Science.gov

Sample records for ad frontotemporal dementia

  1. Genetics of Frontotemporal Dementia.

    PubMed

    Olszewska, Diana A; Lonergan, Roisin; Fallon, Emer M; Lynch, Tim

    2016-12-01

    Frontotemporal dementia (FTD) is the second most common cause of dementia following Alzheimer's disease (AD). Between 20 and 50% of cases are familial. Mutations in MAPT, GRN and C9orf72 are found in 60% of familial FTD cases. C9orf72 mutations are the most common and account for 25%. Rarer mutations (<5%) occur in other genes such as VPC, CHMP2B, TARDP, FUS, ITM2B, TBK1 and TBP. The diagnosis is often challenging due to symptom overlap with AD and other conditions. We review the genetics, clinical presentations, neuroimaging, neuropathology, animal studies and therapeutic trials in FTD. We describe clinical scenarios including the original family with the tau stem loop mutation (+14) and also the recently discovered 'missing tau' mutation +15 that 'closed the loop' in 2015.

  2. Stereotypical movements and frontotemporal dementia.

    PubMed

    Mendez, Mario F; Shapira, Jill S; Miller, Bruce L

    2005-06-01

    Stereotypical movements are characteristic of autism or mental retardation but can also occur in patients with dementia, particularly frontotemporal dementia (FTD). In this study, we administered the Abnormal Involuntary Movement Scale (AIMS) to 18 patients with FTD and to 18 patients with the most common form of dementia, Alzheimer's disease (AD). The AIMS scores were gathered at the initial presentation of patients who had not received antipsychotic medications. Compared to the AD patients, the FTD patients had significantly more stereotypical movements, including frequent rubbing behaviors and some self-injurious acts. All the FTD patients with stereotypical movements had compulsive-like behaviors, suggesting a similar pathophysiologic cause, and most had a decrease in their stereotypical movements with the administration of sertraline, a serotonin selective reuptake inhibitor. (c) 2005 Movement Disorder Society.

  3. Psychosis in frontotemporal dementia.

    PubMed

    Shinagawa, Shunichiro; Nakajima, Shinichiro; Plitman, Eric; Graff-Guerrero, Ariel; Mimura, Masaru; Nakayama, Kazuhiko; Miller, Bruce L

    2014-01-01

    Frontotemporal dementia (FTD) is a neurodegenerative disorder, associated with a progressive decline in behavior caused by focal degeneration of the frontal lobes. Psychosis was an underestimated symptom of FTD, however, recent genetic research has revealed a high prevalence of psychosis in certain genetic groups. The primary objective of this work is to review the literature on psychosis in FTD and to propose directions for future research, with reference to findings on psychosis in schizophrenia. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included "frontotemporal dementia", "psychosis", "schizophreni*", "psychotic symptoms", "hallucinations", and "delusions", and it identified 122 articles. Results revealed: 1) prevalence is approximately 10%, 2) TDP-43 type B and FUS pathologies might have relatively high frequency of psychosis, 3) psychosis in FTD is higher with genetic mutations of C9ORF72 and GRN, 4) imaging researches did not achieve conclusive results, and 5) no treatment for psychosis in FTD is currently available. A limitation of this systematic review is that it includes a small number of studies specifically examining psychosis in FTD. It is suggested that a possible overlap exists between FTD and schizophrenia. This potential overlap indicates a vulnerability to psychosis due to brain systems and pathways shared by these disorders.

  4. Frontotemporal dementia: therapeutic interventions.

    PubMed

    Mendez, Mario F

    2009-01-01

    The management of frontotemporal dementia (FTD), a disorder characterized by varied behavioral symptoms, primarily involves the use of psychoactive medications. Although there are no approved treatments for the disorder, selective serontonin receptor inhibitors, such as sertraline, paroxetine, or fluoxetine, can decrease disinhibition-impulsivity, repetitive behaviors, and eating disorders in FTD. Low doses of trazodone or an atypical antipsychotic such as aripriprazole can also help manage significantly disturbed or agitated behavior. The acetylcholinesterase inhibitors used for patients with Alzheimer's disease have not had significant efficacy for patients with FTD, but memantine, another dementia medication, is under investigation for the treatment of this disorder. In addition to drug therapy, the nonpharmacological management of patients with FTD focuses on education, behavioral interventions, and care of the caregivers. Most recently, investigators have initiated steps toward rational drug therapy with the development of outcome measures for clinical drug trials in FTD and the characterization of treatment targets such tau protein or the TAR DNA-binding protein 43. This approach holds great promise for an eventual treatment for this devastating early-onset dementia. Copyright (c) 2009 S. Karger AG, Basel.

  5. Brain atrophy in frontotemporal dementia.

    PubMed Central

    Frisoni, G B; Beltramello, A; Geroldi, C; Weiss, C; Bianchetti, A; Trabucchi, M

    1996-01-01

    OBJECTIVES--To evaluate the pattern of regional brain atrophy in patients with frontotemporal dementia by comparing it with that in patients with Alzheimer's disease and normal controls. METHODS--Fourteen patients with frontotemporal dementia, 13 with moderate, and 33 with mild Alzheimer's disease, and 31 controls were studied. Atrophy was evaluated with linear measures in the anterior brain, medial temporal lobe, and hippocampal formation regions using MRI. RESULTS--Patients with frontotemporal dementia had greater atrophy in the anterior brain regions than patients with Alzheimer's disease or controls. Atrophy of the hippocampal formation, which best discriminates Alzheimer's disease from controls, was present also in patients with frontotemporal dementia. By contrast, atrophy of the medial temporal lobe, which is also present in Alzheimer's disease, was absent in frontotemporal dementia. CONCLUSION--A pattern of atrophy in the frontal lobes and hippocampal formation with sparing of the medial temporal lobe might be distinctive of frontotemporal dementia. Hippocampal involvement might not be specific for Alzheimer's disease and specific patterns of atrophy might be distinctive of some forms of degenerative dementia. Images PMID:8708683

  6. Treatment of Frontotemporal Dementia

    PubMed Central

    Boxer, Adam L.

    2016-01-01

    Opinion statement Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative diseases with heterogeneous clinical presentations and two predominant types of underlying neuropathology. FTD typically comprises three distinct clinical syndromes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA). FTD also frequently overlaps both clinically and neuropathologically with three other neurodegenerative syndromes: corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). Each syndrome can be associated with one or more underlying neuropathological diagnoses and are referred to as frontotemporal lobar degeneration (FTLD). Although the various FTD syndromes can substantially differ in terms of clinical symptoms and underlying pathology, the symptoms can be broadly categorized into behavioral, cognitive and motor domains. Currently there are no Food and Drug Administration (FDA) approved therapies for the above syndromes except riluzole for ALS. FTD treatment strategies generally rely on off-label use of medications for symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. For behavioral symptoms, selective serotonin reuptake inhibitors may be effective, while case reports hint at possible efficacy with antipsychotics or antiepileptics, but use of these latter agents is limited due to concerns regarding side effects. There are no effective therapies for cognitive complaints in FTD, which frequently involve executive function, memory, and language. Motor difficulties associated with FTD may present with parkinsonian symptoms or motor neuron disease, for which riluzole is indicated as therapy. Compared to idiopathic Parkinson’s disease, FTD-related atypical parkinsonism is generally not responsive to dopamine replacement therapies, but a

  7. Oxytocin for frontotemporal dementia

    PubMed Central

    MacKinley, Julia; Blair, Mervin; Oliver, Lindsay D.; Jesso, Sarah; Tartaglia, Maria C.; Borrie, Michael; Wells, Jennie; Dziobek, Isabel; Pasternak, Stephen; Mitchell, Derek G.V.; Rankin, Katherine; Kertesz, Andrew; Boxer, Adam

    2015-01-01

    Objective: To determine the safety and tolerability of 3 doses of intranasal oxytocin (Syntocinon; Novartis, Bern, Switzerland) administered to patients with frontotemporal dementia (FTD). Methods: We conducted a randomized, parallel-group, double-blind, placebo-controlled study using a dose-escalation design to test 3 clinically feasible doses of intranasal oxytocin (24, 48, or 72 IU) administered twice daily for 1 week to 23 patients with behavioral variant FTD or semantic dementia (clinicaltrials.gov registration number NCT01386333). Primary outcome measures were safety and tolerability at each dose. Secondary measures explored efficacy across the combined oxytocin vs placebo groups and examined potential dose-related effects. Results: All 3 doses of intranasal oxytocin were safe and well tolerated. Conclusions: A multicenter trial is warranted to determine the therapeutic efficacy of long-term intranasal oxytocin for behavioral symptoms in FTD. Classification of evidence: This study provides Class I evidence that for patients with FTD, intranasal oxytocin is not significantly associated with adverse events or significant changes in the overall neuropsychiatric inventory. PMID:25503617

  8. Frontotemporal Dementia (Pick's Disease)

    MedlinePlus

    ... nia.nih.gov Tel: 301-496-1752; 800-222-2225; 800-222-4225 (TTY) The Bluefield Project to Cure Frontotemporal ... nia.nih.gov Tel: 301-496-1752; 800-222-2225; 800-222-4225 (TTY) The Bluefield Project ...

  9. Sorting out frontotemporal dementia?

    PubMed

    Lewis, Jada; Golde, Todd E

    2010-11-18

    Mutations within the granulin (GRN) gene that encodes progranulin (PGRN) cause the neurodegenerative disease frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U). The receptor for PGRN in the CNS has not been previously identified. In this issue of Neuron, Hu and colleagues identify Sortilin (SORT1) as a key neuronal receptor for PGRN that facilitates its endocytosis and regulates PGRN levels in vitro and in vivo. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Motor neuron dysfunction in frontotemporal dementia.

    PubMed

    Burrell, James R; Kiernan, Matthew C; Vucic, Steve; Hodges, John R

    2011-09-01

    Frontotemporal dementia and motor neuron disease share clinical, genetic and pathological characteristics. Motor neuron disease develops in a proportion of patients with frontotemporal dementia, but the incidence, severity and functional significance of motor system dysfunction in patients with frontotemporal dementia has not been determined. Neurophysiological biomarkers have been developed to document motor system dysfunction including: short-interval intracortical inhibition, a marker of corticospinal motor neuron dysfunction and the neurophysiological index, a marker of lower motor neuron dysfunction. The present study performed detailed clinical and neurophysiological assessments on 108 participants including 40 consecutive patients with frontotemporal dementia, 42 age- and gender-matched patients with motor neuron disease and 26 control subjects. Of the 40 patients with frontotemporal dementia, 12.5% had concomitant motor neuron disease. A further 27.3% of the patients with frontotemporal dementia had clinical evidence of minor motor system dysfunction such as occasional fasciculations, mild wasting or weakness. Biomarkers of motor system function were abnormal in frontotemporal dementia. Average short-interval intracortical inhibition was reduced in frontotemporal dementia (4.3 ± 1.7%) compared with controls (9.1 ± 1.1%, P < 0.05). Short-interval intracortical inhibition was particularly reduced in the progressive non-fluent aphasia subgroup, but was normal in patients with behavioural variant frontotemporal dementia and semantic dementia. The neurophysiological index was reduced in frontotemporal dementia (1.1) compared with controls (1.9, P < 0.001), indicating a degree of lower motor neuron dysfunction, although remained relatively preserved when compared with motor neuron disease (0.7, P < 0.05). Motor system dysfunction in frontotemporal dementia may result from pathological involvement of the primary motor cortex, with secondary

  11. Implicit emotional awareness in frontotemporal dementia.

    PubMed

    Ibáñez, Agustín; Velásquez, María Marcela; Caro, Miguel Martorell; Manes, Facundo

    2013-01-01

    The preserved "implicit awareness" in patients with Alzheimer disease (AD) presenting anosognosia has opened a new branch of research regarding explicit-implicit integration. The behavioral variant of frontotemporal dementia (bvFTD), contrary to AD, would present impaired anosognosia-related implicit awareness due to a dysfunctional implicit integration of contextual information caused by an abnormal fronto-insular-temporal network. Loss of insight and anosognosia are pervasive in bvFTD, but no reports have assessed the implicit emotional awareness in this condition. We emphasize the need to investigate and extend our knowledge of implicit contextual integration impairments and their relation with anosognosia in bvFTD vs AD.

  12. [New insights in frontotemporal dementia].

    PubMed

    Rosso, S M; Heutink, P; Tibben, A; Niermeijer, M F; van Swieten, J C

    2000-08-12

    Frontotemporal dementia (FTD) is a neurodegenerative disorder characterised by progressive behavioural disturbance, aphasia and a decline in frontal cognitive functions. Frontotemporal atrophy on CT and MRI, and hypoperfusion of the frontal brain regions on single-photon emission computed tomography (SPECT), are characteristic findings. Neuropathological examination reveals deposition of abnormally phosphorylated tau protein in neurons and glial cells in a number of the sporadic and familial cases, while aspecific changes with neuronal loss, spongiosis and gliosis are found in the remaining cases. A familial form with an autosomal dominant pattern of inheritance is seen in 20% of FTD patients. Mutations in the tau gene have been identified in a number of families with deposition of abnormal tau protein in affected brain regions. Presymptomatic DNA testing is now available for relatives of patients with tau mutations, but must only be considered after extensive genetic counselling in a centre with neurogenetic expertise.

  13. Semantic and gender priming in frontotemporal dementia.

    PubMed

    Repetto, Claudia; Manenti, Rosa; Cappa, Stefano; Miniussi, Carlo; Riva, Giuseppe

    2009-01-01

    Modifications of language processing can be observed both in normal aging and in the most common forms of degenerative dementia, such as Alzheimer's disease and the spectrum of frontotemporal dementias. The present experiment tests at the same time semantic and syntactic aspects of language processing in patients with frontotemporal dementia, using an online paradigm that allows researchers to evaluate the real linguistic competence of the patients.

  14. Mouse Models of Frontotemporal Dementia

    PubMed Central

    Roberson, Erik D.

    2012-01-01

    The pace of discovery in frontotemporal dementia (FTD) has accelerated dramatically with the discovery of new genetic causes and pathological substrates of the disease. MAPT/Tau, GRN/progranulin, and C9ORF72 have emerged as common FTD genes, and TARDBP/TDP-43, VCP, FUS, and CHMP2B have been identified as less common genetic causes. TDP-43 and FUS have joined Tau as common neuropathological substrates of the disease. Mouse models provide an important tool for understanding the role of these molecules in FTD pathogenesis. Here, we review recent progress with mouse models based on Tau, TDP-43, progranulin, VCP, and CHMP2B. We also consider future prospects for FTD models, including developing new models to address unanswered questions. There are also opportunities for capitalizing on conservation of the salience network, which is selectively vulnerable in FTD, and the availability of FTD-related behavioral paradigms to analyze mouse models of the disease. PMID:23280835

  15. Diogenes Syndrome in Frontotemporal Dementia.

    PubMed

    Finney, Catherine M; Mendez, Mario F

    2017-01-01

    Diogenes syndrome refers to the combination of extreme self-neglect and excessive collecting with clutter and squalor, which is often present in patients with dementia. Diogenes syndrome may be particularly common in behavioral variant frontotemporal dementia (bvFTD), and the investigation of these patients may help clarify the nature of this syndrome. We describe 5 patients with bvFTD who exhibited a decline in self-care accompanied by hoarding behaviors. These patients, and a review of the literature, suggest a combination of frontal lobe disturbances: loss of insight or self-awareness with a failure to clean up or discard, a general compulsive drive, and an innate impulse to take environmental items. This impulse may be part of the environmental dependency syndrome in frontal disease, with specific involvement of a right frontolimbic-striatal system. Further investigation of the similarities and mechanisms of these symptoms in bvFTD could help in understanding Diogenes syndrome and lead to potential treatment options.

  16. In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias.

    PubMed

    Di Lazzaro, V; Pilato, F; Dileone, M; Saturno, E; Oliviero, A; Marra, C; Daniele, A; Ranieri, F; Gainotti, G; Tonali, P A

    2006-04-11

    The test of short latency afferent inhibition (SAI) of the motor cortex is helpful in demonstrating dysfunction of central cholinergic circuits in Alzheimer disease (AD). The authors evaluated SAI in 20 patients with frontotemporal dementia (FTD) and compared data with those from 20 patients with AD and 20 controls. SAI was normal in FTD, whereas it was reduced in AD. SAI may represent an additional tool to discriminate FTD from AD.

  17. Mouse models of frontotemporal dementia.

    PubMed

    Roberson, Erik D

    2012-12-01

    The pace of discovery in frontotemporal dementia (FTD) has accelerated dramatically with the discovery of new genetic causes and pathological substrates of the disease. MAPT/tau, GRN/progranulin, and C9ORF72 have emerged as common FTD genes, and TARDBP/TDP-43, VCP, FUS, and CHMP2B have been identified as less common genetic causes. TDP-43 and FUS have joined tau as common neuropathological substrates of the disease. Mouse models provide an important tool for understanding the role of these molecules in FTD pathogenesis. Here, we review recent progress with mouse models based on tau, TDP-43, progranulin, VCP, and CHMP2B. We also consider future prospects for FTD models, including developing new models to address unanswered questions. There are also opportunities for capitalizing on conservation of the salience network, which is selectively vulnerable in FTD, and the availability of FTD-related behavioral paradigms to analyze mouse models of the disease. Copyright © 2012 American Neurological Association.

  18. ESCRT, autophagy, and frontotemporal dementia.

    PubMed

    Lee, Jin-A; Gao, Fen-Biao

    2008-12-31

    Many age-dependent neurodegenerative diseases are associated with the accumulation of abnormally folded proteins within neurons. One of the major proteolytic pathways in the cell is the autophagy pathway, which targets cytoplasmic contents and organelles to the lysosomes for bulk degradation under various physiological and stressful conditions. Although the importance of autophagy in cellular physiology is well appreciated, its precise roles in neurodegeneration remain largely unclear. Recent studies indicate that components of the endosomal sorting complex required for transport (ESCRT) are important in the autophagy pathway. Reduced activity of some ESCRT subunits leads to the accumulation of autophagosomes and failure to clear intracellular protein aggregates. Interestingly, rare mutations in CHMP2B, an ESCRT-III subunit, are associated with frontotemporal dementia linked to chromosome 3 (FTD3). Mutant CHMP2B proteins seem to disrupt the fusion of autophagosomes and lysosomes in cell culture models. These findings suggest a potential mechanism for the pathogenesis of FTD3 and possibly other neurodegenerative diseases as well.

