in visual confrontation naming tasks, impairment on tests of non-verbal semantic memory and preservation of autobiographical memory and visuospatial skills. Regarding radiological investigations, temporal lobe atrophy and/or hypoperfusion were found in all patients. Conclusions The cognitive, linguistic and of neuroimaging data in our case series corroborate other studies showing that semantic dementia constitutes a syndrome with well defined clinical characteristics associated to temporal lobe atrophy. PMID:29213413

Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease.

PubMed

Ibanez, Laura; Dube, Umber; Davis, Albert A; Fernandez, Maria V; Budde, John; Cooper, Breanna; Diez-Fairen, Monica; Ortega-Cubero, Sara; Pastor, Pau; Perlmutter, Joel S; Cruchaga, Carlos; Benitez, Bruno A

2018-01-01

Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established. Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients. Methods: We analyzed the coding regions of the amyloid-beta precursor protein ( APP ), Presenilin 1 and 2 ( PSEN1, PSEN2 ), and Granulin ( GRN ) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status. Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2 , and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients ( p = 2.0 × 10 -4 ), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site. Conclusions: Pathogenic mutations

Performance of patients with frontotemporal lobar degeneration on artistic tasks: A pilot study.

PubMed

Anauate, Maria Cristina; Bahia, Valéria Santoro; Nitrini, Ricardo; Radanovic, Marcia

2014-01-01

Several studies have addressed visuospatial and executive skills in artistic activities in Frontotemporal Lobar Degeneration (FTLD) and Alzheimer's disease (AD). To investigate the performance of FTLD patients compared to controls on two artistic tasks. Four FTLD patients with mean age of 57 (8.7) years and schooling of 12.2 (4.5) years plus 10 controls with mean age of 62.9 (8.6) years and schooling of 12.3 (4.6) years, were assessed using the Lowenstein Occupational Therapy Cognitive Assessment (LOTCA) and by a three-stage artistic protocol including visual observation, copying and collage, based on a Sisley painting. FTLD patients had lower scores than controls on Visuospatial Perception, Copy, Collage, Examiner's Observation, and Total, showing distinct patterns of performance according to FTLD sub-type: semantic PPA, nonfluent PPA and bvFTD. FTLD patients presented impairment in the visuospatial and executive skills required to perform artistic tasks. We demonstrated that the application of the instrument as a complimentary method for assessing cognitive skills in this group of patients is possible. Further studies addressing larger and more homogeneous samples of FTLD patients as well as other dementias are warranted.

Performance of patients with frontotemporal lobar degeneration on artistic tasks: A pilot study

PubMed Central

Anauate, Maria Cristina; Bahia, Valéria Santoro; Nitrini, Ricardo; Radanovic, Marcia

2014-01-01

Several studies have addressed visuospatial and executive skills in artistic activities in Frontotemporal Lobar Degeneration (FTLD) and Alzheimer's disease (AD). Objective To investigate the performance of FTLD patients compared to controls on two artistic tasks. Methods Four FTLD patients with mean age of 57 (8.7) years and schooling of 12.2 (4.5) years plus 10 controls with mean age of 62.9 (8.6) years and schooling of 12.3 (4.6) years, were assessed using the Lowenstein Occupational Therapy Cognitive Assessment (LOTCA) and by a three-stage artistic protocol including visual observation, copying and collage, based on a Sisley painting. Results FTLD patients had lower scores than controls on Visuospatial Perception, Copy, Collage, Examiner's Observation, and Total, showing distinct patterns of performance according to FTLD sub-type: semantic PPA, nonfluent PPA and bvFTD. Conclusion FTLD patients presented impairment in the visuospatial and executive skills required to perform artistic tasks. We demonstrated that the application of the instrument as a complimentary method for assessing cognitive skills in this group of patients is possible. Further studies addressing larger and more homogeneous samples of FTLD patients as well as other dementias are warranted. PMID:29213882

Clinical features and multidisciplinary approaches to dementia care

PubMed Central

Grand, Jacob HG; Caspar, Sienna; MacDonald, Stuart WS

2011-01-01

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

Individual Patient Diagnosis of AD and FTD via High-Dimensional Pattern Classification of MRI

PubMed Central

Davatzikos, C.; Resnick, S. M.; Wu, X.; Parmpi, P.; Clark, C. M.

2008-01-01

The purpose of this study is to determine the diagnostic accuracy of MRI-based high-dimensional pattern classification in differentiating between patients with Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), and healthy controls, on an individual patient basis. MRI scans of 37 patients with AD and 37 age-matched cognitively normal elderly individuals, as well as 12 patients with FTD and 12 age-matched cognitively normal elderly individuals, were analyzed using voxel-based analysis and high-dimensional pattern classification. Diagnostic sensitivity and specificity of spatial patterns of regional brain atrophy found to be characteristic of AD and FTD were determined via cross-validation and via split-sample methods. Complex spatial patterns of relatively reduced brain volumes were identified, including temporal, orbitofrontal, parietal and cingulate regions, which were predominantly characteristic of either AD or FTD. These patterns provided 100% diagnostic accuracy, when used to separate AD or FTD from healthy controls. The ability to correctly distinguish AD from FTD averaged 84.3%. All estimates of diagnostic accuracy were determined via cross-validation. In conclusion, AD- and FTD-specific patterns of brain atrophy can be detected with high accuracy using high-dimensional pattern classification of MRI scans obtained in a typical clinical setting. PMID:18474436

Drawing Disorders in Alzheimer's Disease and Other Forms of Dementia.

PubMed

Trojano, Luigi; Gainotti, Guido

2016-04-21

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.

The Modified Frontal Behavioral Inventory (FBI-mod) for Patients with Frontotemporal Lobar Degeneration, Alzheimer's Disease, and Mild Cognitive Impairment.

PubMed

Suhonen, Noora-Maria; Hallikainen, Ilona; Hänninen, Tuomo; Jokelainen, Jari; Krüger, Johanna; Hall, Anette; Pikkarainen, Maria; Soininen, Hilkka; Remes, Anne M

2017-01-01

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.

Functional Network Disruption in the Degenerative Dementias

PubMed Central

Pievani, Michela; de Haan, Willem; Wu, Tao; Seeley, William W; Frisoni, Giovanni B

2011-01-01

Despite considerable advances toward understanding the molecular pathophysiology of the neurodegenerative dementias, the mechanisms linking molecular changes to neuropathology and the latter to clinical symptoms remain largely obscure. Connectivity is a distinctive feature of the brain and the integrity of functional network dynamics is critical for normal functioning. A better understanding of network disruption in the neurodegenerative dementias may help bridge the gap between molecular changes, pathology and symptoms. Recent findings on functional network disruption as assessed with “resting-state” or intrinsic connectivity fMRI and EEG/MEG have shown distinct patterns of network disruption across the major neurodegenerative diseases. These network abnormalities are relatively specific to the clinical syndromes, and in Alzheimer's disease and frontotemporal dementia network disruption tracks the pattern of pathological changes. These findings may have a practical impact on diagnostic accuracy, allowing earlier detection of neurodegenerative diseases even at the pre-symptomatic stage, and tracking of disease progression. PMID:21778116

Medical Management of Frontotemporal Dementias: The Importance of the Caregiver in Symptom Assessment and Guidance of Treatment Strategies

PubMed Central

2011-01-01

There are no currently Food and Drug Administration-approved or proven off-label treatments for the frontotemporal dementias (FTD). Clinicians, care-givers, and patients struggle regularly to find therapeutic regimens that can alleviate the problematic behavioral and cognitive symptoms associated with these devastating conditions. Success is “hit or miss” and the lessons learned are largely anecdotal to date. Drug discovery in this area has been largely hampered by the heterogeneous clinical presentations and pathological phenotypes of disease that represent significant obstacles to progress in this area. Biologically, plausible treatment strategies include the use of antidepressants (selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor and monoamine oxidase inhibitors), acetylcholinesterase inhibitors, N-methyl-D-aspartic acid antagonists, mood stabilizers, antipsychotics, stimulants, antihypertensives, and agents that may ameliorate the symptoms of parkinsonism, pseudobulbar affect, and motor neuron disease that can often coexist with FTD. These medications all carry potential risks as well as possible benefits for the person suffering from FTD, and a clear understanding of these factors is critical in selecting an appropriate therapeutic regimen to maximize cognition and daily functions, reduce behavioral symptoms, and alleviate caregiver burden in an individual patient. The role of the caregiver in tracking and reporting of symptoms and the effects of individual therapeutic interventions is pivotal in this process. This manuscript highlights the importance of establishing an effective therapeutic partnership between the physician and caregiver in the medical management of the person suffering from FTD. PMID:21647712

MicroRNA-29b Regulates the Expression Level of Human Progranulin, a Secreted Glycoprotein Implicated in Frontotemporal Dementia

PubMed Central

Jiao, Jian; Herl, Lauren D.; Farese, Robert V.; Gao, Fen-Biao

2010-01-01

Progranulin deficiency is thought to cause some forms of frontotemporal dementia (FTD), a major early-onset age-dependent neurodegenerative disease. How progranulin (PGRN) expression is regulated is largely unknown. We identified an evolutionarily conserved binding site for microRNA-29b (miR-29b) in the 3′ untranslated region (3′UTR) of the human PGRN (hPGRN) mRNA. miR-29b downregulates the expression of luciferase through hPGRN or mouse PGRN (mPGRN) 3′UTRs, and the regulation was abolished by mutations in the miR-29b binding site. To examine the direct effect of manipulating endogenous miR-29b on hPGRN expression, we established a stable NIH3T3 cell line that expresses hPGRN under the control of the cytomegalovirus promoter. Ectopic expression of miR-29b decreased hPGRN expression at the both mRNA and protein levels. Conversely, knockdown of endogenous miR-29b with locked nucleic acid increased the production and secretion of hPGRN in NIH3T3 cells. Endogenous hPGRN in HEK 293 cells was also regulated by miR-29b. These findings identify miR-29b as a novel posttranscriptional regulator of PGRN expression, raising the possibility that miR-29b or other miRNAs might be targeted therapeutically to increase hPGRN levels in some FTD patients. PMID:20479936

Is the emotion recognition deficit associated with frontotemporal dementia caused by selective inattention to diagnostic facial features?

PubMed

Oliver, Lindsay D; Virani, Karim; Finger, Elizabeth C; Mitchell, Derek G V

2014-07-01

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

Frontotemporal lobar degeneration: current perspectives

PubMed Central

Riedl, Lina; Mackenzie, Ian R; Förstl, Hans; Kurz, Alexander; Diehl-Schmid, Janine

2014-01-01

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

Mental States in Moving Shapes: Distinct Cortical and Subcortical Contributions to Theory of Mind Impairments in Dementia.