  19. 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

  20. Genetics of Alzheimer's Disease and Frontotemporal Dementia.

    PubMed

    Nacmias, B; Piaceri, I; Bagnoli, S; Tedde, A; Piacentini, S; Sorbi, S

    2014-01-01

    The genetics of neurodegenerative diseases has an important role to clarify the pathogenetic mechanism, the diagnosis and finally the therapeutic and ethical implications. Moreover, the genetic approach to the study of the main clinical forms of dementia (Alzheimer's disease-AD and Frontotemporal Dementia-FTD) suggests clinical guidelines for helping families to navigate through these complexities. AD and FTD are multifactorial, genetically complex diseases involving many candidate genes. Mutations in three genes (i.e. Amyloid Precursor Protein, APP; presenilin 1, PSEN1; presenilin 2, PSEN2) have been linked to 50% of all familial forms of AD (FAD). Genome wide association studies (GWAS) have involved an increasing number of genes with a possible role in the disease pathogenesis. Up to now, the genetics of familial forms of FTD is related to 7 genes: the microtubule-associated protein tau (MAPT) progranulin (GRN), the valosin-containing protein (VCP), chromatin-modifying 2B (CHMP2B), the TARDNA binding protein 43 encoding gene (TARBDP), fused in sarcoma (FUS) and the last hexanucleotide expansion repeats in the open reading frame of chromosome 9 (C9orf72). Pre-test counseling and the identification of genetic defects are important in both patients and asymptomatic at risk family members. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. 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.

  2. 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

  3. 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.

  4. Responding to safety issues in frontotemporal dementias.

    PubMed

    Talerico, K A; Evans, L K

    2001-06-01

    As frontotemporal dementia progresses in individuals, safety issues related to behaviors and injury become a paramount concern. In addition to self-care deficits, frontotemporal dementias are often characterized by behavioral manifestations that include aggression and disinhibition. These behaviors may place the patient and caregivers at risk of injury, stress, and social embarrassment, and frequently lead to institutionalization. Additionally, motor disturbances associated with frontotemporal dementias may contribute to risk of injury from falls. The authors present an integrated biopsychosocial model to guide assessment of needs that may be expressed through behavior. Environmental, behavioral, and psychosocial strategies to assist caregivers in preventing and responding to behaviors and risks are discussed, with the goal of promoting maximum function and quality of life and minimizing caregiver strain. The authors discuss the dangers of physical restraints, which are commonly suggested as a response to fall risk and behavioral symptoms without an awareness of research-based data regarding their lack of efficacy. Benefits and risks of a variety of need-based interventions are presented in a practical, clinically relevant manner. The discussion of diverse safety-enhancing interventions is intended to enable clinicians and caregivers to identify individualized care strategies for patients with frontotemporal dementia.

  5. Kissing or "osculation" in frontotemporal dementia.

    PubMed

    Mendez, Mario F; Shapira, Jill S

    2014-01-01

    The authors investigated the neuropsychiatry of kissing in frontotemporal dementia. Among 15 patients, two had compulsive social kissing, bitemporal involvement, and Klüver-Bucy symptoms, and four pursued kissing with sexually disinhibited behavior. Future research should clarify the neuropsychiatric significance of kissing behavior.

  6. 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.

  7. [Diagnosing frontotemporal dementia, a chameleon in psychiatry].

    PubMed

    Vleugel, E E; Chong, Y K; van der Mast, R C

    2006-01-01

    Frontotemporal dementia (FTD) generally has a presenile onset, behavioural problems dominate the clinical picture and cognitive functions are still relatively intact. Therefore particularly in the early stages of FTD it is difficult to differentiate this type of dementia from other types of dementia and psychiatric disorders. To review the options currently available for diagnosing FTD and to evaluate their significance for clinical practice. A literature search via PubMed, Embase and the Cochrane Library (1999-2005) using the key words 'frontotemporal dementia' and 'diagnosis' or 'differential diagnosis'. Genetic and post-mortem studies were excluded. The selected literature concerned differential clinical symptoms, neuropsychological research and questionnaires, neuroimaging and fluid abnormalities and dealt mainly with the difference between FTD and other types of dementia but not with differences between FTD and psychiatric disorders. Measuring instruments that are helpful for diagnosing FTD are the Manchester Behavioural Questionnaire, the Frontal Behaviour Inventory and the Frontal Assessment Battery. Even better indicators of FTD are asymmetrical frontotemporal structural abnormalities in a CT- or MRI-scan and a decrease infrontal metabolism and perfusion in a PET- or SPECT-scan, although not all detected abnormalities are specific for FTD. Whatever the method used, early diagnosis is difficult; the sensitivity of nearly all diagnostic methods increases as the illness progresses. On the basis of this review of the literature some diagnostic techniques are recommended that can be applied if FTD is suspected.

  8. 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

  9. The frontotemporal dementia-motor neuron disease continuum.

    PubMed

    Burrell, James R; Halliday, Glenda M; Kril, Jillian J; Ittner, Lars M; Götz, Jürgen; Kiernan, Matthew C; Hodges, John R

    2016-08-27

    Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia-motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. 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.

  11. Divergent thinking in Alzheimer's and frontotemporal dementia.

    PubMed

    Hart, Robert P; Wade, James B

    2006-01-01

    Twenty-three patients with mild dementia of the Alzheimer's type (DAT) or frontotemporal type (DFT) and age- and education-matched control subjects were administered tests of complex fluency involving divergent thinking and tests of letter, category, and figural fluency. The tests of complex fluency discriminated the dementia patients from control subjects more strongly than did the other fluency tests. The results suggest that divergent thinking as assessed by complex fluency tests is a cognitive domain that is impaired early in the course of dementia. The sensitivity of complex fluency tests compared to that of letter, category, and figural fluency tests may be related to greater demands for conceptualization in relating stimulus attributes to function and greater demands for flexible thinking during self-directed search processes.

  12. Neuroeconomic dissociation of semantic dementia and behavioural variant frontotemporal dementia

    PubMed Central

    Wood, Kristie A.; Beagle, Alexander J.; Hsu, Ming; Kayser, Andrew S.; Miller, Bruce L.; Kramer, Joel H.

    2016-01-01

    Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients’ subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer’s disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders. PMID:26667277

  13. Frontotemporal dementia: a bridge between dementia and neuromuscular disease

    PubMed Central

    Ng, Adeline SL; Rademakers, Rosa; Miller, BL

    2015-01-01

    The concept that frontotemporal dementia (FTD) is a purely “cortical” dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery of the C9ORF72 locus as responsible for majority of hereditary FTD, ALS and FTD-ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE) given its association with TDP-43 pathology, increased dementia risk and reports of ALS in CTE patients. Additionally we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget’s disease and frontotemporal dementia (IBMPFD). PMID:25557955

  14. Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia.

    PubMed

    Jellinger, Kurt A

    2008-01-01

    Proteinopathies are a heterogenous group of neurodegenerative disorders, characterized by intra- and extracellular accumulation of abnormal filament proteins. To describe the neuropathology of specific forms of tauopathies and synucleinopathies, the overlap of morphologic features and molecular interactions. The study uses currently available morphologic criteria of different proteinopathies. Alzheimer disease (AD) is featured by deposition of beta-amyloid peptides, phosphorylated tau protein (3- and 4-repeat tau) and frequent alpha-synuclein (aSyn) deposits. Lewy body diseases (LBD), such as sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), show aSyn-positive deposits in neurons, neurites, glia, and presynaptic terminals, while frontotemporal dementias present tau-positive and tau-negative, ubiquitin- and TDP-43-positive neuronal and glial inclusions. The latter have also been observed in AD, PD, PD dementia and motor neuron disorders. Molecular interactions between major proteins, which may occur within the same brain in various distribution patterns, cause variable phenotypes and mixed pathologies, e.g. AD with aSyn pathology in the brainstem and amygdala, PD and DLB with AD lesions, and frontotemporal dementia with a mixture of various deposits, while others are featured by one principal pathology without other lesions (e.g. tangle-predominant type of dementia, pure PD, brainstem-predominant LBD). Animal models and in vitro studies showing co-occurrence and mutual promotion of fibrillation of these proteins indicate their synergistic interactions in the pathogenesis of these disorders which, at least in part, are genetically influenced. 2008 S. Karger AG, Basel

  15. Vestibular Impairment in Frontotemporal Dementia Syndrome

    PubMed Central

    Nakamagoe, Kiyotaka; Kadono, Kotarou; Koganezawa, Tadachika; Takiguchi, Mao; Terada, Makoto; Yamamoto, Fumiko; Moriyama, Tetsuya; Yanagiha, Kumi; Nohara, Seitaro; Tozaka, Naoki; Miyake, Zenshi; Aizawa, Satoshi; Furusho, Kentaro; Tamaoka, Akira

    2016-01-01

    Background No studies to date have attempted to evaluate frontotemporal lobar degeneration from the perspective of the vestibular system. Objective The present study examined vestibular function in patients with frontotemporal dementia (FTD) clinical syndrome and evaluated whether vestibular disorders are involved in the clinical symptoms due to FTD. Methods Fourteen patients with FTD syndrome, as well as healthy elderly controls without dementia, were included in the present study. All subjects underwent vestibular function tests using electronystagmography, such as caloric tests and visual suppression (VS) tests, in which the induced caloric nystagmus was suppressed by visual stimuli. The association between clinical symptoms and vestibular function in the FTD syndrome group was further examined. Results In the FTD syndrome group, caloric nystagmus was not necessarily suppressed during VS tests. Furthermore, VS was observed to be significantly impaired in FTD syndrome patients with gait disturbance as compared to those without such disturbance. Conclusion The present study revealed that impairment of VS in patients with FTD results in an inability to regulate vestibular function by means of visual perception, regardless of multiple presumed neuropathological backgrounds. This could also be associated with gait disturbance in patients with FTD syndrome. PMID:27350780

  16. 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

  17. Presymptomatic studies in genetic frontotemporal dementia.

    PubMed

    Rohrer, J D; Warren, J D; Fox, N C; Rossor, M N

    2013-10-01

    Approximately 20% of patients with the neurodegenerative disorder frontotemporal dementia (FTD) have an autosomal dominant pattern of inheritance. Genetic FTD is caused by mutations in three genes in most cases (progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72) although a number of other genes are rare causes. Studies of other neurodegenerative diseases have shown imaging and biomarker evidence of disease onset many years prior to the development of symptoms. Similar studies in genetic FTD are now revealing evidence of a series of presymptomatic changes, initially in plasma biomarkers followed by MR imaging abnormalities of functional and structural connectivity and then grey matter atrophy. Lastly, neuropsychometric tests become abnormal in proximity to the onset of symptoms. Such studies have been relatively small until now but research centres with an expertise in genetic FTD are now forming consortia such as the Genetic Frontotemporal Dementia Initiative (GenFI) to create larger cohorts that can form the basis of future clinical trials. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  18. Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia

    PubMed Central

    Benussi, Alberto; Padovani, Alessandro; Borroni, Barbara

    2015-01-01

    Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease. PMID:26388768

  19. Frontotemporal dementia: implications for understanding Alzheimer disease.

    PubMed

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

    2012-02-01

    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.

  20. Visual rating versus volumetry to detect frontotemporal dementia.

    PubMed

    Chow, T W; Gao, F; Links, K A; Ween, J E; Tang-Wai, D F; Ramirez, J; Scott, C J M; Freedman, M; Stuss, D T; Black, S E

    2011-01-01

    Automated, volumetrically defined atrophy in the left anterior cingulate (LAC) and anterior temporal regions (LAT) on MRI can be used to distinguish most patients with frontotemporal dementia (FTD) from controls. FTD and Alzheimer's disease (AD) can differ in the degree of anterior temporal atrophy. We explored whether clinicians can visually detect this atrophy pattern and whether they can use it to classify the 2 groups of dementia patients with the same accuracy. Four neurologists rated atrophy in the LAC and LAT regions on MRI slices from 21 FTD, 21 controls, and 14 AD participants. Inter-rater reliability and diagnostic accuracy were assessed. All 4 raters agreed on the presence of clinically significant atrophy, and their atrophy scoring correlated with the volumes, but without translation into high inter-rater diagnostic agreement. Volumetric analyses are difficult to translate into routine clinical practice. Copyright © 2011 S. Karger AG, Basel.

  1. The impact of dementia severity on caregiver burden in frontotemporal dementia and Alzheimer disease.

    PubMed

    Mioshi, Eneida; Foxe, David; Leslie, Felicity; Savage, Sharon; Hsieh, Sharpley; Miller, Laurie; Hodges, John R; Piguet, Olivier

    2013-01-01

    Caregiver burden is greater in frontotemporal dementia (FTD) than in Alzheimer disease (AD). However, little is known of the impact of the 3 main clinical variants of FTD- behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SemDem), and progressive nonfluent aphasia (PNFA)-or the role of disease severity in caregiver burden. The Zarit Burden Inventory was used to measure caregiver burden of bvFTD (n=17), SemDem (n=20), PNFA (n=20), and AD (n=19) patients. Symptom duration, caregiver age, and relationship type were matched across groups. Moreover, a number of caregiver (mood, social network) and patient variables (functional disability, behavioral changes, relationship with caregiver, and dementia stage) were addressed to investigate their impact on caregiver burden. Caregivers of bvFTD patients reported the highest burden, whereas SemDem and PNFA caregivers reported burden similar to AD. A regression analysis revealed that caregiver burden in FTD, regardless of subtype, was explained by a model combining disease staging, relationship changes, and caregiver depression. Burden increased with disease severity in FTD. This study is the first to show that caregivers of SemDem, PNFA, and AD patients show similar burden, while confirming that bvFTD caregivers show higher burden than AD caregivers. More importantly, this study demonstrates that burden worsens with disease progression in FTD.

  2. The molecular basis of frontotemporal dementia.

    PubMed

    Neumann, Manuela; Tolnay, Markus; Mackenzie, Ian R A

    2009-07-29

    Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Familial FTD has been linked to mutations in several genes, including those encoding the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B). The associated neuropathology is characterised by selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration, FTLD), usually with the presence of abnormal intracellular protein accumulations. The current classification of FTLD neuropathology is based on the identity of the predominant protein abnormality, in the belief that this most closely reflects the underlying pathogenic process. Major subgroups include those characterised by the pathological tau, TDP-43, intermediate filaments and a group with cellular inclusions composed of an unidentified ubiquitinated protein. This review will focus on the current understanding of the molecular basis of each of the major FTLD subtypes. It is anticipated that this knowledge will provide the basis of future advances in the diagnosis and treatment of FTD.

  3. Frontotemporal dementia: diagnosis, deficits and management

    PubMed Central

    Bott, Nicholas T; Radke, Anneliese; Stephens, Melanie L; Kramer, Joel H

    2016-01-01

    Summary Frontotemporal dementia (FTD) is a progressive neurologic syndrome with diverse clinical presentations and attendant underlying pathologies. Psychiatric prodrome, neuropsychiatric symptoms and language difficulties are common in FTD, but the diversity of presentation raises unique diagnostic challenges that can significantly impact patient care and counsel for caregivers regarding clinical status and prognosis. While neuropsychiatric symptom measures are helpful, more sensitive assessments delineating the specific behavioral and linguistic deficits accompanying FTD are needed. Comprehensive clinical assessment in combination with evaluation of language, socio-emotional functioning, cognition and neuroimaging aid in accurate and early diagnosis and treatment planning. In what follows, we review each of the FTD syndromes, highlight current research investigating the cognitive, behavioral and socio-emotional deficits observed with this disease, address common diagnostic challenges and summarize best practices associated with management of FTD. PMID:25531687

  4. Advances in neuroimaging in frontotemporal dementia.

    PubMed

    Gordon, Elizabeth; Rohrer, Jonathan D; Fox, Nick C

    2016-08-01

    Frontotemporal dementia (FTD) is a clinically and neuroanatomically heterogeneous neurodegenerative disorder with multiple underlying genetic and pathological causes. Whilst initial neuroimaging studies highlighted the presence of frontal and temporal lobe atrophy or hypometabolism as the unifying feature in patients with FTD, more detailed studies have revealed diverse patterns across individuals, with variable frontal or temporal predominance, differing degrees of asymmetry, and the involvement of other cortical areas including the insula and cingulate, as well as subcortical structures such as the basal ganglia and thalamus. Recent advances in novel imaging modalities including diffusion tensor imaging, resting-state functional magnetic resonance imaging and molecular positron emission tomography imaging allow the possibility of investigating alterations in structural and functional connectivity and the visualisation of pathological protein deposition. This review will cover the major imaging modalities currently used in research and clinical practice, focusing on the key insights they have provided into FTD, including the onset and evolution of pathological changes and also importantly their utility as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. Validating neuroimaging biomarkers that are able to accomplish these tasks will be crucial for the ultimate goal of powering upcoming clinical trials by correctly stratifying patient enrolment and providing sensitive markers for evaluating the effects and efficacy of disease-modifying therapies. This review describes the key insights provided by research into the major neuroimaging modalities currently used in research and clinical practice, including what they tell us about the onset and evolution of FTD and how they may be used as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. This article is

  5. Cortical function in Alzheimer’s disease and frontotemporal dementia

    PubMed Central

    Wang, Pan; Zhang, Huihong; Han, Lu

    2016-01-01

    Abstract Objectives Alzheimer’s disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD) are the most common causes of dementia; however, their overlapping clinical syndromes and involved brain regions make a differential diagnosis difficult. We aimed to identify the differences in the cognition and motor cortex excitability between AD and bvFTD patients. Methods Twenty-seven AD patients and 30 bvFTD patients were included in the study. Each participant received a neurological evaluation. Cognitive event-related potentials (P300) were recorded during an auditory oddball task. Next, the excitability of the motor cortex, including the resting, facilitated motor threshold (RMT and FMT) and cortical silent period (CSP), were assessed during transcranial magnetic stimulation (TMS). Results The bvFTD patients exhibited significantly longer P300 latencies compared with AD patients. There was a significant negative correlation between cognition and P300 latency in the bvFTD group. The AD patients showed significantly reduced RMT and FMT values compared to the bvFTD group; however, no significant correlation was found between AD severity and the excitability of the motor cortex. Conclusions Cognition and motor cortical functions are different between AD and bvFTD patients. Noninvasive electrophysiological examinations have the potential to identify unique pathophysiological features that can be used to differentially diagnose AD and bvFTD patients. PMID:28123831

  6. Verb Agreements during On-Line Sentence Processing in Alzheimer's Disease and Frontotemporal Dementia

    ERIC Educational Resources Information Center

    Price, C.C.; Grossman, M.