PubMed

Synn, Artemis; Mothakunnel, Annu; Kumfor, Fiona; Chen, Yu; Piguet, Olivier; Hodges, John R; Irish, Muireann

2018-01-01

Impaired capacity for Theory of Mind (ToM) represents one of the hallmark features of the behavioral variant of frontotemporal dementia (bvFTD) and is suggested to underpin an array of socioemotional disturbances characteristic of this disorder. In contrast, while social processing typically remains intact in Alzheimer's disease (AD), the cognitive loading of socioemotional tasks may adversely impact mentalizing performance in AD. Here, we employed the Frith-Happé animations as a dynamic on-line assessment of mentalizing capacity with reduced incidental task demands in 18 bvFTD, 18 AD, and 25 age-matched Controls. Participants viewed silent animations in which geometric shapes interact in Random, Goal-Directed, and ToM conditions. An exclusive deficit in ToM classification was observed in bvFTD relative to Controls, while AD patients were impaired in the accurate classification of both Random and ToM trials. Correlation analyses revealed robust associations between ToM deficits and carer ratings of affective empathy disruption in bvFTD, and with episodic memory dysfunction in AD. Voxel-based morphometry analyses further identified dissociable neural correlates contingent on patient group. A distributed network of medial prefrontal, frontoinsular, striatal, lateral temporal, and parietal regions were implicated in the bvFTD group, whereas the right hippocampus correlated with task performance in AD. Notably, subregions of the cerebellum, including lobules I-IV and V, bilaterally were implicated in task performance irrespective of patient group. Our findings reveal new insights into the mechanisms potentially mediating ToM disruption in dementia syndromes, and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated.

Parsing cognitive and emotional empathy deficits for negative and positive stimuli in frontotemporal dementia.

PubMed

Oliver, Lindsay D; Mitchell, Derek G V; Dziobek, Isabel; MacKinley, Julia; Coleman, Kristy; Rankin, Katherine P; Finger, Elizabeth C

2015-01-01

Behavioural variant frontotemporal dementia (bvFTD) is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe atrophy primarily affecting social cognition and emotion, including loss of empathy. Many consider empathy to be a multidimensional construct, including cognitive empathy (the ability to adopt and understand another's perspective) and emotional empathy (the capacity to share another's emotional experience). Cognitive and emotional empathy deficits have been associated with bvFTD; however, little is known regarding the performance of patients with bvFTD on behavioural measures of emotional empathy, and whether empathic responses differ for negative versus positive stimuli. 24 patients with bvFTD and 24 healthy controls completed the Multifaceted Empathy Test (MET; Dziobek et al., 2008), a performance-based task that taps both cognitive and emotional facets of empathy, and allows for the discrimination of responses to negative versus positive realistic images. MET scores were also compared with caregiver ratings of patient behaviour on the Interpersonal Reactivity Index, which assesses patients' everyday demonstrations of perspective taking and empathic concern. Patients with bvFTD were less accurate than controls at inferring mental states for negative and positive stimuli. They also demonstrated lower levels of shared emotional experience, more positive emotional reactions, and diminished arousal to negative social stimuli relative to controls. Patients showed reduced emotional reactions to negative non-social stimuli as well. Lastly, the MET and IRI measures of emotional empathy were found to be significantly correlated within the bvFTD group. The results suggest that patients with bvFTD show a global deficit in cognitive empathy, and deficient emotional empathy for negative, but not positive, experiences. Further, a generalized emotional processing impairment for negative stimuli was observed, which could contribute to the

ADNP: in search for molecular mechanisms and innovative therapeutic strategies for frontotemporal degeneration

PubMed Central

Gozes, Illana; Ivashko-Pachima, Yanina

2015-01-01

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

Cardiovascular risk factors and dementia.

PubMed

Fillit, Howard; Nash, David T; Rundek, Tatjana; Zuckerman, Andrea

2008-06-01

Dementias, such as Alzheimer's disease (AD) and vascular dementia, are disorders of aging populations and represent a significant economic burden. Evidence is accumulating to suggest that cardiovascular disease (CVD) risk factors may be instrumental in the development of dementia. The goal of this review was to discuss the relationship between specific CVD risk factors and dementia and how current treatment strategies for dementia should focus on reducing CVD risks. We conducted a review of the literature for the simultaneous presence of 2 major topics, cardiovascular risk factors and dementia (eg, AD). Special emphasis was placed on clinical outcome studies examining the effects of treatments of pharmacologically modifiable CVD risk factors on dementia and cognitive impairment. Lifestyle risk factors for CVD, such as obesity, lack of exercise, smoking, and certain psychosocial factors, have been associated with an increased risk of cognitive decline and dementia. Some evidence suggests that effectively managing these factors may prevent cognitive decline/dementia. Randomized, placebo-controlled trials of antihypertensive medications have found that such therapy may reduce the risk of cognitive decline, and limited data suggest a benefit for patients with AD. Some small open-label and randomized clinical trials of statins have observed positive effects on cognitive function; larger studies of statins in patients with AD are ongoing. Although more research is needed, current evidence indicates an association between CVD risk factors--such as hypertension, dyslipidemia, and diabetes mellitus--and cognitive decline/dementia. From a clinical perspective, these data further support the rationale for physicians to provide effective management of CVD risk factors and for patients to be compliant with such recommendations to possibly prevent cognitive decline/dementia.

Assessment and Reporting of Driving Fitness in Patients with Dementia in Clinical Practice: Data from SveDem, the Swedish Dementia Registry.

PubMed

Lovas, Joel; Fereshtehnejad, Seyed-Mohammad; Cermakova, Pavla; Lundberg, Catarina; Johansson, Björn; Johansson, Kurt; Winblad, Bengt; Eriksdotter, Maria; Religa, Dorota

2016-05-05

Driving constitutes a very important aspect of daily life and is dependent on cognitive functions such as attention, visuo-spatial skills and memory, which are often compromised in dementia. Therefore, the driving fitness of patients with dementia needs to be addressed by physicians and those that are deemed unfit should not be allowed to continue driving. We aimed at investigating to what extent physicians assess driving fitness in dementia patients and determinant factors for revoking of their licenses. This study includes 15113 patients with newly diagnosed dementia and driver's license registered in the Swedish Dementia Registry (SveDem). The main outcomes were reporting to the licensing authority and making an agreement about driving eligibility with the patients. Physicians had not taken any action in 16% of dementia patients, whereas 9% were reported to the authority to have their licenses revoked. Males (OR = 3.04), those with an MMSE score between 20-24 (OR = 1.35) and 10-19 (OR = 1.50), patients with frontotemporal (OR = 3.09) and vascular dementia (OR = 1.26) were more likely to be reported to the authority. For the majority of patients with dementia, driving fitness was assessed. Nevertheless, physicians did not address the issue in a sizeable proportion of dementia patients. Type of dementia, cognitive status, age, sex and burden of comorbidities are independent factors associated with the assessment of driving fitness in patients with dementia. Increased knowledge on how these factors relate to road safety may pave the way for more specific guidelines addressing the issue of driving in patients with dementia.

The neurologist facing pain in dementia.

PubMed

Álvaro González, Luis Carlos

2015-01-01

Ageing, a common background in dementia, is usually associated with painful disorders. Nevertheless, the use of analgesics is limited due to poor communication. On the other hand, dementia lesions are placed in the nociceptive pathways. For this reason, the painful experience becomes different and distinctive for every lesional type. The lateral nociceptive pathway (lateral thalamic nuclei and primary parietal cortex), which is in charge of the primary pain perception, is preserved in dementia. Thereafter, the shear painful perception, including pain intensity and threshold, remains unmodified. Distinctly, the medial pain pathways are affected by dementia lesions. In this pathway are included: the intralaminar thalamic nuclei, the pons (locus ceruleus:LC), the mesencephalon (periaacueductal grey substance: PGS), the hypothalamus (paraventricular nuclei, mamilary tuberculum) and different areas of the parietal (primary, secondary, operculum), temporal (amigdala, hypoccampus) and frontal (anterior cingular: ACC). As a consequence, the features of pain executed by these areas will be compromised: the cognitive assessment, the mood and emotion inherent to pain, the pain memory or the autonomic responses are modified in dementia. Specifically, in Alzheimer's disease (AD) there is a reduction in the anticipatory and avoidance responses and also a flattening of the autonomic responses. These are essentially secondary to the degenerative changes in the medial temporal (pain memory) and ACC (cognitive and mood aspects) areas. In vascular dementias, there is a cortico-subcortical deafferentation secondary to the white matter lesions. The consequence is the presence of hyperpathy and hyperalgesia. In the frontotemporal dementias, there is a reduction in pain expressivity. It is linked to the lesions in the orbitofrontal and anterior temporal areas, which are responsible of the emotional aspects of pain. In Parkinson's disease, painful conditions are a common characteristic

White matter tract signatures of impaired social cognition in frontotemporal lobar degeneration

PubMed Central

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.

2015-01-01

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

Orbitofrontal and limbic signatures of empathic concern and intentional harm in the behavioral variant frontotemporal dementia.

PubMed

Baez, Sandra; Morales, Juan P; Slachevsky, Andrea; Torralva, Teresa; Matus, Cristian; Manes, Facundo; Ibanez, Agustin

2016-02-01

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

No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy.

PubMed

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

2014-08-01

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. Copyright © 2014 Elsevier Inc. All rights reserved.

Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale

PubMed Central

Bickart, Kevin C; Brickhouse, Michael; Negreira, Alyson; Sapolsky, Daisy

2015-01-01

Patients with frontotemporal dementia (FTD) often exhibit prominent, early and progressive impairments in social behaviour. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview, which grades the types and severity of social behavioural symptoms in seven domains. In 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others’ social and emotional behaviour. Our findings underscore observations that FTD is associated with heterogeneous social symptoms that can be understood in a refined manner by measuring impairments in component processes subserved by dissociable neural networks. Furthermore, these findings support the validity of the SIRS as an instrument to measure the social symptoms of patients with FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in natural history studies and in clinical trials of putative interventions to improve social functioning. PMID:24133285

Urethral masturbation and sexual disinhibition in dementia: a case report.

PubMed

Rosenthal, Michal; Berkman, Pinhas; Shapira, Adi; Gil, Israel; Abramovitz, Jancu

2003-01-01

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.

[Regional network for patients with dementia--carrying out Kumamoto model for dementia].

PubMed

Ikeda, Manabu

2014-01-01

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

Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis.

PubMed

Ferrari, Raffaele; Forabosco, Paola; Vandrovcova, Jana; Botía, Juan A; Guelfi, Sebastian; Warren, Jason D; Momeni, Parastoo; Weale, Michael E; Ryten, Mina; Hardy, John

2016-02-24

In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes (MAPT, GRN, CHMP2B, CTSC, HLA-DRA, TMEM106B, C9orf72, VCP, UBQLN2, OPTN, TARDBP and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products. Gene co-expression networks revealed that several FTD-genes (such as MAPT and GRN, CTSC and HLA-DRA, TMEM106B, and C9orf72, VCP, UBQLN2 and OPTN) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling (MAPT and GRN modules); ii) immune and lysosomal processes (CTSC and HLA-DRA modules), and; iii) protein meta/catabolism (C9orf72, VCP, UBQLN2 and OPTN, and TMEM106B modules). PPI analysis supported the results of the functional annotation and pathway analyses. This work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD

Neurodegenerative dementias: From MR Physics lab to assessment room

NASA Astrophysics Data System (ADS)

Bruno, S. D.; Cercignani, M.; Wheeler-Kingshott, C. A. M.