    2005-01-01

    An on-line ''word detection'' paradigm was used to assess the comprehension of thematic and transitive verb agreements during sentence processing in individuals diagnosed with probable Alzheimer's Disease (AD, n=15) and Frontotemporal Dementia (FTD, n=14). AD, FTD, and control participants (n=17) were asked to listen for a word in a sentence.…

  7. Verb Agreements during On-Line Sentence Processing in Alzheimer's Disease and Frontotemporal Dementia

    ERIC Educational Resources Information Center

    Price, C.C.; Grossman, M.

    2005-01-01

    An on-line ''word detection'' paradigm was used to assess the comprehension of thematic and transitive verb agreements during sentence processing in individuals diagnosed with probable Alzheimer's Disease (AD, n=15) and Frontotemporal Dementia (FTD, n=14). AD, FTD, and control participants (n=17) were asked to listen for a word in a sentence.…

  8. Magnetoencephalography of frontotemporal dementia: spatiotemporally localized changes during semantic decisions.

    PubMed

    Hughes, Laura E; Nestor, Peter J; Hodges, John R; Rowe, James B

    2011-09-01

    Behavioural variant frontotemporal dementia is a neurodegenerative disorder with dysfunction and atrophy of the frontal lobes leading to changes in personality, behaviour, empathy, social conduct and insight, with relative preservation of language and memory. As novel treatments begin to emerge, biomarkers of frontotemporal dementia will become increasingly important, including functionally relevant neuroimaging indices of the neurophysiological basis of cognition. We used magnetoencephalography to examine behavioural variant frontotemporal dementia using a semantic decision task that elicits both frontal and temporal activity in healthy people. Twelve patients with behavioural variant frontotemporal dementia (age 50-75) and 16 matched controls made categorical semantic judgements about 400 pictures during continuous magnetoencephalography. Distributed source analysis was used to compare patients and controls. The patients had normal early responses to picture confrontation, indicating intact visual processing. However, a predominantly posterior set of regions including temporoparietal cortex showed reduced source activity 250-310 ms after stimulus onset, in proportion to behavioural measures of semantic association. In contrast, a left frontoparietal network showed reduced source activity at 550-650 ms, proportional to patients' deficits in attention and orientation. This late deficit probably reflects impairment in the neural substrate of goal-oriented decision making. The results demonstrate behaviourally relevant neural correlates of semantic processing and decision making in behavioural variant frontotemporal dementia, and show for the first time that magnetoencephalography can be used to study cognitive systems in the context of frontotemporal dementia.

  9. Psychosis in behavioral variant frontotemporal dementia.

    PubMed

    Gossink, Flora T; Vijverberg, Everard Gb; Krudop, Welmoed; Scheltens, Philip; Stek, Max L; Pijnenburg, Yolande Al; Dols, Annemiek

    2017-01-01

    Dementia is generally characterized by cognitive impairment that can be accompanied by psychotic symptoms; for example, visual hallucinations are a core feature of dementia with Lewy bodies, and delusions are often seen in Alzheimer's disease. However, for behavioral variant of frontotemporal dementia (bvFTD), studies on the broad spectrum of psychotic symptoms are still lacking. The aim of this study was to systematically and prospectively subtype the wide spectrum of psychotic symptoms in probable and definite bvFTD. In this study, a commonly used and validated clinical scale that quantifies the broad spectrum of psychotic symptoms (Positive and Negative Symptom Scale) was used in patients with probable and definite bvFTD (n=22) and with a primary psychiatric disorder (n=35) in a late-onset frontal lobe cohort. Median symptom duration was 2.8 years, and the patients were prospectively followed for 2 years. In total, 22.7% of bvFTD patients suffered from delusions, hallucinatory behavior, and suspiciousness, although the majority of the patients exhibited negative psychotic symptoms such as social and emotional withdrawal and blunted affect (95.5%) and formal thought disorders (81.8%). "Difficulty in abstract thinking" and "stereotypical thinking" (formal thought disorders) differentiated bvFTD from psychiatric disorders. The combined predictors difficulty in abstract thinking, stereotypical thinking, "anxiety", "guilt feelings," and "tension" explained 75.4% of variance in the diagnosis of bvFTD versus psychiatric diagnoses (P<0.001). Delusions, hallucinatory behavior, and suspiciousness were present in one-fifth of bvFTD patients, whereas negative psychotic symptoms such as social and emotional withdrawal, blunted affect, and formal thought disorders were more frequently present. This suggests that negative psychotic symptoms and formal thought disorders have an important role in the psychiatric misdiagnosis in bvFTD; misdiagnosis in bvFTD might be reduced by

  10. Family caregivers of patients with frontotemporal dementia: An integrative review.

    PubMed

    Caceres, Billy A; Frank, Mayu O; Jun, Jin; Martelly, Melissa T; Sadarangani, Tina; de Sales, Paloma Cesar

    2016-03-01

    The purpose of this integrative review is to: (1) identify the characteristics of family caregivers of patients with frontotemporal dementia, (2) explore the impact of providing care on family caregivers' health and well-being, and (3) identify coping strategies used by family caregivers. Frontotemporal dementia is thought to be the second most common form of dementia after Alzheimer's disease. Family caregivers of patients with frontotemporal dementia face unique challenges due to its early onset, behavioral symptoms, and slow progression of decline. However, there is a dearth of research evaluating the health and wellbeing of family caregivers of patients with frontotemporal dementia. An integrative review was conducted using the Whittemore and Knafl methodology. An electronic search of the literature was conducted using four electronic databases: PubMed, Embase, CINAHL, and Web of Science. The Crowe Critical Appraisal tool was used to evaluate the quality of the selected articles. Findings of 11 articles informed this integrative review. Family caregivers of patients with frontotemporal dementia identify behavioral disturbances as most troubling. Spouses and female caregivers experience greater caregiver burden, distress, increased rates of depression, as well as decreased sleep related to behavior disturbances. Though less explored, providing care to those with behavioral disturbances may also impact caregiver physical health. Additionally, female caregivers are most likely to employ coping strategies, most commonly, adaptation and reframing. Effective interventions to reduce family caregiver burden are poorly understood but family caregivers suggest education and internet-based support groups are most helpful. Family caregivers of patients with frontotemporal dementia experience significant distress, which impacts their health and wellbeing. It is important for healthcare providers who care for patients with frontotemporal dementia to recognize the unique

  11. Are we comparing frontotemporal dementia and Alzheimer disease patients with the right measures?

    PubMed Central

    Deutsch, Mariel B.; Liang, Li-Jung; Jimenez, Elvira E.; Mather, Michelle J.; Mendez, Mario F.

    2016-01-01

    Background Clinical research studies of behavioral variant frontotemporal dementia (bvFTD) often use Alzheimer disease (AD) as a comparison group for control of dementia variables, using tests of cognitive function to match the groups. These two dementia syndromes, however, are very different in clinical manifestations, and the comparable severity of these dementias may not be reflected by commonly used cognitive scales such as the Mini-Mental State Examination (MMSE). Methods We evaluated different measures of dementia severity and symptoms among 20 people with bvFTD compared to 24 with early-onset AD. Results Despite similar ages, disease-duration, education, and cognitive performance on two tests of cognitive function, the MMSE and the Montreal Cognitive Assessment (MoCA), the bvFTD participants, compared to the AD participants, were significantly more impaired on other measures of disease severity, including function (Functional Assessment Questionnaire (FAQ)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)), and global dementia stage (Clinical Dementia Rating Scales (CDRs)). However, when we adjusted for the frontotemporal lobar degeneration-CDR (FTLD-CDR) in the analyses, the two dementia groups were comparable across all measures despite significant differences on the cognitive scales. Conclusion We found tests of cognitive functions (MMSE and MoCA) to be insufficient measures for ensuring comparability between bvFTD and AD groups. In clinical studies, the FTLD-CDR, which includes additional language and behavior items, may be a better overall way to match bvFTD and AD groups on dementia severity. PMID:27079571

  12. Are we comparing frontotemporal dementia and Alzheimer disease patients with the right measures?

    PubMed

    Deutsch, Mariel B; Liang, Li-Jung; Jimenez, Elvira E; Mather, Michelle J; Mendez, Mario F

    2016-09-01

    Clinical research studies of behavioral variant frontotemporal dementia (bvFTD) often use Alzheimer disease (AD) as a comparison group for control of dementia variables, using tests of cognitive function to match the groups. These two dementia syndromes, however, are very different in clinical manifestations, and the comparable severity of these dementias may not be reflected by commonly used cognitive scales such as the Mini-Mental State Examination (MMSE). We evaluated different measures of dementia severity and symptoms among 20 people with bvFTD compared to 24 with early-onset AD. Despite similar ages, disease-duration, education, and cognitive performance on two tests of cognitive function, the MMSE and the Montreal Cognitive Assessment (MoCA), the bvFTD participants, compared to the AD participants, were significantly more impaired on other measures of disease severity, including function (Functional Assessment Questionnaire (FAQ)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)), and global dementia stage (Clinical Dementia Rating Scales (CDRs)). However, when we adjusted for the frontotemporal lobar degeneration-CDR (FTLD-CDR) in the analyses, the two dementia groups were comparable across all measures despite significant differences on the cognitive scales. We found tests of cognitive functions (MMSE and MoCA) to be insufficient measures for ensuring comparability between bvFTD and AD groups. In clinical studies, the FTLD-CDR, which includes additional language and behavior items, may be a better overall way to match bvFTD and AD groups on dementia severity.

  13. Frontotemporal dementia due to C9ORF72 mutations

    PubMed Central

    Takada, Leonel T.; Rankin, Katherine P.; Yokoyama, Jennifer S.; Rutherford, Nicola J.; Fong, Jamie C.; Khan, Baber; Karydas, Anna; Baker, Matt C.; DeJesus-Hernandez, Mariely; Pribadi, Mochtar; Coppola, Giovanni; Geschwind, Daniel H.; Rademakers, Rosa; Lee, Suzee E.; Seeley, William; Miller, Bruce L.; Boxer, Adam L.

    2012-01-01

    Objective: To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion. Methods: A total of 648 patients with frontotemporal dementia (FTD)–related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD–motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS). Results: All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers. Conclusions: Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature. PMID:22875087

  14. Oxytocin for frontotemporal dementia: a systematic review.

    PubMed

    Tampi, Rajesh R; Maksimowski, Michael; Ahmed, Mohsina; Tampi, Deena J

    2017-01-01

    The aim of this systematic review is to identify published randomized controlled trials (RCTs) that evaluated the use of oxytocin in individuals with frontotemporal dementia (FTD). A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases for RCTs in any language that evaluated the use of oxytocin in individuals with FTD. Bibliographic databases of published articles were also searched for additional studies. A total of two RCTs that evaluated the use of oxytocin in individuals with FTD were identified. In one study, the use of oxytocin in individuals with FTD produced a reduction in identification of negative facial expressions (anger and fear) which can be hypothesized to improve trust and increase cooperation in these individuals. Both studies noted oxytocin was well tolerated and showed short term benefits on behavioral symptoms in individuals with FTD. Oxytocin appears to improve social aspects of cognition and behavioral symptoms in individuals with FTD and is well tolerated. However, positive data from larger and longer duration RCTs are needed before the routine use of oxytocin in individuals with FTD can be recommended.

  15. Intelligence and executive functions in frontotemporal dementia

    PubMed Central

    Roca, María; Manes, Facundo; Gleichgerrcht, Ezequiel; Watson, Peter; Ibáñez, Agustín; Thompson, Russell; Torralva, Teresa; Duncan, John

    2013-01-01

    Recently (Roca et al. (2010), we used the relationship with general intelligence (Spearman’s g) to define two sets of frontal lobe or “executive” tests. For one group, including Wisconsin card sorting and verbal fluency, reduction in g entirely explained the deficits found in frontal patients. For another group, including tests of social cognition and multitasking, frontal deficits remained even after correction for g. Preliminary evidence suggested a link of the latter tasks to more anterior frontal regions. Here we develop this distinction in the context of behavioural-variant frontotemporal dementia (bvFTD), a disorder which progressively affects frontal lobe cortices. In bvFTD, some executive tests, including tests of social cognition and multitasking, decline from the early stage of the disease, while others, including classical executive tests such as Wisconsin card sorting, verbal fluency or Trail Making Test part B, show deficits only later on. Here we show that, while deficits in the classical executive tests are entirely explained by g, deficits in the social cognition and multitasking tests are not. The results suggest a relatively selective cognitive deficit at mild stages of the disease, followed by more widespread cognitive decline well predicted by g. PMID:23347963

  16. Oxytocin for frontotemporal dementia: a systematic review

    PubMed Central

    Tampi, Rajesh R.; Maksimowski, Michael; Ahmed, Mohsina; Tampi, Deena J.

    2016-01-01

    Background: The aim of this systematic review is to identify published randomized controlled trials (RCTs) that evaluated the use of oxytocin in individuals with frontotemporal dementia (FTD). Methods: A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO and Cochrane collaboration databases for RCTs in any language that evaluated the use of oxytocin in individuals with FTD. Bibliographic databases of published articles were also searched for additional studies. Results: A total of two RCTs that evaluated the use of oxytocin in individuals with FTD were identified. In one study, the use of oxytocin in individuals with FTD produced a reduction in identification of negative facial expressions (anger and fear) which can be hypothesized to improve trust and increase cooperation in these individuals. Both studies noted oxytocin was well tolerated and showed short term benefits on behavioral symptoms in individuals with FTD. Conclusions: Oxytocin appears to improve social aspects of cognition and behavioral symptoms in individuals with FTD and is well tolerated. However, positive data from larger and longer duration RCTs are needed before the routine use of oxytocin in individuals with FTD can be recommended. PMID:28101324

  17. Intelligence and executive functions in frontotemporal dementia.

    PubMed

    Roca, María; Manes, Facundo; Gleichgerrcht, Ezequiel; Watson, Peter; Ibáñez, Agustín; Thompson, Russell; Torralva, Teresa; Duncan, John

    2013-03-01

    Recently (Roca et al. (2010), we used the relationship with general intelligence (Spearman's g) to define two sets of frontal lobe or "executive" tests. For one group, including Wisconsin card sorting and verbal fluency, reduction in g entirely explained the deficits found in frontal patients. For another group, including tests of social cognition and multitasking, frontal deficits remained even after correction for g. Preliminary evidence suggested a link of the latter tasks to more anterior frontal regions. Here we develop this distinction in the context of behavioural-variant frontotemporal dementia (bvFTD), a disorder which progressively affects frontal lobe cortices. In bvFTD, some executive tests, including tests of social cognition and multitasking, decline from the early stage of the disease, while others, including classical executive tests such as Wisconsin card sorting, verbal fluency or Trail Making Test part B, show deficits only later on. Here we show that, while deficits in the classical executive tests are entirely explained by g, deficits in the social cognition and multitasking tests are not. The results suggest a relatively selective cognitive deficit at mild stages of the disease, followed by more widespread cognitive decline well predicted by g. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Self-Consciousness Deficits in Alzheimer's Disease and Frontotemporal Dementia.

    PubMed

    Arroyo-Anlló, Eva Ma; Bouston, Adèle Turpin; Fargeau, Marie-Noëlle; Orgaz Baz, Begoña; Gil, Roger

    2017-01-01

    Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The main aim of this paper is to compare SC in patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Three groups (control and patient groups) of 23 subjects each were assessed using an SC questionnaire. Both types of dementia clearly induce an alteration of SC. The bvFTD group showed a greater impairment in SC than the AD and control groups. The SC score was strongly associated with frontal functions. The most significantly impaired SC aspects in the bvFTD group were Anosognosia, Introspection, and Moral Judgments. For the AD group, the significantly impaired aspects of SC were Anosognosia and Prospective Memory. The differences in SC between the AD and bvFTD groups were essentially centered on the Anosognosia, Moral Judgments, and Introspection aspects, which were highly impaired in the bvFTD patients. This suggests that SC is related to orbito-frontal functioning and thus, to the default mode network.

  19. Energy expenditure in frontotemporal dementia: a behavioural and imaging study.

    PubMed

    Ahmed, Rebekah M; Landin-Romero, Ramon; Collet, Tinh-Hai; van der Klaauw, Agatha A; Devenney, Emma; Henning, Elana; Kiernan, Matthew C; Piguet, Olivier; Farooqi, I Sadaf; Hodges, John R

    2017-01-01

    SEE FINGER DOI101093/AWW312 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Abnormal eating behaviour and metabolic parameters including insulin resistance, dyslipidaemia and body mass index are increasingly recognized as important components of neurodegenerative disease and may contribute to survival. It has previously been established that behavioural variant frontotemporal dementia is associated with abnormal eating behaviour characterized by increased sweet preference. In this study, it was hypothesized that behavioural variant frontotemporal dementia might also be associated with altered energy expenditure. A cohort of 19 patients with behavioural variant frontotemporal dementia, 13 with Alzheimer's disease and 16 (age- and sex-matched) healthy control subjects were studied using Actiheart devices (CamNtech) to assess resting and stressed heart rate. Actiheart devices were fitted for 7 days to measure sleeping heart rate, activity levels, and resting, active and total energy expenditure. Using high resolution structural magnetic resonance imaging the neural correlates of increased resting heart rate were investigated including cortical thickness and region of interest analyses. In behavioural variant frontotemporal dementia, resting (P = 0.001), stressed (P = 0.037) and sleeping heart rate (P = 0.038) were increased compared to control subjects, and resting heart rate (P = 0.020) compared to Alzheimer disease patients. Behavioural variant frontotemporal dementia was associated with decreased activity levels compared to controls (P = 0.002) and increased resting energy expenditure (P = 0.045) and total energy expenditure (P = 0.035). Increased resting heart rate correlated with behavioural (Cambridge Behavioural Inventory) and cognitive measures (Addenbrooke's Cognitive Examination). Increased resting heart rate in behavioural variant frontotemporal dementia correlated with atrophy involving the mesial temporal cortex, insula, and amygdala, regions previously

  20. Double dissociation of social functioning in frontotemporal dementia.

    PubMed

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

    2003-01-28

    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. 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. 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. 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.