2012-11-01

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.

Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study.

PubMed

Robinson, John L; Corrada, Maria M; Kovacs, Gabor G; Dominique, Myrna; Caswell, Carrie; Xie, Sharon X; Lee, Virginia M-Y; Kawas, Claudia H; Trojanowski, John Q

2018-06-18

The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to

The Cambridge Behavioural Inventory revised.

PubMed

Wear, Helen J; Wedderburn, Catherine J; Mioshi, Eneida; Williams-Gray, Caroline H; Mason, Sarah L; Barker, Roger A; Hodges, John R

2008-01-01

Neurobehavioural and psychiatric symptoms are common in a range of neurodegenerative disorders with distinct profiles which are helpful in the diagnosis and monitoring of these disorders. The Cambridge Behavioural Inventory (CBI) has been shown to distinguish frontotemporal dementia (FTD), Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD), but it is lengthy. To develop a shorter version of the 81 item CBI. CBI data from 450 participants with behavioural variant frontotemporal dementia (bv-FTD) (64), AD (96), PD (215) and HD (75) were analysed using Principal Components Analysis and measures of internal consistency (Cronbach alpha). A reduced 45-item questionnaire was developed. The instrument identified distinct behavioural profiles and performed as well as the original version. A shorter (45 item) version of the CBI is capable of differentiating bv-FTD and AD from PD and HD. It may be useful in delineating the type and extent of problems in these disorders as well as monitoring therapeutic interventions.

The Cambridge Behavioural Inventory revised

PubMed Central

Wear, Helen J.; Wedderburn, Catherine J.; Mioshi, Eneida; Williams-Gray, Caroline H.; Mason, Sarah L.; Barker, Roger A.; Hodges, John R.

2008-01-01

Neurobehavioural and psychiatric symptoms are common in a range of neurodegenerative disorders with distinct profiles which are helpful in the diagnosis and monitoring of these disorders. The Cambridge Behavioural Inventory (CBI) has been shown to distinguish frontotemporal dementia (FTD), Alzheimer’s disease (AD), Huntington’s disease (HD) and Parkinson’s disease (PD), but it is lengthy. Objective To develop a shorter version of the 81 item CBI. Methods CBI data from 450 participants with behavioural variant frontotemporal dementia (bv-FTD) (64), AD (96), PD (215) and HD (75) were analysed using Principal Components Analysis and measures of internal consistency (Cronbach alpha). Results A reduced 45-item questionnaire was developed. The instrument identified distinct behavioural profiles and performed as well as the original version. Conclusions A shorter (45 item) version of the CBI is capable of differentiating bv-FTD and AD from PD and HD. It may be useful in delineating the type and extent of problems in these disorders as well as monitoring therapeutic interventions. PMID:29213551

Improved Diagnostic Accuracy of SPECT Through Statistical Analysis and the Detection of Hot Spots at the Primary Sensorimotor Area for the Diagnosis of Alzheimer Disease in a Community-Based Study: "The Osaki-Tajiri Project".

PubMed

Kaneta, Tomohiro; Nakatsuka, Masahiro; Nakamura, Kei; Seki, Takashi; Yamaguchi, Satoshi; Tsuboi, Masahiro; Meguro, Kenichi

2016-01-01

SPECT is an important diagnostic tool for dementia. Recently, statistical analysis of SPECT has been commonly used for dementia research. In this study, we evaluated the accuracy of visual SPECT evaluation and/or statistical analysis for the diagnosis (Dx) of Alzheimer disease (AD) and other forms of dementia in our community-based study "The Osaki-Tajiri Project." Eighty-nine consecutive outpatients with dementia were enrolled and underwent brain perfusion SPECT with 99mTc-ECD. Diagnostic accuracy of SPECT was tested using 3 methods: visual inspection (SPECT Dx), automated diagnostic tool using statistical analysis with easy Z-score imaging system (eZIS Dx), and visual inspection plus eZIS (integrated Dx). Integrated Dx showed the highest sensitivity, specificity, and accuracy, whereas eZIS was the second most accurate method. We also observed that a higher than expected rate of SPECT images indicated false-negative cases of AD. Among these, 50% showed hypofrontality and were diagnosed as frontotemporal lobar degeneration. These cases typically showed regional "hot spots" in the primary sensorimotor cortex (ie, a sensorimotor hot spot sign), which we determined were associated with AD rather than frontotemporal lobar degeneration. We concluded that the diagnostic abilities were improved by the integrated use of visual assessment and statistical analysis. In addition, the detection of a sensorimotor hot spot sign was useful to detect AD when hypofrontality is present and improved the ability to properly diagnose AD.

Vascular lesions in mixed dementia, vascular dementia, and Alzheimer disease with cerebrovascular disease: the Kurihara Project.

PubMed

Meguro, Kenichi; Tanaka, Naofumi; Nakatsuka, Masahiro; Nakamura, Kei; Satoh, Masayuki

2012-11-15

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. Copyright © 2012 Elsevier B.V. All rights reserved.

Music therapy modulates fronto-temporal activity in rest-EEG in depressed clients.

PubMed

Fachner, Jörg; Gold, Christian; Erkkilä, Jaakko

2013-04-01

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.

Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer's disease and frontotemporal lobar degeneration: a real-time PCR study.

PubMed

Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica

2013-12-01

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.

Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer's disease and Frontotemporal lobar degeneration: A Real-time PCR study.

PubMed

Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica

2013-10-26

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. © 2013.

Depressive symptoms and risk of dementia

PubMed Central

Saczynski, J.S.; Beiser, A.; Seshadri, S.; Auerbach, S.; Wolf, P.A.; Au, R.

2010-01-01

Objectives: Depression may be associated with an increased risk for dementia, although results from population-based samples have been inconsistent. We examined the association between depressive symptoms and incident dementia over a 17-year follow-up period. Methods: In 949 Framingham original cohort participants (63.6% women, mean age = 79), depressive symptoms were assessed at baseline (1990-1994) using the 60-point Center for Epidemiologic Studies Depression Scale (CES-D). A cutpoint of ≥16 was used to define depression, which was present in 13.2% of the sample. Cox proportional hazards models adjusting for age, sex, education, homocysteine, and APOE ε4 examined the association between baseline depressive symptoms and the risk of dementia and Alzheimer disease (AD). Results: During the 17-year follow-up period, 164 participants developed dementia; 136 of these cases were AD. A total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. Depressed participants (CES-D ≥16) had more than a 50% increased risk for dementia (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.04-2.84, p = 0.035) and AD (HR 1.76, 95% CI 1.03-3.01, p = 0.039). Results were similar when we included subjects taking antidepressant medications as depressed. For each 10-point increase on the CES-D, there was significant increase in the risk of dementia (HR 1.46, 95% CI 1.18-1.79, p < 0.001) and AD (HR 1.39, 95% CI 1.11-1.75, p = 0.005). Results were similar when we excluded persons with possible mild cognitive impairment. Conclusions: Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up. GLOSSARY AD = Alzheimer disease; CDR = Clinical Dementia Rating; CES-D = Center for Epidemiologic Studies Depression Scale; CI = confidence interval; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HR = hazard ratio; MCI = mild

Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by GRN Mutations

PubMed Central

Taylor, Georgia; Deng, Qiudong

2017-01-01

Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain. PGRN is trafficked to the lysosome where its functional role is unknown. PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD-GRN mutation carriers. Here, we report the identification and characterization of antibodies that reliably detect several human GRNs by immunoblot and immunocytochemistry. Using these tools, we find that endogenous GRNs are present within multiple cell lines and are constitutively produced. Further, extracellular PGRN is endocytosed and rapidly processed into stable GRNs within lysosomes. Processing of PGRN into GRNs is conserved between humans and mice and is modulated by sortilin expression and mediated by cysteine proteases (i.e. cathpesin L). Induced lysosome dysfunction caused by alkalizing agents or increased expression of transmembrane protein 106B (TMEM106B) inhibit processing of PGRN into GRNs. Finally, we find that multiple GRNs are haploinsufficient in primary fibroblasts and cortical brain tissue from FTD-GRN patients. Taken together, our findings raise the interesting possibility that GRNs carry out critical lysosomal functions and that loss of GRNs should be explored as an initiating factor in lysosomal dysfunction and neurodegeneration caused by GRN mutations. PMID:28828399

The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy.

PubMed

Hogg, Marion; Grujic, Zoran M; Baker, Matt; Demirci, Serpil; Guillozet, Angela L; Sweet, Alison P; Herzog, Laura L; Weintraub, Sandra; Mesulam, M-Marsel; LaPointe, Nichole E; Gamblin, T C; Berry, Robert W; Binder, Lester I; de Silva, Rohan; Lees, Andrew; Espinoza, Marisol; Davies, Peter; Grover, Andrew; Sahara, Naruhiko; Ishizawa, Takashi; Dickson, Dennis; Yen, Shu-Hui; Hutton, Michael; Bigio, Eileen H

2003-10-01

We report a case of rapidly progressive frontotemporal dementia presenting at age 33 years. At autopsy there was severe atrophy of the frontal and temporal lobes. Tau-positive Pick bodies, which ultrastructurally were composed of straight filaments, were present, accompanied by severe neuronal loss and gliosis. RD3, a tau antibody specific for the three-repeat (3R) isoforms, labeled the Pick bodies. ET3, a four-repeat (4R) isoform-specific tau antibody, did not label Pick bodies, but highlighted rare astrocytes, and threads in white matter bundles in the corpus striatum. Analysis of the tau gene revealed an L266V mutation in exon 9. Analysis of brain tissue from this case revealed elevated levels of exon 10+ tau RNA and soluble 4R tau. However, both 3R and 4R isoforms were present in sarkosyl-insoluble tau fractions with a predominance of the shortest 3R isoform. The L266V mutation is associated with decreased rate and extent of tau-induced microtubule assembly, and a 3R isoform-specific increase in tau self assembly as measured by an in vitro assay. Combined, these data indicate that L266V is a pathogenic tau mutation that is associated with Pick-like pathology. In addition, the results of the RD3 and ET3 immunostains clearly explain for the first time the presence of both 3R and 4R tau isoforms in preparations of insoluble tau from some Pick's disease cases.

Psychometric properties of the Spanish QoL-AD with institutionalized dementia patients and their family caregivers in Spain.