  1. Pavlov's Orienting Response in Frontotemporal Dementia.

    PubMed

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

    2017-05-03

    Behavior variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder with initial disturbances in socioemotional behavior in the absence of a sensitive diagnostic test. This study evaluated Pavlov's "orienting response" (OR) or "what is it?" reflex as a measure of their ability to refocus attention on socioemotional stimuli and as a potentially distinguishing measure for bvFTD. Ten patients with bvFTD were compared with 18 normal controls (NC) on ORs (defined as initial heart rate [HR] deceleration) to different pictures based on social and emotional (valence) differences from the International Affective Picture Stimuli. HR was measured while participants viewed pleasant-nonsocial (e.g., food), unpleasant-nonsocial (e.g., garbage), pleasant-social (e.g., babies), and unpleasant-social (e.g., violence) pictures. Participants watched each picture for 6 seconds, and the study examined HR changes during the first 2-second OR interval. The results showed significant differences in valence (pleasant-unpleasant) and valence-group interactions, but no effects of nonsocial-social. Whereas the NCs showed the expected HR deceleration (OR) to unpleasant stimuli, the bvFTD patients showed increased HRs without an initial refocusing. Decreased HR slowing to stimuli among the bvFTD patients correlated with increased scores on an emotional blunting scale. These findings suggest that decreased socioemotional behavior in bvFTD may be associated with decreased appreciation of emotional aspects of stimuli as evidenced by decreased ORs to emotional stimuli, regardless of social content. These findings also suggest further investigation of the OR in bvFTD as an early diagnostic measure for this disorder.

  2. Parkinsonian Syndrome in Familial Frontotemporal Dementia

    PubMed Central

    Siuda, Joanna; Fujioka, Shinsuke; Wszolek, Zbigniew K.

    2014-01-01

    Parkinsonism in frontotemporal dementia (FTD) was first described in families with mutations in the microtubule-associated protein tau (MAPT) and progranulin (PRGN) genes. Since then, mutations in several other genes have been identified for FTD with Parkinsonism, including chromosome 9 open reading frame 72 (C9ORF72), chromatin modifying protein 2B (CHMP2B), valosin-containing protein (VCP), fused in sarcoma (FUS) and transactive DNA-binding protein (TARDBP). The clinical presentation of patients with familial forms of FTD with Parkinsonism is highly variable. The Parkinsonism seen in FTD patients is usually characterized by akinetic-rigid syndrome and is mostly associated with the behavioral variant of FTD (bvFTD); however, some cases may present with classical Parkinson’s disease. In other cases, atypical Parkinsonism resembling progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) has also been described. Although rare, Parkinsonism in FTD may coexist with motor neuron disease. Structural neuroimaging, which is crucial for the diagnosis of FTD, shows characteristic patterns of brain atrophy associated with specific mutations. Structural neuroimaging is not helpful in distinguishing among patients with parkinsonian features. Furthermore, dopaminergic imaging that shows nigrostriatal neurodegeneration in FTD with Parkinsonism cannot discriminate parkinsonian syndromes that arise from different mutations. Generally, Parkinsonism in FTD is levodopa unresponsive, but there have been cases where a temporary benefit has been reported, so dopaminergic treatment is worth trying, especially, when motor and non-motor manifestations can cause significant problems with daily functioning. In this review, we present an update on the clinical and genetic correlations of FTD with Parkinsonism. PMID:24998994

  3. Parkinsonian syndrome in familial frontotemporal dementia.

    PubMed

    Siuda, Joanna; Fujioka, Shinsuke; Wszolek, Zbigniew K

    2014-09-01

    Parkinsonism in frontotemporal dementia (FTD) was first described in families with mutations in the microtubule-associated protein tau (MAPT) and progranulin (PRGN) genes. Since then, mutations in several other genes have been identified for FTD with parkinsonism, including chromosome 9 open reading frame 72 (C9ORF72), chromatin modifying protein 2B (CHMP2B), valosin-containing protein (VCP), fused in sarcoma (FUS) and transactive DNA-binding protein (TARDBP). The clinical presentation of patients with familial forms of FTD with parkinsonism is highly variable. The parkinsonism seen in FTD patients is usually characterized by akinetic-rigid syndrome and is mostly associated with the behavioral variant of FTD (bvFTD); however, some cases may present with classical Parkinson's disease. In other cases, atypical parkinsonism resembling progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) has also been described. Although rare, parkinsonism in FTD may coexist with motor neuron disease. Structural neuroimaging, which is crucial for the diagnosis of FTD, shows characteristic patterns of brain atrophy associated with specific mutations. Structural neuroimaging is not helpful in distinguishing among patients with parkinsonian features. Furthermore, dopaminergic imaging that shows nigrostriatal neurodegeneration in FTD with parkinsonism cannot discriminate parkinsonian syndromes that arise from different mutations. Generally, parkinsonism in FTD is levodopa unresponsive, but there have been cases where a temporary benefit has been reported, so dopaminergic treatment is worth trying, especially, when motor and non-motor manifestations can cause significant problems with daily functioning. In this review, we present an update on the clinical and genetic correlations of FTD with parkinsonism. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Longitudinal Diffusion Tensor Imaging in Frontotemporal Dementia

    PubMed Central

    Mahoney, Colin J; Simpson, Ivor J A; Nicholas, Jennifer M; Fletcher, Phillip D; Downey, Laura E; Golden, Hannah L; Clark, Camilla N; Schmitz, Nicole; Rohrer, Jonathan D; Schott, Jonathan M; Zhang, Hui; Ourselin, Sebastian; Warren, Jason D; Fox, Nick C

    2015-01-01

    Objective Novel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD). Methods Twenty-three patients with bvFTD (12 having genetic mutations), and 18 age-matched control participants were assessed using DTI and neuropsychological batteries at baseline and ∼1.3 years later. Baseline and follow-up DTI scans were registered using a groupwise approach. Annualized rates of change for DTI metrics, neuropsychological measures, and whole brain volume were calculated. DTI metric performances were compared, and sample sizes for potential clinical trials were calculated. Results In the bvFTD group as a whole, rates of change in fractional anisotropy (FA) and mean diffusivity (MD) within the right paracallosal cingulum were greatest (FA: −6.8%/yr, p < 0.001; MD: 2.9%/yr, p = 0.01). MAPT carriers had the greatest change within left uncinate fasciculus (FA: −7.9%/yr, p < 0.001; MD: 10.9%/yr, p < 0.001); sporadic bvFTD and C9ORF72 carriers had the greatest change within right paracallosal cingulum (sporadic bvFTD, FA: −6.7%/yr, p < 0.001; MD: 3.8%/yr, p = 0.001; C9ORF72, FA: −6.8%/yr, p = 0.004). Sample size estimates using FA change were substantially lower than neuropsychological or whole brain measures of change. Interpretation Serial DTI scans may be useful for measuring disease progression in bvFTD, with particular trajectories of WM damage emerging. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials. PMID:25363208

  5. 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.

  6. 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

  7. Clinicopathologic differences among patients with behavioral variant frontotemporal dementia

    PubMed Central

    Joshi, Aditi; Tassniyom, Kanida; Teng, Edmond; Shapira, Jill S.

    2013-01-01

    Objective: To characterize the presenting symptoms and signs of patients clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and who had different neuropathologic findings on autopsy. Methods: This study reviewed all patients entered as clinical bvFTD in the National Alzheimer's Coordinating Center's database and who had both clinical and neuropathologic data from 2005 to 2011. Among the 107 patients identified, 95 had unambiguous pathologic findings, including 74 with frontotemporal lobar degeneration (bvFTD-FTLD) and 21 with Alzheimer disease (bvFTD-AD). The patients with bvFTD-FTLD were further subdivided into τ-positive (n = 23) or τ-negative (n = 51) histopathology subgroups. Presenting clinical signs and symptoms were compared between these neuropathologic groups. Results: The patients with bvFTD-FTLD were significantly more likely than patients with bvFTD-AD to have initially predominant personality changes and poor judgment/decision-making. In contrast, patients with bvFTD-AD were more likely than patients with bvFTD-FTLD to have memory difficulty and delusions/hallucinations and agitation. Within the bvFTD-FTLD group, the τ-positive subgroup had more patients with initial behavioral problems and personality change than the τ-negative subgroup, who, in turn, had more patients with initial cognitive impairment and speech problems. Conclusion: During life, patients with AD pathology may be misdiagnosed with bvFTD if they have an early age at onset and prominent neuropsychiatric features despite having greater memory difficulties and more intact personality and executive functions than patients with bvFTD-FTLD. Among those with FTLD pathology, patients with τ-positive bvFTD were likely to present with behavior/personality changes. These findings offer clues for antemortem recognition of neuropathologic subtypes of bvFTD. PMID:23325909

  8. Clinicopathologic differences among patients with behavioral variant frontotemporal dementia

    PubMed Central

    Mendez, Mario F.; Joshi, Aditi; Tassniyom, Kanida; Teng, Edmond; Shapira, Jill S.

    2012-01-01

    Objective To characterize the presenting symptoms and signs of patients clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and who had different neuropathologic findings on autopsy. Methods This study reviewed all patients entered as clinical bvFTD in the National Alzheimer’s Coordinating Center’s database and who had both clinical and neuropathologic data from 2005 to 2011. Among the 107 patients identified, 95 had unambiguous pathologic findings, including 74 with frontotemporal lobar degeneration (bvFTD-FTLD) and 21 with Alzheimer disease (bvFTD-AD). The patients with bvFTD-FTLD were further subdivided into τ-positive (n = 23) or τ-negative (n = 51) histopathology subgroups. Presenting clinical signs and symptoms were compared between these neuropathologic groups. Results The patients with bvFTD-FTLD were significantly more likely than patients with bvFTD-AD to have initially predominant personality changes and poor judgment/decision-making. In contrast, patients with bvFTD-AD were more likely than patients with bvFTD-FTLD to have memory difficulty and delusions/hallucinations and agitation. Within the bvFTD-FTLD group, the τ-positive subgroup had more patients with initial behavioral problems and personality change than the τ-negative subgroup, who, in turn, had more patients with initial cognitive impairment and speech problems. Conclusion During life, patients with AD pathology may be misdiagnosed with bvFTD if they have an early age at onset and prominent neuropsychiatric features despite having greater memory difficulties and more intact personality and executive functions than patients with bvFTD-FTLD. Among those with FTLD pathology, patients with τ-positive bvFTD were likely to present with behavior/personality changes. These findings offer clues for antemortem recognition of neuropathologic subtypes of bvFTD. PMID:17522386

  9. 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…

  10. 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…

  11. 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

  12. Frontotemporal dementia affecting a U.S. Air Force officer.

    PubMed

    Faber, Raymond; Hill, Victoria M; Kim, Billy J

    2003-04-01

    We present the case of a 51-year-old former U.S. Air Force officer who developed marked behavioral and personality changes over a 9-year period, ultimately leading to his discharge from the Air Force at a rank below that which he achieved during service. Clinical diagnostic features, neuropsychological testing and neuroimaging together confirmed a diagnosis of frontotemporal dementia. This form of presenile dementia is discussed with reference to his case.

  13. 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…

  14. Improving response inhibition systems in frontotemporal dementia with citalopram

    PubMed Central

    Rittman, Timothy; Regenthal, Ralf; Robbins, Trevor W.; Rowe, James B.

    2015-01-01

    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

  15. von Economo neurones are selectively targeted in frontotemporal dementia.

    PubMed

    Santillo, A F; Nilsson, C; Englund, E

    2013-08-01

    von Economo neurones (VEN) are bipolar neurones located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population. A previous study has shown a selective loss of VEN in FTD above other neurones in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology. VEN and neighbouring neurones (NN) were quantified in layers Va and Vb of the right dorsal ACC in 21 cases of bvFTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC). A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n = 13), VEN/10,000 NN was significantly reduced by 53% compared with NDC (P < 0.001) and 41% compared with AD (P = 0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10,000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups. In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process. © 2013 British Neuropathological Society.

  16. 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…

  17. 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…

  18. Temporal Variant Frontotemporal Dementia is Associated with Globular Glial Tauopathy.

    PubMed

    Clark, Camilla N; Lashley, Tammaryn; Mahoney, Colin J; Warren, Jason D; Revesz, Tamas; Rohrer, Jonathan D

    2015-06-01

    Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick's disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant.

  19. Diminished Disgust Reactivity in Behavioral Variant Frontotemporal Dementia

    PubMed Central

    Eckart, Janet A.; Sturm, Virginia E.; Miller, Bruce L.; Levenson, Robert W.

    2012-01-01

    Frontotemporal dementia is a neurodegenerative disease that impacts emotion and social behavior. Using laboratory measures of emotional reactivity, our past work has found that reactivity to loud noises and to thematically simple happy and sad emotional films are preserved in the early stages of the disease while other emotional responses (e.g., embarrassment) are severely compromised. In the present study we examined disgust, an emotion whose function is to distance us from offending objects and situations. We measured disgust reactivity in 21 patients with behavioral variant frontotemporal dementia (bvFTD, a subtype of frontotemporal dementia characterized by emotional blunting) and 25 neurologically healthy controls. Disgust is an emotion of particular interest in bvFTD, due to caregiver and clinician reports that patients engage in acts that suggest this emotion may be compromised; in addition, the pattern of neurodegeneration in bvFTD includes atrophy of key frontotemporal structures (e.g., anterior insula) with known roles in visceral emotions such as disgust. In the present study, participants had their emotional facial behavior, physiology, and self-reported emotional experience measured while watching a disgust-eliciting film. We found that behavioral, physiological, and self-reported experiential responses were all reduced in bvFTD patients compared to controls (with behavioral and physiological differences still found after controlling for patients’ cognitive deficits). We discuss the implications of these findings for bvFTD patients’ problems in social functioning and their typical patterns of neurodegeneration. PMID:22285794

  20. Dementia Apraxia Test (DATE): A Brief Tool to Differentiate Behavioral Variant Frontotemporal Dementia from Alzheimer's Dementia Based on Apraxia Profiles.

    PubMed

    Johnen, Andreas; Frommeyer, Jana; Modes, Fenja; Wiendl, Heinz; Duning, Thomas; Lohmann, Hubertus

    2016-01-01

    Standardized praxis assessments with modern, empirically validated screening tests have substantially improved clinical evaluation of apraxia in patients with stroke. Although apraxia may contribute to early differential diagnosis of Alzheimer's dementia (AD) and behavioral variant frontotemporal dementia (bvFTD), no comparable test is readily available to clinicians for this purpose to date. To design a clinically useful apraxia test for the differentiation of AD and bvFTD. 84 test items pertaining to twelve praxis subdomains were evaluated for their efficacy to discriminate between patients with bvFTD (n = 24), AD (n = 28), and elderly healthy controls (HC; n = 35). Items were then selected based on discriminative value and psychometric properties. Items indicative of mild AD comprised spatially complex imitation of hand and finger postures and to a lesser degree, pantomime of common object-use. Buccofacial apraxia including imitation of face postures, emblematic face postures, and repetition of multisyllabic pseudowords differentiated bvFTD from HC and AD. The final test version consisting of 20 items proved highly efficient for the discrimination of biologically confirmed dementia patients from HC (sensitivity 91% , specificity 71%) but also for differential diagnosis of bvFTD and AD (sensitivity 74% , specificity 93%). Assessment of praxis profiles effectively contributes to diagnosis and differential diagnosis of AD and bvFTD. The Dementia Apraxia Test (DATE) is a brief and easy to administer cognitive tool for dementia assessment, has a high inter-rater reliability (Cohen's κ= 0.885) and demonstrates content validity.

  1. 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

  2. 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.

  3. Frontotemporal dementia-related gene mutations in clinical dementia patients from a Chinese population.

    PubMed

    Shi, Zhihong; Liu, Shuai; Xiang, Lei; Wang, Ying; Liu, Mengyuan; Liu, Shuling; Han, Tong; Zhou, Yuying; Wang, Jinhuan; Cai, Li; Gao, Shuo; Ji, Yong

    2016-12-01

    Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia that show overlapping clinical symptoms. The aim of this study was to perform genetic analyses on GRN, VCP, CHMP2B, FUS, TARDBP, C9orf72 and MAPT genes in Chinese AD and FTD patients. We performed gene sequencing of the GRN, VCP, CHMP2B, FUS, TARDBP, MAPT and C9orf72 genes in 61 clinical AD and 38 FTD Chinese patients. We identified a known mutation of MAPT (p.Pro301Leu, c.902C>T) in four patients from an autosomal dominant FTD family with behavioral variant FTD (bvFTD) and progressive nonfluent aphasia (PNFA) phenotypes, and a novel mutation in MAPT (p.Leu48Val, c.142 G>C) in a sporadic progressive supranuclear palsy patient. Two novel variations in VCP (p.Thr127Ala, c. 379A>G; p.Asn401Ser, c.1202A>G) were present in both a sporadic FTD and an AD case, and a novel deletion in GRN (560del p.Leufs) was found in a sporadic primary progressive aphasia patient. Mutations of VCP, GRN and MAPT genes are present in Chinese FTD cases. In the case of the MAPT mutation, the family presented with both bvFTD and PNFA phenotypes, while the VCP mutation was also related to an early-onset AD phenotype.

  4. Functional MRI of music emotion processing in frontotemporal dementia

    PubMed Central

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

    2015-01-01

    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. PMID:25773639

  5. 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.

  6. Functional Status in Behavioral Variant Frontotemporal Dementia: A Systematic Review

    PubMed Central

    Lima-Silva, Thais Bento; Bahia, Valéria Santoro; Nitrini, Ricardo; Yassuda, Mônica Sanches

    2013-01-01

    The aim was to conduct a systematic review of studies that described the functional profile of patients with behavioral variant frontotemporal dementia (bvFTD), published between 2000 and 2013. The bibliographic search was conducted using the terms “frontotemporal dementia” and “frontotemporal lobar degeneration” in combination with “independence,” “functionality,” “basic activities of daily living,” “disability,” and scales that measure functional performance: “Disability Assessment for Dementia-DAD,” “Functional Activities Questionnaire (FAQ),” “Direct Assessment of Functional Status (DAFS).” To be included in the review, the study had to mention the characterization of the functional status of patients with bvFTD in the objectives of the study, using a previously validated instrument of functional assessment. Fourteen studies met this criterion. The reviewed studies suggested that individuals with bvFTD have greater functional impairment when compared to those with other subtypes of frontotemporal lobar degeneration or Alzheimer's disease. The studies documented a significant association between cognitive impairment and measures of functionality in these patients. The cognitive profile of patients may predict faster functional decline. PMID:24308008

  7. Frontotemporal Dementia Caused by CHMP2B Mutations

    PubMed Central

    Isaacs, A.M; Johannsen, P; Holm, I; Nielsen, J.E; Consortium, FReJA

    2011-01-01

    CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease. PMID:21222599

  8. The role of CHMP2B in frontotemporal dementia.

    PubMed

    Urwin, Hazel; Ghazi-Noori, Shabnam; Collinge, John; Isaacs, Adrian

    2009-02-01

    Mutations in the CHMP2B (charged multivesicular body protein 2B) gene that lead to C-terminal truncations of the protein can cause frontotemporal dementia. CHMP2B is a member of ESCRT-III (endosomal sorting complex required for transport III), which is required for formation of the multivesicular body, a late endosomal structure that fuses with the lysosome to degrade endocytosed proteins. Overexpression of mutant C-terminally truncated CHMP2B proteins produces an enlarged endosomal phenotype in PC12 and human neuroblastoma cells, which is likely to be due to a dominant-negative effect on endosomal function. Disruption of normal endosomal trafficking is likely to affect the transport of neuronal growth factors and autophagic clearance of proteins, both of which could contribute to neurodegeneration in frontotemporal dementia.

  9. Frontotemporal dementia caused by CHMP2B mutations.

    PubMed

    Isaacs, A M; Johannsen, P; Holm, I; Nielsen, J E

    2011-05-01

    CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease.

  10. 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

  11. Precision medicine of frontotemporal dementia: from genotype to phenotype.

    PubMed

    Che, Xiang-Qian; Song, Ning; Gao, Ying; Ren, Ru-Jing; Wang, Gang

    2018-01-01

    Frontotemporal dementia (FTD) is the second most common neurodegenerative  cause of early-onset dementia. FTD has an important genetic component contributing to its pathogenic mechanisms. Currently, extensive research on neuroimaging biomarkers and neurochemical biomarkers in FTD is being conducted to address the clinical need for a sensitive and specific diagnostic marker. Here, we review the advances in genetics, biomarkers and treatment of FTD and how this may represent a shift towards precision medicine. To advance the clinical use of precision medicine, big data cohort for genotype/phenotype research and multidisciplinary team approaches are necessary.

  12. Agenesis of corpus callosum and frontotemporal dementia: a casual finding?

    PubMed

    Calabrò, Rocco Salvatore; Spadaro, Letteria; Marra, Angela; Balletta, Tina; Cammaroto, Simona; Bramanti, Placido

    2015-06-01

    Agenesis of corpus callosum (AgCC) is a congenital malformation characterized by total or partial absence of corpus callosum with a good neuropsychological profile. Frontotemporal dementia (FTD) is the third most common cause of cortical dementia, and it is characterized by alterations in personality and social relationship, often associated with deficits in attention, abstraction, planning, and problem solving. Herein, we report a case of a 73-year-old woman presenting with FTD associated with primary AgCC. The possible "causal or casual" relationship between these 2 different conditions should be investigated in large prospective studies.

  13. 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.

  14. Behavioural variant frontotemporal dementia: clinical and therapeutic approaches.

    PubMed

    Fernández-Matarrubia, M; Matías-Guiu, J A; Moreno-Ramos, T; Matías-Guiu, J

    2014-10-01

    Behavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. We reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. BvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  15. Etiology and Pathophysiology of Frontotemporal Dementia, Parkinson Disease and Alzheimer Disease: Lessons from Genetic Studies

    PubMed Central

    Wider, Christian; Wszolek, Zbigniew K.

    2008-01-01

    Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA, PRKN, DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease. PMID:18322368

  16. Etiology and pathophysiology of frontotemporal dementia, Parkinson disease and Alzheimer disease: lessons from genetic studies.

    PubMed

    Wider, Christian; Wszolek, Zbigniew K

    2008-01-01

    Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease. 2008 S. Karger AG, Basel

  17. 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.

  18. 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

  19. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.

    PubMed

    Goetzl, Edward J; Kapogiannis, Dimitrios; Schwartz, Janice B; Lobach, Iryna V; Goetzl, Laura; Abner, Erin L; Jicha, Gregory A; Karydas, Anna M; Boxer, Adam; Miller, Bruce L

    2016-12-01

    Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia in patients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid β-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias.-Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., Jicha, G. A., Karydas, A. M., Boxer, A., Miller, B. L. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.

  20. A Systematic Review of Metacognitive Differences Between Alzheimer's Disease and Frontotemporal Dementia.

    PubMed

    DeLozier, Sarah J; Davalos, Deana

    2016-08-01

    Clinicians often have difficulty distinguishing between various forms of dementia to achieve a correct diagnosis. Little research has been done to examine whether awareness of one's cognitive deficits, or metacognitive monitoring, might differ between dementia diagnoses, thereby providing an additional means of differentiating between dementia subtypes. We review articles examining metacognitive comparisons between two of the most common dementia subtypes: Alzheimer's disease and frontotemporal dementia. Greater monitoring deficits were apparent in frontotemporal dementia than in Alzheimer's disease, and participants with frontotemporal dementia were less likely to utilize task experience to update and improve the accuracy of subsequent monitoring judgments. Results provide evidence for the utility of metacognitive measures as a means of distinguishing between Alzheimer's disease and frontotemporal dementia.

  1. 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

  2. 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

  3. Frontotemporal dementia and primary progressive aphasia, a review

    PubMed Central

    Kirshner, Howard S

    2014-01-01

    Frontotemporal dementias are neurodegenerative diseases in which symptoms of frontal and/or temporal lobe disease are the first signs of the illness, and as the diseases progress, they resemble a focal left hemisphere process such as stroke or traumatic brain injury, even more than a neurodegenerative disease. Over time, some patients develop a more generalized dementia. Four clinical subtypes characterize the predominant presentations of this illness: behavioral or frontal variant FTD, progressive nonfluent aphasia, semantic dementia, and logopenic primary progressive aphasia. These clinical variants correlate with regional patterns of atrophy on brain imaging studies such as MRI and PET scanning, as well as with biochemical and molecular genetic variants of the disorder. The treatment is as yet only symptomatic, but advances in molecular genetics promise new therapies. PMID:24966676

  4. Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy.

    PubMed

    Borroni, B; Turrone, R; Galimberti, D; Nacmias, B; Alberici, A; Benussi, A; Caffarra, P; Caltagirone, C; Cappa, S F; Frisoni, G B; Ghidoni, R; Marra, C; Padovani, A; Rainero, I; Scarpini, E; Silani, V; Sorbi, S; Tagliavini, F; Tremolizzo, L; Bruni, A C

    2015-05-01

    In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

  5. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

    PubMed

    Rascovsky, Katya; Hodges, John R; Knopman, David; Mendez, Mario F; Kramer, Joel H; Neuhaus, John; van Swieten, John C; Seelaar, Harro; Dopper, Elise G P; Onyike, Chiadi U; Hillis, Argye E; Josephs, Keith A; Boeve, Bradley F; Kertesz, Andrew; Seeley, William W; Rankin, Katherine P; Johnson, Julene K; Gorno-Tempini, Maria-Luisa; Rosen, Howard; Prioleau-Latham, Caroline E; Lee, Albert; Kipps, Christopher M; Lillo, Patricia; Piguet, Olivier; Rohrer, Jonathan D; Rossor, Martin N; Warren, Jason D; Fox, Nick C; Galasko, Douglas; Salmon, David P; Black, Sandra E; Mesulam, Marsel; Weintraub, Sandra; Dickerson, Brad C; Diehl-Schmid, Janine; Pasquier, Florence; Deramecourt, Vincent; Lebert, Florence; Pijnenburg, Yolande; Chow, Tiffany W; Manes, Facundo; Grafman, Jordan; Cappa, Stefano F; Freedman, Morris; Grossman, Murray; Miller, Bruce L

    2011-09-01

    Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older

  6. Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia.

    PubMed

    Rostgaard, Nina; Waldemar, Gunhild; Nielsen, Jørgen Erik; Simonsen, Anja Hviid

    2015-01-01

    As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

  7. 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

  8. Insight in frontotemporal dementia: conceptual analysis and empirical evaluation of the consensus criterion "loss of insight" in frontotemporal dementia.

    PubMed

    Evers, Kathinka; Kilander, Lena; Lindau, Maria

    2007-02-01

    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 tomography (PET) participated in the study). The results indicated that insight was present in three out of eight patients, and that insight appears to be a heterogeneous concept. Two types of insight emerged: Emotional insight associated with frontotemporal functions, and cognitive insight, related to posterior cognitive functions. These results suggest that loss of insight should not serve as a core criterion on FTD, but serves well as a supportive criterion of the disease.

  9. Emotional evaluation and memory in behavioral variant frontotemporal dementia.

    PubMed

    St Jacques, Peggy L; Grady, Cheryl; Davidson, Patrick S R; Chow, Tiffany W

    2015-01-01

    Behavioral variant frontotemporal dementia (bvFTD) affects emotional evaluation, but less is known regarding the patients' ability to remember emotional stimuli. Here, bvFTD patients and age-matched controls studied positive, negative, and neutral pictures followed by a recognition memory test. Compared to controls, bvFTD patients showed a reduction in emotional evaluation of negative scenes, but not of positive or neutral scenes. Additionally, the patients showed an overall reduction in recognition memory accuracy, due to impaired recollection in the face of relatively preserved familiarity. These results show that bvFTD reduces the emotional evaluation of negative scenes and impairs overall recognition memory accuracy and recollection.

  10. Acquired extroversion associated with bitemporal variant of frontotemporal dementia.

    PubMed

    Mendez, Mario F; Chen, Andrew K; Shapira, Jill S; Lu, Po-Huang; Miller, Bruce L

    2006-01-01

    Frontotemporal dementia (FTD) is characterized by alterations in personality. The nature of the personality changes depend on the localization of the pathology. The authors present three patients with acquired extroversion who met criteria for FTD. All three patients exhibited predominant bilateral temporal involvement as determined with functional neuroimaging. Possible mechanisms for acquired extroversion in bitemporal FTD include bilateral amygdalar damage with decreased interpersonal fear or sense of threat, orbitofrontal-ventromedial damage with social disinhibition, and relative sparing of dorsolateral frontal and anterior cingulate regions with preserved interpersonal agency. FTD can be a vehicle for unraveling the basis of personality characteristics such as the introversion/extroversion dimension.

  11. Overlap in frontotemporal atrophy between normal aging and patients with frontotemporal dementias.

    PubMed

    Chow, Tiffany W; Binns, Malcolm A; Freedman, Morris; Stuss, Donald T; Ramirez, Joel; Scott, Chris J M; Black, Sandra

    2008-01-01

    Normal aging leads to frontocortical atrophy. The degree to which this complicates the use of frontotemporal atrophy as a diagnostic criterion for the frontotemporal dementias (FTDs) has not been reported. The present case-control study compared frontotemporal volumes delineated with semi-automatic brain region extraction [n=30 controls vs. 16 behavioral variant FTD (bvFTD) vs. 14 primary progressive aphasia]. Logistic regression identified those regions least helpful for distinguishing bvFTD and primary progressive aphasia from controls. Linear regression tested the correlation of duration of illness to atrophy severity. The control group showed high variance in volumes. Controls had right frontal lobe volumes that overlapped considerably with bvFTD volumes, but, as anticipated, the left anterior temporal volumes of interest showed 91% accuracy in distinguishing the aphasic subgroup from controls. Left-sided and not right-sided atrophy in the medial middle frontal region distinguished the bvFTD group from controls. The relegation of structural imaging to a supportive criterion for diagnosis is reasonable in the context of the range of atrophy due to normal aging. While volumetry identified left-sided atrophy as useful for identifying FTD cases, future studies should determine whether clinicians could make these distinctions on viewing routine diagnostic magnetic resonance imaging scans.

  12. Biomarkers: a new approach to behavioural variant frontotemporal dementia.

    PubMed

    Fernández-Matarrubia, M; Matías-Guiu, J A; Moreno-Ramos, T; Matías-Guiu, J

    2015-01-01

    Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  13. CADASIL presenting with a behavioural variant frontotemporal dementia phenotype.

    PubMed

    Alexander, S K; Brown, J M; Graham, A; Nestor, P J

    2014-01-01

    The behavioural variant of frontotemporal dementia (bvFTD) is characterised by personality change with a decline in cognition. We describe two patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) who presented with behavioural phenotypes similar to bvFTD. The first patient presented with progressive personality and behavioural change, had florid white matter hyperintensity, and had a novel missense mutation C366W in exon 7 of the Notch3 gene. The second patient presented with progressive memory impairment and marked personality changes after a transient ischaemic attack. In this second patient, the radiological features were subtle and only the family history of stroke prompted testing for CADASIL using Notch3 genotyping. We present these patients to demonstrate that CADASIL may mimic bvFTD, with little clinical or radiological evidence to distinguish the two. CADASIL may be an under-recognised diagnosis in apparent bvFTD. Screening Notch3 in a substantial and unselected cohort of frontotemporal dementia patients might be appropriate to investigate this possibility.

  14. 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

  15. Neuropsychiatric symptom profile differs based on pathology in patients with clinically diagnosed behavioral variant frontotemporal dementia

    PubMed Central

    Léger, Gabriel C; Banks, Sarah J

    2014-01-01

    Background/Aims Behavioral variant frontotemporal dementia (bvFTD) is pathologically heterogeneous. With emerging therapeutics, determining underlying pathology during life is increasingly important. Neuropsychiatric symptoms are prevalent and diagnostic in bvFTD. Methods We assessed the neuropsychiatric profile in patients with clinically diagnosed bvFTD as a function of pathology at autopsy. Patients with a clinical diagnosis of bvFTD at initial visit were selected from the National Alzheimer's Coordinating Center database. Neuropsychiatric symptoms endorsed on the Neuropsychiatric Inventory Questionnaire were analyzed. Results Of 149 patients with clinically diagnosed bvFTD, pathology was primarily Alzheimer's disease in 20.5%. These patients differed from those with underlying frontotemporal lobar degeneration: patients with AD pathology (plaques and tangles) were more likely to have hallucinations, delusions, or agitation. Patients were further differentiated into tau positive (30 % of cases, including Pick's disease, frontotemporal dementia and parkinsonism with tau-positive, and other tauopathies) or tau-negative (70% of cases including bvFTD tau-negative ubiquitin-positive inclusions). These patients also differed in some of the neuropsychiatric symptoms seen. Tau-negative cases were more likely to demonstrate depression, delusions, and changes in appetite and eating. Conclusions These preliminary findings contribute to our increasing ability to predict, using simple clinical tools the neuropathological underpinnings of bvFTD during life. PMID:24135712

  16. The Free and Cued Selective Reminding Test Distinguishes Frontotemporal Dementia From Alzheimer's Disease

    PubMed Central

    Lemos, Raquel; Duro, Diana; Simões, Mário R.; Santana, Isabel

    2014-01-01

    Memory impairment is often present in frontotemporal dementia (FTD) as a result of an inefficient use of learning strategies, sometimes leading to a misdiagnosis of Alzheimer's disease (AD). The Free and Cued Selective Reminding Test (FCSRT) is a memory test that controls attention and acquisition, by providing category cues in the learning process. The main goal of this study was to show the usefulness of the FCSRT in the distinction between behavioral (bv-) FTD and AD. Three matched subgroups of participants were considered: bv-FTD (n = 32), AD (n = 32), and a control group of healthy adults (n = 32). Results proved that while AD patients exhibited an overall impairment in FCSRT, bv-FTD subjects showed to benefit more from the controlled learning through category cues. AD patients were 25 times more likely to have an impaired FCSRT. The FCSRT has shown its utility in the distinction between bv-FTD and AD, therefore increasing the diagnostic accuracy. PMID:25062746

  17. Role of Brain Infarcts in Behavioral Variant Frontotemporal Dementia

    PubMed Central

    Torralva, Teresa; Sposato, Luciano A.; Riccio, Patricia M.; Gleichgerrcht, Ezequiel; Roca, María; Toledo, Jon B.; Trojanowski, John Q.; Kukull, Walter A.; Manes, Facundo; Hachinski, Vladimir

    2015-01-01

    Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). We compared demographic data, clinical diagnoses, vascular risk factors, functional status, and normalized neuropsychological z-scores between patients with V-bvFTD vs. bvFTD without concomitant cerebrovascular disease (NV-bvFTD) from the National Alzheimer’s Coordinating Centre database. We included 391 neuropathologically diagnosed cases of frontotemporal lobe degeneration (FTLD). We excluded patients that were diagnosed with aphasic variants of frontotemporal dementia before death. Patients with V-bvFTD (n=62) were older at the time of onset of cognitive decline (71.6 vs. 62.5years, p<0.001) and death (78.7 vs. 69.6, p<0.001), more likely to be hypertensive (75.8 vs. 45.7%, p=0.002), and to have a history of stroke (21.2 vs. 6.1%, p=0.007) than those with NV-bvFTD (n=329). V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that FTLD-related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD. PMID:26220367

  18. Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia

    PubMed Central

    Khan, Baber K.; Natesan, Alamelu; Karydas, Anna; Dallman, Mary; Havel, Peter; Miller, Bruce L.; Rankin, Katherine P.

    2014-01-01

    Objective: To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study. Methods: Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healthy normal controls [NCs]) were recruited from a tertiary-care dementia clinic. During a standardized breakfast, blood was drawn before, during, and after the breakfast protocol to quantify levels of peripheral satiety-related hormones (ghrelin, cortisol, insulin, leptin, and peptide YY) and glucose. To further explore the role of patients' feeding abnormalities on hormone levels, patients were classified into overeating and nonovereating subgroups based on feeding behavior during separate laboratory-based standardized lunch feeding sessions. Results: Irrespective of their feeding behavior in the laboratory, patients with bvFTD, but not patients with Alzheimer disease dementia, have significantly lower levels of ghrelin and cortisol and higher levels of insulin compared with NCs. Furthermore, while laboratory feeding behavior did not predict alterations in levels of ghrelin, cortisol, and insulin, only patients with bvFTD who significantly overate in the laboratory demonstrated significantly higher levels of leptin compared with NCs, suggesting that leptin may be sensitive to particularly severe feeding abnormalities in bvFTD. Conclusions: Despite a tendency to overeat, patients with bvFTD have a hormonal profile that should decrease food intake. Aberrant hormone levels may represent a compensatory response to the behavioral or neuroanatomical abnormalities of bvFTD. PMID:24415571

  19. Do NIA-AA criteria distinguish Alzheimer's disease from frontotemporal dementia?

    PubMed

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

    2015-02-01

    Clinical criteria are important for improving diagnostic accuracy and ensuring comparability of patient cohorts in research studies. The aim was to assess the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer's disease (AD) dementia in AD and frontotemporal lobar degeneration (FTLD). Two hundred twelve consecutive patients with pathologically confirmed AD or FTLD who were clinically assessed in a specialist cognitive unit were identified. Fifty-five patients were excluded predominantly because of insufficient clinical information. Anonymized clinical data were rated against the NIA-AA criteria by raters who were blinded to clinical and pathologic diagnosis. The NIA-AA AD dementia criteria had a sensitivity of 65.6% for probable and 79.5% for possible AD and a specificity of 95.2% and 94.0% for probable and possible, respectively. In patients with FTLD and predominantly early-onset AD, the NIA-AA AD dementia criteria have high specificity but lower sensitivity. The high specificity is due to the broad exclusion criteria. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  20. Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia.