PubMed

León-Salas, B; Logsdon, R G; Olazarán, J; Martínez-Martín, P; The Msu-Adru

2011-08-01

To evaluate the psychometric attributes of the Spanish version of the Quality of Life-Alzheimer's Disease Scale (QoL-AD) in institutionalized patients and family caregivers in Spain. 101 patients (88.1% women; mean age, 83.2  ±  6.3) with Alzheimer's disease (AD) (n = 82) and mixed dementia (n = 19) and their closest family caregivers. Patient-related variables included severity of dementia, cognitive status, perceived general health, quality of life, behavior, apathy, depression, and functional status. QoL-AD acceptability, reliability, and construct validity were analyzed. The mean Mini-Mental State Examination (MMSE) score was 7.2  ±  6.1 and Global Deterioration Scale was: stage four (4%); five (21.2%); six (34.3%); and seven (40.4%). Both, QoL-AD patient version (QoL-ADp) (n = 40; MMSE = 12.0  ±  4.5) and QoL-AD caregiver version (QoL-ADc) (n = 101) lacked significant floor and ceiling effects and the Cronbach α index was 0.90 and 0.86, respectively. The corrected item-total correlation was 0.11-0.68 (QoL-ADc) and 0.28-0.84 (QoL-ADp). Stability was satisfactory for QoL-ADp (intraclass correlation coefficient [ICC]=0.83) but low for QoL-ADc (ICC = 0.51); the standard error of measurement was 2.72 and 4.69. Construct validity was moderate/high for QoL-ADc (QUALID=-0.43; EQ-5D = 0.65), but lower for QoL-ADp. No significant correlations were observed between QoL-ADp and patient variables or QoL-ADc. A low to high association (r = 0.18-0.55) was obtained between QoL-ADc and patient-related measures of neuropsychiatric, function, and cognitive status. Differences in their psychometric attributes, and discrepancy between them, were found for QoL-ADp and QoL-ADc. In patients with AD and advanced dementia, the QoL perceived by the patient could be based on a construct that is different from the traditional QoL construct.

Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer's disease and frontotemporal lobar degeneration.

PubMed

Oeckl, Patrick; Steinacker, Petra; von Arnim, Christine A F; Straub, Sarah; Nagl, Magdalena; Feneberg, Emily; Weishaupt, Jochen H; Ludolph, Albert C; Otto, Markus

2014-11-07

The impairment of the ubiquitin-proteasome system (UPS) is thought to be an early event in neurodegeneration, and monitoring UPS alterations might serve as a disease biomarker. Our aim was to establish an alternate method to antibody-based assays for the selective measurement of free monoubiquitin in cerebrospinal fluid (CSF). Free monoubiquitin was measured with liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MS/MS) in CSF of patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), behavioral variant of frontotemporal dementia (bvFTD), Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD), primary progressive aphasia (PPA), and progressive supranuclear palsy (PSP). The LC-MS/MS method showed excellent intra- and interassay precision (4.4-7.4% and 4.9-10.3%) and accuracy (100-107% and 100-106%). CSF ubiquitin concentration was increased compared with that of controls (33.0 ± 9.7 ng/mL) in AD (47.5 ± 13.1 ng/mL, p < 0.05) and CJD patients (171.5 ± 103.5 ng/mL, p < 0.001) but not in other neurodegenerative diseases. Receiver operating characteristic curve (ROC) analysis of AD vs control patients revealed an area under the curve (AUC) of 0.832, and the specificity and sensitivity were 75 and 75%, respectively. ROC analysis of AD and FTLD patients yielded an AUC of 0.776, and the specificity and sensitivity were 53 and 100%, respectively. In conclusion, our LC-MS/MS method may facilitate ubiquitin determination to a broader community and might help to discriminate AD, CJD, and FTLD patients.

Assessment of socioemotional processes facilitates the distinction between frontotemporal lobar degeneration and Alzheimer's disease.

PubMed

Narme, Pauline; Mouras, Harold; Roussel, Martine; Devendeville, Agnès; Godefroy, Olivier

2013-01-01

We explored the value of a battery of socioemotional tasks for differentiating between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Patients with FTLD (n = 13) or AD (n = 13) and healthy controls (n = 26) underwent a neuropsychological assessment and the socioemotional battery (an empathy questionnaire, an emotion recognition task, and theory of mind tasks). Socioemotional processes were markedly impaired in FTLD but relatively unaffected in mild AD. The computed Socioemotional Index discriminated more accurately between FTLD from AD than behavioral and executive assessments did. Furthermore, impairments in socioemotional processes were correlated with indifference to others.

Free and Cued Selective Reminding Identifies Very Mild Dementia in Primary Care

PubMed Central

Grober, Ellen; Sanders, Amy E.; Hall, Charles; Lipton, Richard B.

2010-01-01

The Free and Cued Selective Reminding Test (FCSRT) is used widely to identify very mild dementia; three alternative scoring procedures have been proposed based on free recall, total recall, and cue efficiency. We compared the predictive validity of these scoring procedures for the identification of very mild prevalent dementia (CDR=0.5), of incident dementia and for distinguishing AD and nonAD dementias. We tested 244 elderly African American and Caucasian primary care patients at 18 month intervals using a screening neuropsychological battery that included the FCSRT and a comprehensive diagnostic neuropsychological battery. Median follow-up was 2.6 years. Dementia diagnoses were assigned using standard criteria without access to the results of the screening battery. There were 50 prevalent and 28 incident dementia cases. At scores selected to provide specificities of 90%, free recall was more sensitive to incident and prevalent dementia than the other two measures. Patients with impaired free recall were 15 times more likely to have a prevalent dementia and their risk of future dementia was four times higher than patients with intact free recall. Neither race nor education affected prediction though older patients were at increased risk of future dementia. Total recall was more impaired in AD dementia than in nonAD dementias. The results indicate that using the FCSRT, free recall is best measure for detecting prevalent dementia and predicting future dementia. Total recall impairment supports the diagnosis of AD rather than nonAD dementia. PMID:20683186

Dementia in MS complicated by coexistent Alzheimer disease

PubMed Central

Flanagan, Eoin P.; Knopman, David S.