    PubMed

    Mukherjee, Odity; Wang, Jun; Gitcho, Michael; Chakraverty, Sumi; Taylor-Reinwald, Lisa; Shears, Shantia; Kauwe, John S K; Norton, Joanne; Levitch, Denise; Bigio, Eileen H; Hatanpaa, Kimmo J; White, Charles L; Morris, John C; Cairns, Nigel J; Goate, Alison

    2008-04-01

    Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3' splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.

  1. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review.

    PubMed

    Seelaar, Harro; Rohrer, Jonathan D; Pijnenburg, Yolande A L; Fox, Nick C; van Swieten, John C

    2011-05-01

    Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will

  2. Memory profiles in pathology or biomarker confirmed Alzheimer disease and frontotemporal dementia.

    PubMed

    Mansoor, Yael; Jastrzab, Laura; Dutt, Shubir; Miller, Bruce L; Seeley, William W; Kramer, Joel H

    2015-01-01

    We examined verbal list memory in participants with pathology-confirmed or biomarker-supported diagnoses to clarify inconsistencies in comparative memory performance. We hypothesized that Alzheimer disease (AD) participants would show more rapid forgetting, whereas behavioral-variant frontotemporal dementia (bvFTD) participants would show a more dysexecutive pattern. We also explored differences in medial temporal volumes, and relative frontal and medial temporal area contributions to memory consolidation. Participants had clinical diagnoses of AD and bvFTD who were pathologically confirmed at autopsy or supported with Pittsburgh compound B amyloid imaging. We used cognitive and imaging data collected at baseline visits for a sample of 26 participants with AD (mean age=63.7, education=16.2, Clinical Dementia Rating=0.8), 25 participants with bvFTD (mean age=60.7; education=15.7; CRD=1.1), and 25 healthy controls (mean age=65.6; education=17.5; Clinical Dementia Rating=0.2). AD participants showed more rapid forgetting than bvFTD, and both groups showed more rapid forgetting than controls. In contrast, bvFTD did not conform to a more dysexecutive pattern of performance as patient groups committed similar number of intrusion errors and showed comparably low rates of improvement on cued recall and recognition trials. For patients with neuroimaging, there were no group differences in medial temporal volumes, which was the only significant predictor of consolidation for both dementia groups.

  3. 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.

  4. 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

  5. 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

  6. A scale of socioemotional dysfunction in frontotemporal dementia.

    PubMed

    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

    2014-12-01

    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.

  7. Substance use history in behavioral-variant frontotemporal dementia versus primary progressive aphasia.

    PubMed

    Kalapatapu, Raj K; Delucchi, Kevin L; Wang, Sophia; Harbison, John D; Nelson, Emily E; Kramer, Joel H

    2016-01-01

    As older adults are prone to cognitive disorders, the interaction of the fields of substance use and misuse and cognitive neuroscience is an emerging area of research. Substance use has been reported in some subtypes of frontotemporal dementia, such as behavioral variant frontotemporal dementia. However, characterization of substance use in other subtypes of frontotemporal dementia, such as primary progressive aphasia, is unknown. The objective of this baseline analysis was to explore whether any measures of substance use history differed significantly among behavioral variant frontotemporal dementia (n = 842) and primary progressive aphasia (n = 526) in a large national dataset. The National Alzheimer's Coordinating Center's Uniform Data Set study is a national dataset that collects data on patients with various cognitive disorders and includes some questions on substance use. Each substance use variable was used as the outcome and the frontotemporal dementia subtype as the predictor. Total years smoked cigarettes, age when last smoked cigarettes, average number of packs/day smoked when participants smoked, and any recent, remote, or combined recent/remote history of alcohol abuse or drug abuse did not significantly differ between the behavioral variant frontotemporal dementia and primary progressive aphasia subtypes (all p-values > .001). A significantly greater percentage of participants smoked in the last 30 days in the behavioral variant frontotemporal dementia subtype (10.4%, n = 834) compared to the primary progressive aphasia subtype (3.3%, n = 517; p < .001). Clinical providers in both the dementia and substance use fields are encouraged to screen for and monitor substance use in all frontotemporal dementia subtypes.

  8. Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer's disease.

    PubMed

    Ferri, Evelyn; Arosio, Beatrice; D'Addario, Claudio; Galimberti, Daniela; Gussago, Cristina; Pucci, Mariangela; Casati, Martina; Fenoglio, Chiara; Abbate, Carlo; Rossi, Paolo Dionigi; Scarpini, Elio; Maccarrone, Mauro; Mari, Daniela

    2016-03-15

    Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) share the accumulation of fibrillar aggregates of misfolded proteins. To better understand these neurodegenerative diseases and identify biomarkers in easily accessible cells, we investigated DNA methylation at Pin1 gene promoter and its expression in peripheral blood mononuclear cells of FTD patients. We found a lower gene expression of Pin1 with a higher DNA methylation in three CpG sites at Pin1 gene promoter analysed in FTD subjects, in contrast to a higher gene expression with a lower methylation in AD subjects and controls. These data suggest an important and distinct involvement of Pin1 in these two types of dementia.

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

    PubMed

    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.

  10. 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

  11. 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

  12. 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.

  13. Frontotemporal dementia selectively impairs transitive reasoning about familiar spatial environments.

    PubMed

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

    2009-09-01

    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 frontal-variant 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.

  14. 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.

  15. Recent Advances in the Imaging of Frontotemporal Dementia

    PubMed Central

    Whitwell, Jennifer L.; Josephs, Keith A.

    2012-01-01

    Neuroimaging has played an important role in the characterization of the frontotemporal dementia (FTD) syndromes, demonstrating neurodegenerative signatures that can aid in the differentiation of FTD from other neurodegenerative disorders. Recent advances have been driven largely by the refinement of the clinical syndromes that underlie FTD, and by the discovery of new genetic and pathological features associated with FTD. Many new imaging techniques and modalities are also now available that allow the assessment of other aspects of brain structure and function, such as diffusion tensor imaging and resting state functional MRI. Studies have utilized these recent techniques, as well as traditional volumetric MRI, to provide further insight into disease progression across the many clinical, genetic and pathological variants of FTD. Importantly, neuroimaging signatures have been identified that will improve the clinician’s ability to predict underlying genetic and pathological features, and hence ultimately improve patient diagnosis. PMID:23015371

  16. Defining the spectrum of frontotemporal dementias associated with TARDBP mutations

    PubMed Central

    Caroppo, Paola; Camuzat, Agnès; Guillot-Noel, Léna; Thomas-Antérion, Catherine; Couratier, Philippe; Wong, Tsz Hang; Teichmann, Marc; Golfier, Véronique; Auriacombe, Sophie; Belliard, Serge; Laurent, Bernard; Lattante, Serena; Millecamps, Stéphanie; Clot, Fabienne; Dubois, Bruno; van Swieten, John C.; Brice, Alexis

    2016-01-01

    Objectives: We describe the largest series of patients with TARDBP mutations presenting with frontotemporal dementia (FTD) and review the cases in the literature to precisely characterize FTD diseases associated with this genotype. Methods: The phenotypic characteristics of 29 TARDBP patients, including 10 new French and Dutch cases and 19 reviewed from the literature, were evaluated. Results: The most frequent phenotype was a behavioral variant frontotemporal dementia (bvFTD), but a significant proportion (40%) of our patients had semantic (svFTD) or nonfluent variants (nfvFTD) at onset; and svFTD was significantly more frequent in TARDBP carriers than in other FTD genotypes (p < 0.001). Remarkably, only a minority (40%) of our patients secondarily developed amyotrophic lateral sclerosis (ALS). Two patients carried a homozygous mutation but strikingly different phenotypes (bvFTD and ALS) indicating that homozygosity does not result in a specific phenotype. Earlier age at onset in children than parent's generations, mimicking an apparent “anticipation” (21.8 ± 9.3 years, p = 0.001), and possible reduced penetrance were present in most families. Conclusions: This study enlarges the phenotypic spectrum of TARDBP and will have important clinical implications: (1) FTD can be the only clinical manifestation of TARDBP mutations; (2) Initial language or semantic disorders might be indicative of a specific genotype; (3) Mutations should be searched in all FTD phenotypes after exclusion of major genes, even in the absence of ALS in the proband or in family history; (4) reduced penetrance and clinical variability should be considered to deliver appropriate genetic counseling. PMID:27280171

  17. The natural history of temporal variant frontotemporal dementia.

    PubMed

    Seeley, W W; Bauer, A M; Miller, B L; Gorno-Tempini, M L; Kramer, J H; Weiner, M; Rosen, H J

    2005-04-26

    The temporal variant of frontotemporal dementia (tvFTD) features asymmetric anterior temporal/amygdala degeneration as well as ventromedial frontal, insular, and inferoposterior temporal involvement. Left temporal atrophy has been linked to loss of semantic knowledge, whereas behavioral symptoms dominate the right temporal variant. To investigate the first symptoms and the timing of subsequent symptoms in patients with left versus right tvFTD. Twenty-six patients with tvFTD were identified. Six had right > left temporal atrophy (right temporal lobe variant [RTLV]) and were matched with six having comparable left > right temporal atrophy (left temporal lobe variant [LTLV]). Clinical records were reviewed to generate individualized symptom chronologies. In all patients, first symptoms involved semantics (4/6 LTLV, 1/6 RTLV), behavior (4/6 RTLV, 1/6 LTLV), or both (1 LTLV, 1 RTLV). Semantic loss began with anomia, word-finding difficulties, and repetitive speech, whereas the early behavioral syndrome was characterized by emotional distance, irritability, and disruption of physiologic drives (sleep, appetite, libido). After an average of 3 years, patients developed whichever of the two initial syndromes--semantic or behavioral--that they lacked at onset. A third stage, 5 to 7 years from onset, saw the emergence of disinhibition, compulsions, impaired face recognition, altered food preference, and weight gain. Compulsions in LTLV were directed toward visual, nonverbal stimuli, whereas patients with RTLV were drawn to games with words and symbols. The temporal variant of frontotemporal dementia follows a characteristic cognitive and behavioral progression that suggests early spread from one anterior temporal lobe to the other. Later symptoms implicate ventromedial frontal, insular, and inferoposterior temporal regions, but their precise anatomic correlates await confirmation.

  18. Non-pharmacological Management of Behavioral Symptoms in Frontotemporal and Other Dementias

    PubMed Central

    Barton, Cynthia; Ketelle, Robin; Merrilees, Jennifer; Miller, Bruce

    2016-01-01

    Worldwide prevalence of dementia is predicted to double every 20 years. The most common cause in individuals over 65 is Alzheimer's disease (AD), but in those under 65, frontotemporal dementia (FTD) is as frequent. The physical and cognitive decline that characterizes these diseases is commonly accompanied by troublesome behavioral symptoms. These behavioral symptoms contribute to significant morbidity and mortality among both patients and caregivers. Medications have been largely ineffective in managing these symptoms and carry significant adverse effects. Non-pharmacological interventions have been recommended to precede the utilization of pharmacological treatments. This article reviews the research about these interventions with special attention to the variations by etiology, especially FTD. The authors offer recommendations for improving utilization of these strategies and future research recommendations. PMID:26750129

  19. 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

    2017-08-24

    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

  20. Shared neural correlates of limb apraxia in early stages of Alzheimer's dementia and behavioural variant frontotemporal dementia.

    PubMed

    Johnen, Andreas; Brandstetter, Lisa; Kärgel, Christian; Wiendl, Heinz; Lohmann, Hubertus; Duning, Thomas

    2016-11-01

    Limb apraxia denotes a cognitive impairment of gesture production. Lesion studies in patients with stroke point towards distinct neural processing streams for limb imitation and object-pantomime within left parietal and temporal cortex, respectively. Despite its frequent occurrence as an early symptom in both, Alzheimer's dementia (AD) and behavioural variant frontotemporal dementia (bvFTD), neural correlates of limb apraxia within these patient groups remain unexplored. Using voxel-based morphometry and multiple regression models, associations between limb apraxia and gray matter (GM) volume were investigated in 36 dementia patients (18 AD, 18 bvFTD) in early disease stages. Both dementia subtypes showed a comparable degree of limb apraxia. Although the patient groups showed distinct atrophy patterns with significantly more severe frontal GM loss in bvFTD, we found similar neural correlates of limb apraxia within posterior brain regions for both dementia subtypes: limb-imitation was associated with bilateral atrophy of superior, inferior and medial parietal cortex. Object-pantomime showed associations with GM volume in right middle temporal and angular gyrus. Our results argue for shared neural correlates of limb apraxia in AD and bvFTD and validate the syndrome as an important neuropsychological feature across different etiologies. Moreover, our results are compatible with neural models derived from patients with stroke, suggesting partly distinct neural representations of imitation and pantomime. Compared to patients with stroke however, AD and bvFTD showed more bilateral or even right lateralized neural representations of limb apraxia, proposing a greater influence of visuospatial impairments and spatial body representation deficits on praxis performance. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. 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

  2. Executive Abilities as Reflected by Clock Hand Placement: Frontotemporal Dementia Versus Early-Onset Alzheimer Disease.

    PubMed

    Barrows, Robin J; Barsuglia, Joseph; Paholpak, Pongsatorn; Eknoyan, Donald; Sabodash, Valeriy; Lee, Grace J; Mendez, Mario F

    2015-12-01

    The clock-drawing test (CDT) is widely used in clinical practice to diagnose and distinguish patients with dementia. It remains unclear, however, whether the CDT can distinguish among the early-onset dementias. Accordingly, we examined the ability of both quantitative and qualitative CDT analyses to distinguish behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer disease (eAD), the 2 most common neurodegenerative dementias with onset <65 years of age. We hypothesized that executive aspects of the CDT would discriminate between these 2 disorders. The study compared 15 patients with bvFTD and 16 patients with eAD on the CDT using 2 different scales and correlated the findings with neuropsychological testing and magnetic resonance imaging. The total CDT scores did not discriminate bvFTD and eAD; however, specific analysis of executive hand placement items successfully distinguished the groups, with eAD exhibiting greater errors than bvFTD. The performance on those executive hand placement items correlated with measures of naming as well as visuospatial and executive function. On tensor-based morphometry of the magnetic resonance images, executive hand placement correlated with right frontal volume. These findings suggest that lower performance on executive hand placement items occurs with involvement of the right dorsolateral frontal-parietal network for executive control in eAD, a network disproportionately affected in AD of early onset. Rather than the total performance on the clock task, the analysis of specific errors, such as executive hand placement, may be useful for early differentiation of eAD, bvFTD, and other conditions.

  3. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease.

    PubMed

    Zhou, Juan; Greicius, Michael D; Gennatas, Efstathios D; Growdon, Matthew E; Jang, Jung Y; Rabinovici, Gil D; Kramer, Joel H; Weiner, Michael; Miller, Bruce L; Seeley, William W

    2010-05-01

    Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer's disease cause atrophy within two major networks, an anterior 'Salience Network' (atrophied in behavioural variant frontotemporal dementia) and a posterior 'Default Mode Network' (atrophied in Alzheimer's disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer's disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer's disease) and the Default Mode Network (disrupted in Alzheimer's disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer's disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer's disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity

  4. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease

    PubMed Central

    Zhou, Juan; Greicius, Michael D.; Gennatas, Efstathios D.; Growdon, Matthew E.; Jang, Jung Y.; Rabinovici, Gil D.; Kramer, Joel H.; Weiner, Michael; Miller, Bruce L.

    2010-01-01

    Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer’s disease cause atrophy within two major networks, an anterior ‘Salience Network’ (atrophied in behavioural variant frontotemporal dementia) and a posterior ‘Default Mode Network’ (atrophied in Alzheimer’s disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer’s disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer’s disease) and the Default Mode Network (disrupted in Alzheimer’s disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer’s disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer’s disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic

  5. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia

    PubMed Central

    Hodges, John R.; Knopman, David; Mendez, Mario F.; Kramer, Joel H.; Neuhaus, John; van Swieten, John C.; Seelaar, Harro; Dopper, Elise G. P.; Onyike, Chiadi U.; Hillis, Argye E.; Josephs, Keith A.; Boeve, Bradley F.; Kertesz, Andrew; Seeley, William W.; Rankin, Katherine P.; Johnson, Julene K.; Gorno-Tempini, Maria-Luisa; Rosen, Howard; Prioleau-Latham, Caroline E.; Lee, Albert; Kipps, Christopher M.; Lillo, Patricia; Piguet, Olivier; Rohrer, Jonathan D.; Rossor, Martin N.; Warren, Jason D.; Fox, Nick C.; Galasko, Douglas; Salmon, David P.; Black, Sandra E.; Mesulam, Marsel; Weintraub, Sandra; Dickerson, Brad C.; Diehl-Schmid, Janine; Pasquier, Florence; Deramecourt, Vincent; Lebert, Florence; Pijnenburg, Yolande; Chow, Tiffany W.; Manes, Facundo; Grafman, Jordan; Cappa, Stefano F.; Freedman, Morris; Grossman, Murray; Miller, Bruce L.

    2011-01-01

    Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised

  6. 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.

  7. Education plays a different role in Frontotemporal Dementia and Alzheimer's disease.

    PubMed

    Borroni, Barbara; Alberici, Antonella; Agosti, Chiara; Premi, Enrico; Padovani, Alessandro

    2008-08-01

    The role of modifiable and non-modifiable variables in Frontotemporal Dementia (FTD) as compared to Alzheimer's dDisease (AD) and to Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration Syndrome (CBDS) has not been extensively evaluated. In particular, low education levels have been reported to be a risk factor for AD, but their contribution in FTD is yet not known. To investigate the role of education, other modifiable and non-modifiable factors in FTD as compared to AD, PSP and CBDS patients. One hundred and seventeen FTD patients, 400 AD, 55 PSP, and 55 CBDS entered the study. Demographic and clinical characteristics were carefully recorded. Age, gender, family history for dementia and Apolipoprotein E (APOE) genotype were considered as non-modifiable factors; education and comorbidities were included as modifiable variables. Regression analyses were applied in order to identify differences among groups. FTD differed from AD patients in terms of younger age, positive family history and gender status. In regard to APOE genotype, no differences between FTD and AD were found, but FTD showed higher prevalence of epsilon 4 allele compared to both CBDS and PSP patients (p < 0.05). When modifiable factors were considered, FTD were higher educated than AD patients (p < 0.001). Regression analysis identified younger age, positive family history, and education levels as independently associated variables to FTD diagnosis compared to AD (F = 21.27, R(2) = 24.1, p = 0.036). Our results highlight that the contribution of education and non-modifiable factors is likely different in FTD and AD. Further work is needed to completely establish the role of this modifiable variable as a potential area of intervention for dementias.

  8. 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.

  9. Therapy and clinical trials in frontotemporal dementia: past, present, and future

    PubMed Central

    Tsai, Richard M.; Boxer, Adam L.

    2017-01-01

    Frontotemporal dementia (FTD) is a common form of dementia with heterogeneous clinical presentations and distinct clinical syndromes. This article will review currently available therapies for FTD, its related disorders and their clinical evidence. It will also discuss recent advancements in FTD pathophysiology, treatment development, biomarker advancement and their relation to recently completed or currently ongoing clinical trials as well as future implications. PMID:27306957

  10. White Matter Tract Damage in the Behavioral Variant of Frontotemporal and Corticobasal Dementia Syndromes

    PubMed Central

    Tovar-Moll, Fernanda; de Oliveira-Souza, Ricardo; Bramati, Ivanei Edson; Zahn, Roland; Cavanagh, Alyson; Tierney, Michael; Moll, Jorge; Grafman, Jordan

    2014-01-01

    The phenotypes of the behavioral variant of frontotemporal dementia and the corticobasal syndrome present considerable clinical and anatomical overlap. The respective patterns of white matter damage in these syndromes have not been directly contrasted. Beyond cortical involvement, damage to white matter pathways may critically contribute to both common and specific symptoms in both conditions. Here we assessed patients with the behavioral variant of frontotemporal dementia and corticobasal syndrome with whole-brain diffusion tensor imaging to identify the white matter networks underlying these pathologies. Twenty patients with the behavioral variant of frontotemporal dementia, 19 with corticobasal syndrome, and 15 healthy controls were enrolled in the study. Differences in tract integrity between (i) patients and controls, and (ii) patients with the corticobasal syndrome and the behavioral variant of frontotemporal dementia were assessed with whole brain tract-based spatial statistics and analyses of regions of interest. Behavioral variant of frontotemporal dementia and the corticobasal syndrome shared a pattern of bilaterally decreased white matter integrity in the anterior commissure, genu and body of the corpus callosum, corona radiata and in the long intrahemispheric association pathways. Patients with the behavioral variant of frontotemporal dementia showed greater damage to the uncinate fasciculus, genu of corpus callosum and forceps minor. In contrast, corticobasal syndrome patients had greater damage to the midbody of the corpus callosum and perirolandic corona radiata. Whereas several compact white matter pathways were damaged in both the behavioral variant of frontotemporal dementia and corticobasal syndrome, the distribution and degree of white matter damage differed between them. These findings concur with the distinctive clinical manifestations of these conditions and may improve the in vivo neuroanatomical and diagnostic characterization of these

  11. White matter tract damage in the behavioral variant of frontotemporal and corticobasal dementia syndromes.

    PubMed

    Tovar-Moll, Fernanda; de Oliveira-Souza, Ricardo; Bramati, Ivanei Edson; Zahn, Roland; Cavanagh, Alyson; Tierney, Michael; Moll, Jorge; Grafman, Jordan

    2014-01-01

    The phenotypes of the behavioral variant of frontotemporal dementia and the corticobasal syndrome present considerable clinical and anatomical overlap. The respective patterns of white matter damage in these syndromes have not been directly contrasted. Beyond cortical involvement, damage to white matter pathways may critically contribute to both common and specific symptoms in both conditions. Here we assessed patients with the behavioral variant of frontotemporal dementia and corticobasal syndrome with whole-brain diffusion tensor imaging to identify the white matter networks underlying these pathologies. Twenty patients with the behavioral variant of frontotemporal dementia, 19 with corticobasal syndrome, and 15 healthy controls were enrolled in the study. Differences in tract integrity between (i) patients and controls, and (ii) patients with the corticobasal syndrome and the behavioral variant of frontotemporal dementia were assessed with whole brain tract-based spatial statistics and analyses of regions of interest. Behavioral variant of frontotemporal dementia and the corticobasal syndrome shared a pattern of bilaterally decreased white matter integrity in the anterior commissure, genu and body of the corpus callosum, corona radiata and in the long intrahemispheric association pathways. Patients with the behavioral variant of frontotemporal dementia showed greater damage to the uncinate fasciculus, genu of corpus callosum and forceps minor. In contrast, corticobasal syndrome patients had greater damage to the midbody of the corpus callosum and perirolandic corona radiata. Whereas several compact white matter pathways were damaged in both the behavioral variant of frontotemporal dementia and corticobasal syndrome, the distribution and degree of white matter damage differed between them. These findings concur with the distinctive clinical manifestations of these conditions and may improve the in vivo neuroanatomical and diagnostic characterization of these

  12. Living with a diagnosis of behavioural-variant frontotemporal dementia: The person's experience.

    PubMed

    Griffin, Julie; Oyebode, Jan R; Allen, Joanne

    2016-11-01

    Research investigating behavioural-variant frontotemporal dementia has concentrated on identifying and quantifying people's difficulties; yet few studies have considered how people with behavioural-variant frontotemporal dementia make sense of their difficulties. Five participants were interviewed and interpretive phenomenological analysis used to analyse the data. Two superordinate themes emerged: 'Bewilderment' and 'Relationships with others'. 'Bewilderment' reflected the feelings of the participants from the start of their dementia, and was divided into two main themes (1) 'Awareness of change: What's the problem? and (2) Threats to self: This is not me. The superordinate theme, 'Relationships with others', reflected difficulties with social relationships and comprised two main themes (1) 'Family and friends: Things haven't changed… but do I say anything wrong?' and (2) Coping with threats to self: Blame others or just avoid them. The themes were discussed in relation to literature evaluating the difficulties associated with behavioural-variant frontotemporal dementia together with implications for clinical practice.

  13. Evolution of autobiographical memory impairments in Alzheimer's disease and frontotemporal dementia - A longitudinal neuroimaging study.

    PubMed

    Irish, Muireann; Landin-Romero, Ramon; Mothakunnel, Annu; Ramanan, Siddharth; Hsieh, Sharpley; Hodges, John R; Piguet, Olivier

    2017-03-10

    Compromised autobiographical memory (ABM) retrieval is well established in dementia, attributable to degeneration of a core memory brain network. It remains unclear, however, how the progressive spread of atrophy with advancing disease severity impacts ABM retrieval across life epochs. To this end, we conducted a longitudinal study of recent and remote ABM in Alzheimer's disease (AD, n =11), and a frontotemporal lobar degeneration group (FTD, n =13) comprising 7 behavioral variant FTD and 6 semantic dementia patients, in comparison with 23 healthy older Controls. Patients were re-assessed approximately one year following their initial visit and underwent repeat testing and brain imaging. Linear mixed modeling neuroimaging analyses explored disease-specific cortical changes driving ABM alterations over time. AD patients showed comparable ABM profiles across assessment periods however, follow-up performance correlated strongly with lateral temporal lobe integrity. In contrast, recent ABMs were disproportionately disrupted at follow-up relative to baseline in the FTD group, attributable to cortical thinning in posterior brain regions, including the right posterior cingulate cortex. Our findings offer new insights regarding the potential time-specific role of discrete cortical regions in ABM retrieval and the differential fate of formerly evocative memories with advancing disease severity in dementia syndromes.

  14. Clinical characteristics of parkinsonism in frontotemporal dementia according to subtypes.

    PubMed

    Park, Hee Kyung; Park, Kee Hyung; Yoon, Bora; Lee, Jae-Hong; Choi, Seong Hye; Joung, Jee H; Yoon, Soo Jin; Kim, Byeong C; Kim, Seung Hyun; Kim, Eun-Joo; Na, Duk L; Park, Kyung Won

    2017-01-15

    We investigated the prevalence of parkinsonism in frontotemporal dementia (FTD) subtypes and the cognitive and behavioral differences between FTD with and without parkinsonism in a well-structured, prospective cohort. One hundred and ninety-one FTD patients were enrolled and all patients underwent comprehensive neurological evaluations, neuropsychological tests, and the Unified Parkinson's Disease Rating Scale. The prevalence of parkinsonism was 38.7% (74 patients), and included 33 (46.5%) behavioral variant FTD (bvFTD), 16 (24.2%) semantic dementia (SD), 19 (45.2%) progressive nonfluent aphasia (PNFA), and 6 (50%) FTD associated with motor neuron disease (FTD-MND). SD patients with parkinsonism had higher CDR sum of boxes scores (9.7±4.5 vs 6.2±4.5, p=0.024), frontal behavioral inventory total score (33.7±20.5 vs 24.3±14.5, p=0.045), and executive function score of frontal executive dysfunction, disinhibition, and apathy (28.9±13.7 vs 19.2±12.9, p=0.021) than those without parkinsonism. Seoul Instrumental Activities of Daily Living score (bvFTD: 23.5±11.7 vs 17.3±11.3, p=0.031, SD: 23.1±11.1 vs 11.3±9.3, p=0.005) was higher for bvFTD and SD with parkinsonism than for those without parkinsonism. Parkinsonism is found to be more common in patients with bvFTD, PNFA, and FTD-MND patients than those with SD. Behavioral disturbances were more prominent in SD with parkinsonism than without. Additional studies are needed to determine the pathomechanism and optimal treatment of parkinsonism in different FTD subtypes. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Randomized controlled trials in frontotemporal dementia: cognitive and behavioral outcomes

    PubMed Central

    2014-01-01

    Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia (FTD). Targets for intervention have been identified, therapies are being developed, and clinical trials are advancing. A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes. The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction, language impairments and behavioral disturbance. Behavioral variant FTD is characterized by an initial presentation of changes in personality, behavior and/or emotion, which are often difficult to objectively capture using traditional neuropsychological measures. The two principal language variants of FTD are Progressive Nonfluent Aphasia (PNFA) with predominant agrammatic/non-fluent impairments and Semantic Dementia (SD) with semantic impairments and visual agnosia. Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change, yet specific enough to isolate signal from noise, and acceptable to regulatory agencies. Given the anticipated potential for small effect sizes, measures must be able to identify small incremental changes over time. It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest. Selected outcome measures should be suitable for repeat administration, yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability. To facilitate widespread adoption as an endpoint, measures should be readily accessible. We provide several examples of potential global, composite, and individual cognitive measures, as well as behavioral measures promising for FTD trials. Development and application of appropriate trial outcomes is critically important to success in advancing new

  16. The effects of behavioral and psychological symptoms on caregiver burden in frontotemporal dementia, Lewy body dementia, and Alzheimer's disease: clinical experience in China.

    PubMed

    Liu, Shuling; Jin, Yi; Shi, Zhihong; Huo, Ya Ruth; Guan, Yalin; Liu, Mengyuan; Liu, Shuai; Ji, Yong

    2017-06-01

    Caregivers of individuals with neurodegenerative diseases, including frontotemporal dementia (FTD), Lewy body dementia (DLB), and Alzheimer's disease (AD), experience high levels of psychological and physical stress, likely due to behavioral and psychological symptoms of dementia (BPSD). This study is the first to simultaneously evaluate the effects of BPSD on caregiver burden in these three types of dementia. A total of 214 dementia patients, including probable FTD (n = 82), DLB (n = 22), and AD (n = 110), as well as their primary caregivers, were assessed using psychological inventories and cognitive evaluation. The FTD group was further divided into the three established clinical variants: behavioral variant frontotemporal dementia (bvFTD, n = 51), non-fluent variant primary progressive aphasia (nfvPPA, n = 15), and semantic variant primary progressive aphasia (svPPA, n = 16). Cognitive impairment and neuropsychiatric symptoms were assessed using the Mini Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test, and Neuropsychiatric Inventory (NPI), respectively. Caregiver burden was assessed using the Zarit Burden Inventory (ZBI). FTD patients had higher NPI and ZBI scores than DLB and AD patients, whose scores were similar. Logistic regression analysis revealed that the factors influencing caregiver burden for each group were: FTD: total NPI scores, agitation, and aberrant motor behavior; bvFTD: total NPI scores; DLB: total NPI scores; and AD: total NPI scores, onset age, apathy, and ADL. Caregivers of bvFTD patients had the highest levels of burden, which were significantly greater than for caregivers of nfvPPA, svPPA, DLB, and AD patients. BPSD was highly correlated with emotional burden in caregivers of FTD, DLB, and AD patients. The highest burden was observed in bvFTD caregivers.

  17. Contextual social cognition and the behavioral variant of frontotemporal dementia.

    PubMed

    Ibañez, Agustin; Manes, Facundo

    2012-04-24

    The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders.

  18. [Genetic tau-variants in patients with frontotemporal dementia].

    PubMed

    Ibach, Bernd; Wittmann, Markus; Pfannenschmid, Frank; Poljansky, Stefan; Haen, Ekkehard; Hajak, Göran

    2004-11-01

    [corrected] To evaluate tau-associated genetic polymorphisms in patients with sporadic frontotemporal dementia (FTD) and healthy control subjects. Tau-gene sequence of 30 patients with FTD and 30 healthy controls was analysed by polymerase-chain-reaction (PCR). Subsequent sequencing was performed to identify exonic and intronic differences between both groups. The following polypmorphisms, which are localized closely to each exon-intron-border, have been identified: In 37 % (n = 11) of the control subjects three different intronic polymorphisms occur simultaneously (Intron 2, 263, C --> Y; Intron 3, 590, A --> R; Intron 11, 150, G --> A). In the FTD group, this coexistance has been observed only in 17 % (n = 5). In how far there exists a significant correlation between the newly identified triple polymorphism in the Tau gene and an alternated risk for FTD must be evaluated in a lager population. The proximity of these polymorphisms to the exon-intron border would facilitate functional influences on gene expression patterns. These preliminary results described, above potentially point to further pathogenetic factors in the genesis of FTD.

  19. Social mind representation: where does it fail in frontotemporal dementia?

    PubMed

    Ruby, Perrine; Schmidt, Christina; Hogge, Michaël; D'Argembeau, Arnaud; Collette, Fabienne; Salmon, Eric

    2007-04-01

    We aimed at investigating social disability and its cerebral correlates in frontotemporal dementia (FTD). To do so, we contrasted answers of patients with early-stage FTD and of their relatives on personality trait judgment and on behavior prediction in social and emotional situations. Such contrasts were compared to control contrasts calculated with answers of matched controls tested with their relatives. In addition, brain metabolism was measured in patients with positron emission tomography and the [(18)F]fluorodeoxyglucose method. Patients turned out to be as accurate as controls in describing their relative's personality, but they failed to predict their relative's behavior in social and emotional circumstances. Concerning the self, patients were impaired both in current personality assessment and in prediction of their own behavior. Those two self-evaluation measures did not correlate. Only patients' anosognosia for social behavioral disability was found to be related to decreased metabolic activity in the left temporal pole. Such results suggest that anosognosia for social disability in FTD originates in impaired processing of emotional autobiographical information, leading to a self-representation that does not match current behavior. Moreover, we propose that perspective-taking disability participates in anosognosia, preventing patients from correcting their inaccurate self-representation based on their relative's perspective.

  20. Parkinsonism, movement disorders and genetics in frontotemporal dementia.

    PubMed

    Baizabal-Carvallo, José Fidel; Jankovic, Joseph

    2016-03-01

    Frontotemporal dementia (FTD) refers to a group of clinically and genetically heterogeneous neurodegenerative disorders that are a common cause of adult-onset behavioural and cognitive impairment. FTD often presents in combination with various hyperkinetic or hypokinetic movement disorders, and evidence suggests that various genetic mutations underlie these different presentations. Here, we review the known syndromatic-genetic correlations in FTD. Although no direct genotype-phenotype correlations have been identified, mutations in multiple genes have been associated with various presentations. Mutations in the genes that encode microtubule-associated protein tau (MAPT) and progranulin (PGRN) can manifest as symmetrical parkinsonism, including the phenotypes of Richardson syndrome and corticobasal syndrome (CBS). Expansions in the C9orf72 gene are most frequently associated with familial FTD, typically combined with motor neuron disease, but other manifestations, such as symmetrical parkinsonism, CBS and multiple system atrophy-like presentations, have been described in patients with these mutations. Less common gene mutations, such as those in TARDBP, CHMP2B, VCP, FUS and TREM2, can also present as atypical parkinsonism. The most common hyperkinetic movement disorders in FTD are motor and vocal stereotypies, which have been observed in up to 78% of patients with autopsy-proven FTD. Other hyperkinetic movements, such as chorea, orofacial dyskinesias, myoclonus and dystonia, are also observed in some patients with FTD.