2014-01-01

Summary Distinguishing dementia due to multiple sclerosis (MS) from that of an accompanying neurodegenerative dementia coexisting with MS has been difficult. The recent introduction of Alzheimer disease (AD) biomarkers of amyloid-β and neuronal degeneration has improved diagnosis of AD premortem. We describe 3 patients with MS with coexisting AD, 1 diagnosed at autopsy before AD biomarkers were available and 2 diagnosed premortem by decreased CSF amyloid-β1-42/tau index, MRI, and 18F-flourodeoxyglucose-PET patterns. AD biomarkers may be of diagnostic value in selected patients with severe dementia and MS. PMID:25110620

Dementia friendly, dementia capable, and dementia positive: concepts to prepare for the future.

PubMed

Lin, Shih-Yin; Lewis, Frances Marcus

2015-04-01

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. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Frontotemporal dementia with Pick-type histology associated with Q336R mutation in the tau gene.

PubMed

Pickering-Brown, S M; Baker, M; Nonaka, T; Ikeda, K; Sharma, S; Mackenzie, J; Simpson, S A; Moore, J W; Snowden, J S; de Silva, R; Revesz, T; Hasegawa, M; Hutton, M; Mann, D M A

2004-06-01

In this report, we describe the clinical and neuropathological features of a case of familial frontotemporal dementia (FTD), with onset at 58 years of age and disease duration of 10 years, associated with a novel mutation, Q336R, in the tau gene (tau). In vitro studies concerning the properties of tau proteins bearing this mutation, with respect to microtubule assembly and tau filament aggregation, are reported. Clinically, the patient showed alterations in memory, language and executive functions and marked behavioural change consistent with FTD, although the extent of memory impairment was more than is characteristic of FTD. At autopsy, there was degeneration of the frontal and temporal lobes associated with the presence of hyperphosphorylated tau proteins in swollen (Pick) cells and intraneuronal inclusions (Pick bodies). By immunohistochemistry, the Pick bodies contained both 3-repeat and 4-repeat tau proteins although, because no fresh tissues were available for analysis, the exact isoform composition of the aggregated tau proteins could not be determined. Neurons within frontal cortex contained neurofibrillary tangle-like structures, comprising both straight and twisted tubules, or Pick bodies in which the filaments were short and randomly orientated. In vitro, and in common with other tau missense mutations, Q336R caused an increase in tau fibrillogenesis. However, in contrast to most other tau missense mutations, Q336R increased, not decreased, the ability of mutant tau to promote microtubule assembly. Nonetheless, this latter functional change may likewise be detrimental to neuronal function by inducing a compensatory phosphorylation that may yield increased intracellular hyperphosphorylated tau species that are also liable to fibrillize. We believe the mutation is indeed pathogenic and disease causing and not simply a coincidental rare and benign polymorphism. Since this mutation is segregating with the FTD clinical and neuropathological phenotype, it has

Comparison of arterial spin labeling registration strategies in the multi-center GENetic frontotemporal dementia initiative (GENFI).

PubMed

Mutsaerts, Henri J M M; Petr, Jan; Thomas, David L; De Vita, Enrico; Cash, David M; van Osch, Matthias J P; Golay, Xavier; Groot, Paul F C; Ourselin, Sebastien; van Swieten, John; Laforce, Robert; Tagliavini, Fabrizio; Borroni, Barbara; Galimberti, Daniela; Rowe, James B; Graff, Caroline; Pizzini, Francesca B; Finger, Elizabeth; Sorbi, Sandro; Castelo Branco, Miguel; Rohrer, Jonathan D; Masellis, Mario; MacIntosh, Bradley J

2018-01-01

To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:131-140. © 2017 International Society for Magnetic Resonance in Medicine.

Statin Use, Incident Dementia and Alzheimer Disease in Elderly African Americans.

PubMed

Hendrie, Hugh C; Hake, Ann; Lane, Kathleen; Purnell, Christianna; Unverzagt, Frederick; Smith-Gamble, Valerie; Murrell, Jill; Ogunniyi, Adesola; Baiyewu, Olusegun; Callahan, Chris; Saykin, Andrew; Taylor, Stanley; Hall, Kathleen; Gao, Su

2015-08-07

To investigate the association between statin use, incident dementia, and Alzheimer disease (AD) in a prospective elderly African American cohort. Two stage design with a screening interview followed by a comprehensive in-home assessment conducted over an eight-year period. Diagnoses of incident AD and dementia were made by consensus. Statin use was collected at each evaluation. Measurements of low-density lipoprotein cholesterol (LDL), C-reactive protein (CRP) and APOE genotype were obtained from baseline blood samples. Logistic regression models were used to test the association of statin use on incident dementia and AD and its possible association with lipid and CRP levels. Indianapolis, Indiana. From an original cohort of 2629 participants, a subsample of 974 African Americans aged >70 years with normal cognition, at least one follow up evaluation, complete statin information, and biomarker availability were included. Incident dementia and incident AD. After controlling for age at diagnosis, sex, education level, presence of the APOE ε4 allele and history of stroke for the incident dementia model, baseline use of statins was associated with a significantly decreased risk of incident dementia (OR=.44, P=.029) and incident AD (OR=.40, P=.029). The significant effect of statin use on reduced AD risk and trend for dementia risk was found only for those participants who reported consistent use over the observational period (incident AD: P=.034; incident dementia: P=.061). Additional models found no significant interaction between baseline statin use, baseline LDL, or CRP level and incident dementia/AD. Consistent use of statin medications during eight years of follow-up resulted in significantly reduced risk for incident AD and a trend toward reduced risk for incident dementia.