  1. Probabilistic association learning in frontotemporal dementia and schizophrenia.

    PubMed

    Weickert, Thomas W; Leslie, Felicity; Rushby, Jacqueline A; Hodges, John R; Hornberger, Michael

    2013-01-01

    Recent neuropsychological studies show substantial cognitive deficits in patients with frontotemporal dementia (FTD). Schizophrenia (SC) overlaps in terms of neurobehavioural symptoms with FTD. Probabilistic association learning, which is thought to assay fronto-striatal function, is well documented to elicit impairment in SC and has not been investigated in FTD to date; this study compared FTD, SC and a healthy comparison group on probabilistic association learning to determine the extent to which FTD patients were similar in performance to SC patients. Twenty FTD patients, 24 SC patients and 26 healthy controls were assessed using the probabilistic association learning weather prediction test. FTD patients were also divided into behavioural and language variants for comparison to the healthy group. FTD patients were impaired during probabilistic association learning in comparison to healthy controls. There was no difference in performance between the FTD and SC groups. FTD behavioural variants performed significantly worse than the healthy comparison group, while FTD language variants did not differ from the healthy comparison group. This study provides the first evidence for impaired probabilistic association learning in FTD which is of an equivalent degree to that seen in SC. These results support recent structural neuroimaging studies showing fronto-striatal abnormalities in FTD and suggest that fronto-striatal dysfunction may contribute to cognitive deficits in a significant proportion of people with FTD. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Contextual social cognition and the behavioral variant of frontotemporal dementia

    PubMed Central

    2012-01-01

    The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders. PMID:22529204

  3. Dyslexia susceptibility genes influence brain atrophy in frontotemporal dementia

    PubMed Central

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

    2015-01-01

    Objective: 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. Methods: 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. Results: 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. Conclusions: Genes involved in dyslexia susceptibility, such as KIAA0319, result in language network vulnerability in FTD, and in PPA in particular. PMID:27066561

  4. False Reports from Patients with Frontotemporal Dementia: Delusions or Confabulations?

    PubMed Central

    Mendez, Mario F.; Fras, Ivan Andrew; Kremen, Sarah A.; Tsai, Po-Heng

    2011-01-01

    Patients with behavioral variant frontotemporal dementia (bvFTD) can make false statements consistent with delusions or confabulations. It is unclear whether bvFTD is primarily associated with either delusions or with confabulations and whether they can be explained by the pathophysiology of this disease. In order to clarify this, we retrospectively surveyed the records of 48 patients with bvFTD for the presence of any false reports and identified four patients. Their false reports included continued interaction with a favorite but dead relation, fictitious marriages with movie stars, and two who claimed that their partner was having an affair. When confronted with the falsity of their statements, the patients conveyed a lack of certainty regarding their external or internal source but persisted in the constancy of their reports. On functional neuroimaging, the patients had predominant frontal involvement. This report found that patients with bvFTD can have both fantastic, wish fulfilling confabulations and typical content-specific delusions. We propose that both phenomena result from known disturbances of ventromedial prefrontal cortex in bvFTD, including deficits in source monitoring and in activating an automatic “doubt tag” for false reports. PMID:21876263

  5. Self-Consciousness in Patients with Behavioral Variant Frontotemporal Dementia.

    PubMed

    Arroyo-Anlló, Eva M; Bouston, Adèle Turpin; Fargeau, Marie-Noëlle; Orgaz Baz, Begõna; Gil, Roger

    2016-01-01

    Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The medial prefrontal cortex may play a critical role in SC. The main aim of this paper was to examine SC in patients with behavioral variant frontotemporal dementia, who are characterized more by changes in personal, social, and emotional conduct and loss of insight than by cognitive disturbances. Control and patient groups of 21 subjects each, matched by age, educational level, gender, and nationality were assessed using a SC questionnaire. It measures several aspects: Personal identity, Anosognosia, Affective state, Body representation, Prospective memory, Introspection, and Moral judgments. The most disturbed ones in patients were Anosognosia, Affective state, and Moral judgments, and the least disturbed aspects were awareness of identity and of body representation. No significant correlations were found between the SC score and any clinical or demographical characteristics. The core deficiency of SC in patients was related to behavioral SC aspects, which are more dependent on orbito-frontal functioning.

  6. Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not.

    PubMed

    Hardy, John; Rogaeva, Ekaterina

    2014-12-01

    Over the last 5 years, several new genes have been described for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While it has long been clear that there are many kindreds in which the two diseases co-occur, there are also many in which the diseases segregate alone. In this brief review, we suggest that keeping the loci which lead to both diseases separate from those which lead to just one gives a clearer conclusion about disease mechanisms than lumping them together. The hypothesis that this separation leads to is that loci which cause both ALS and FTD affect the autophagic machinery leading to damaged protein aggregation and those which lead to just ALS are mainly involved in RNA/DNA metabolism. Two of the genes causing FTD alone (CHMP2B and GRN) are associated with damaged autophagy/lysosomal pathway. However, the third FTD gene (MAPT) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology characterized by abnormal tau filaments. We conclude that the current state of knowledge points to common mechanisms responsible for susceptibilities specific to neuronal classes. This includes the disruption of RNA metabolism in motor neurons and protein clearance, which is common between cortical and motor neurons. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Brain Network Organization and Social Executive Performance in Frontotemporal Dementia.

    PubMed

    Sedeño, Lucas; Couto, Blas; García-Cordero, Indira; Melloni, Margherita; Baez, Sandra; Morales Sepúlveda, Juan Pablo; Fraiman, Daniel; Huepe, David; Hurtado, Esteban; Matallana, Diana; Kuljis, Rodrigo; Torralva, Teresa; Chialvo, Dante; Sigman, Mariano; Piguet, Olivier; Manes, Facundo; Ibanez, Agustin

    2016-02-01

    Behavioral variant frontotemporal dementia (bvFTD) is characterized by early atrophy in the frontotemporoinsular regions. These regions overlap with networks that are engaged in social cognition-executive functions, two hallmarks deficits of bvFTD. We examine (i) whether Network Centrality (a graph theory metric that measures how important a node is in a brain network) in the frontotemporoinsular network is disrupted in bvFTD, and (ii) the level of involvement of this network in social-executive performance. Patients with probable bvFTD, healthy controls, and frontoinsular stroke patients underwent functional MRI resting-state recordings and completed social-executive behavioral measures. Relative to the controls and the stroke group, the bvFTD patients presented decreased Network Centrality. In addition, this measure was associated with social cognition and executive functions. To test the specificity of these results for the Network Centrality of the frontotemporoinsular network, we assessed the main areas from six resting-state networks. No group differences or behavioral associations were found in these networks. Finally, Network Centrality and behavior distinguished bvFTD patients from the other groups with a high classification rate. bvFTD selectively affects Network Centrality in the frontotemporoinsular network, which is associated with high-level social and executive profile.

  8. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

    PubMed

    Williams, Kelly L; Topp, Simon; Yang, Shu; Smith, Bradley; Fifita, Jennifer A; Warraich, Sadaf T; Zhang, Katharine Y; Farrawell, Natalie; Vance, Caroline; Hu, Xun; Chesi, Alessandra; Leblond, Claire S; Lee, Albert; Rayner, Stephanie L; Sundaramoorthy, Vinod; Dobson-Stone, Carol; Molloy, Mark P; van Blitterswijk, Marka; Dickson, Dennis W; Petersen, Ronald C; Graff-Radford, Neill R; Boeve, Bradley F; Murray, Melissa E; Pottier, Cyril; Don, Emily; Winnick, Claire; McCann, Emily P; Hogan, Alison; Daoud, Hussein; Levert, Annie; Dion, Patrick A; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Kost, Jason; Gellera, Cinzia; Gkazi, Athina Soragia; Miller, Jack; Stockton, Joanne; Brooks, William S; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luis; Esteban-Pérez, Jesús; Rábano, Alberto; Hardiman, Orla; Morrison, Karen E; Ticozzi, Nicola; Silani, Vincenzo; de Belleroche, Jacqueline; Glass, Jonathan D; Kwok, John B J; Guillemin, Gilles J; Chung, Roger S; Tsuji, Shoji; Brown, Robert H; García-Redondo, Alberto; Rademakers, Rosa; Landers, John E; Gitler, Aaron D; Rouleau, Guy A; Cole, Nicholas J; Yerbury, Justin J; Atkin, Julie D; Shaw, Christopher E; Nicholson, Garth A; Blair, Ian P

    2016-04-15

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

  9. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

    PubMed Central

    Williams, Kelly L.; Topp, Simon; Yang, Shu; Smith, Bradley; Fifita, Jennifer A.; Warraich, Sadaf T.; Zhang, Katharine Y.; Farrawell, Natalie; Vance, Caroline; Hu, Xun; Chesi, Alessandra; Leblond, Claire S.; Lee, Albert; Rayner, Stephanie L.; Sundaramoorthy, Vinod; Dobson-Stone, Carol; Molloy, Mark P.; van Blitterswijk, Marka; Dickson, Dennis W.; Petersen, Ronald C.; Graff-Radford, Neill R.; Boeve, Bradley F.; Murray, Melissa E.; Pottier, Cyril; Don, Emily; Winnick, Claire; McCann, Emily P.; Hogan, Alison; Daoud, Hussein; Levert, Annie; Dion, Patrick A.; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Kost, Jason; Gellera, Cinzia; Gkazi, Athina Soragia; Miller, Jack; Stockton, Joanne; Brooks, William S.; Boundy, Karyn; Polak, Meraida; Muñoz-Blanco, José Luis; Esteban-Pérez, Jesús; Rábano, Alberto; Hardiman, Orla; Morrison, Karen E.; Ticozzi, Nicola; Silani, Vincenzo; de Belleroche, Jacqueline; Glass, Jonathan D.; Kwok, John B. J.; Guillemin, Gilles J.; Chung, Roger S.; Tsuji, Shoji; Brown, Robert H.; García-Redondo, Alberto; Rademakers, Rosa; Landers, John E.; Gitler, Aaron D.; Rouleau, Guy A.; Cole, Nicholas J.; Yerbury, Justin J.; Atkin, Julie D.; Shaw, Christopher E.; Nicholson, Garth A.; Blair, Ian P.

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration. PMID:27080313

  10. Agreement among neuropsychological and behavioral data and PiB findings in diagnosing Frontotemporal Dementia.

    PubMed

    Ryan, Kelly A; Hammers, Dustin; DeLeon, Angeline; Bilen, Hande; Frey, Kirk; Burke, James; Albin, Roger; Barbas, Nancy; Heidebrink, Judith; Giordani, Bruno

    2017-10-01

    Diagnostic inaccuracies have been reported in Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) using clinical data alone. The [(11)C]-PiB PET scan offers a new method of identifying AD based on the detection of amyloid deposits. Our study investigated whether there was an agreement between neuropsychological and behavioral data and PiB findings in the diagnosis of FTD. Participants were 32 patients diagnosed with suspected FTD by clinical consensus. All participants underwent neuropsychological testing and PiB imaging. In addition, caregivers completed behavioral ratings of participants' memory, frontal behaviors, and mood. Seventeen participants were classified as PiB positive (+). Results of MANOVA and subsequent ANOVA analyses showed a significant difference on memory performance between the PiB- and PiB+groups, with the PiB- group performing better than the PiB+group. There were no significant differences between the groups on cognitive or behavioral measures of executive/frontal impairment, mood. Both groups showed similar severity of dementia. These findings provide evidence for the utility of the [(11)C]-PiB PET scan in distinguishing between AD and FTD, with evaluation of memory at clinical diagnosis serving as a valuable indicator of the absence of FTD and consideration for an AD diagnosis. Our results would support the concern that patients who may present with primary behavioral or executive dysfunction may not necessarily have FTD, particularly if memory deficits are evident. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. 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.

  12. 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…

  13. 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…

  14. Apraxia profile differentiates behavioural variant frontotemporal from Alzheimer's dementia in mild disease stages.

    PubMed

    Johnen, Andreas; Tokaj, Amelie; Kirschner, Anne; Wiendl, Heinz; Lueg, Gero; Duning, Thomas; Lohmann, Hubertus

    2015-07-01

    Despite refined criteria for behavioural variant frontotemporal dementia (bvFTD), its differentiation from Alzheimer's dementia (AD) remains difficult at early clinical presentation. Apraxia is not considered as a supportive feature for the diagnosis of bvFTD, but for AD. However, only few studies have quantified praxis disturbances in mild disease stages and their specificity for AD compared with bvFTD remains indistinct. We explore apraxia in bvFTD and investigate the differential validity of apraxia screening tests to distinguish between AD, bvFTD and healthy controls (HC). We compared composite apraxia scores assessed with standardised neuropsychological screening tests as well as performance in praxis subdomains in patients who fulfil current clinical criteria for AD (N=20), bvFTD (N=20), and in HC (N=20). Composite scores of apraxia screening tests provided high diagnostic accuracy for detecting mild stages of both neurodegenerative disorders compared with HC (sensitivity: 75-95%; specificity: 70-90%). Both patient groups showed pronounced impairments in limb praxis, especially in imitation of hand and finger postures (bvFTD: 71.7%; AD: 55.5%; HC: 86.7%) and pantomime of object use (bvFTD: 88.6%; AD: 81.4%; HC: 97.5%). Beyond that, patients with bvFTD displayed a unique profile of deficits for imitating face postures (bvFTD: 69%; AD: 88%; HC: 95.5%). Praxis disturbances are important but under-represented diagnostic features in mild stages of AD and bvFTD. Apraxia screening tests are easily applicable diagnostic tools, which may support clinical diagnoses of both neurodegenerative diseases. The analysis of individual apraxia profiles can effectively facilitate differential diagnosis of AD and bvFTD. 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.

  15. Mutational analysis of PRNP in Alzheimer’s disease and frontotemporal dementia in China

    PubMed Central

    Zhang, Weiwei; Jiao, Bin; Xiao, Tingting; Pan, Chuzheng; Liu, Xixi; Zhou, Lin; Tang, Beisha; Shen, Lu

    2016-01-01

    The prion protein (PRNP) gene is associated with prion diseases, whereas variants of the PRNP gene may also explain some cases of Alzheimer disease (AD) and frontotemporal dementia (FTD) in Caucasian populations. To determine the prevalence of the PRNP gene in patients with AD and FTD in China, we screened all exons of the PRNP gene in a cohort of 683 cases (606 AD and 77 FTD) in the Chinese Han population and we detected a novel missense mutation p.S17G in a late-onset AD (LOAD) patient. Furthermore, we analyzed the PRNP M/V polymorphism at codon 129, which was previously reported as a risk factor. However, there were no significant differences in genotype and allele frequency either in AD (OR = 0.75[0.378–1.49], P = 0.492), or FTD patients (OR = 2.046[0.265–15.783], P = 0.707). To our knowledge, this is the first study to reveal a correlation between the PRNP gene and Chinese AD and FTD patients in a large cohort. This study reports a novel p.S17G mutation in a clinically diagnosed LOAD patient, suggesting that the PRNP mutation is present in Chinese AD patients, whereas, M129V polymorphism is not a risk factor for AD or FTD in the Chinese Han population. PMID:27910931

  16. Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia.

    PubMed

    Mishra, Aniket; Ferrari, Raffaele; Heutink, Peter; Hardy, John; Pijnenburg, Yolande; Posthuma, Danielle

    2017-04-05

    Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.

  17. Theory of mind in behavioural-variant frontotemporal dementia and Alzheimer's disease: a meta-analysis.

    PubMed

    Bora, Emre; Walterfang, Mark; Velakoulis, Dennis

    2015-07-01

    Current evidence suggests that neurocognitive testing has limited practical benefit in distinguishing behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). In this meta-analysis of 30 studies, theory of mind (ToM) performances of 784 individuals with bvFTD (n=273) and AD (n=511) were compared with 671 healthy controls. ToM performances of 227 patients with bvFTD and 229 with AD were also compared in studies matched for general cognition. ToM was impaired in both bvFTD (d=1.79) and AD (d=1.15). In bvFTD, patients were particularly impaired in advanced tasks such as recognition of faux pas and sarcasm (d>2.0). In AD, ToM deficits were relatively modest. In studies matched for general cognition, ToM was significantly impaired in bvFTD in comparision to AD (d=1.29), especially for faux pas recognition (d=1.75). ToM dysfunction is a robust and more specific feature of bvFTD. In contrast, ToM deficits are modest compared with level of general cognitive impairment in AD. In both disorders, longer duration of disease and level of general cognitive impairment are related to relatively more severe ToM deficits. Assessment of ToM can be beneficial for early identification of bvFTD.

  18. 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.

  19. MRI patterns of atrophy and hypoperfusion associations across brain regions in frontotemporal dementia.

    PubMed

    Tosun, Duygu; Rosen, Howard; Miller, Bruce L; Weiner, Michael W; Schuff, Norbert

    2012-02-01

    Magnetic Resonance Imaging (MRI) provides various imaging modes to study the brain. We tested the benefits of a joint analysis of multimodality MRI data in combination with a large-scale analysis that involved simultaneously all image voxels using joint independent components analysis (jICA) and compared the outcome to results using conventional voxel-by-voxel unimodality tests. Specifically, we designed a jICA to decompose multimodality MRI data into independent components that explain joint variations between the image modalities as well as variations across brain regions. We tested the jICA design on structural and perfusion-weighted MRI data from 12 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 12 cognitively normal elderly individuals. While unimodality analyses showed widespread brain atrophy and hypoperfusion in the patients, jICA further revealed two significant joint components of variations between atrophy and hypoperfusion across brain regions. The 1st joint component revealed associated brain atrophy and hypoperfusion predominantly in the right brain hemisphere in behavioral variant frontotemporal dementia, and the 2nd joint component revealed greater atrophy relative to hypoperfusion affecting predominantly the left hemisphere in behavioral variant frontotemporal dementia. The patterns are consistent with the clinical symptoms of behavioral variant frontotemporal dementia that relate to asymmetric compromises of the left and right brain hemispheres. The joint components also revealed that that structural alterations can be associated with physiological alterations in spatially separated but potentially connected brain regions. Finally, jICA outperformed voxel-by-voxel unimodal tests significantly in terms of an effect size, separating the behavioral variant frontotemporal dementia patients from the controls. Taken together, the results demonstrate the benefit of multimodality MRI in conjunction with jICA for mapping

  20. MRI Patterns of Atrophy and Hypoperfusion Associations Across Brain Regions in Frontotemporal Dementia

    PubMed Central

    Tosun, Duygu; Rosen, Howard; Miller, Bruce L.; Weiner, Michael W.; Schuff, Norbert

    2011-01-01

    Magnetic Resonance Imaging (MRI) provides various imaging modes to study the brain. We tested the benefits of a joint analysis of multimodality MRI data in combination with a large-scale analysis that involved simultaneously all image voxels using joint independent components analysis (jICA) and compared the outcome to results using conventional voxel-by-voxel unimodality tests. Specifically, we designed a jICA to decompose multimodality MRI data into independent components that explain joint variations between the image modalities as well as variations across brain regions. We tested the jICA design on structural and perfusion-weighted MRI data from 12 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 12 cognitively normal elderly individuals. While unimodality analyses showed widespread brain atrophy and hypoperfusion in the patients, jICA further revealed two significant joint components of variations between atrophy and hypoperfusion across brain regions. The 1st joint component revealed associated brain atrophy and hypoperfusion predominantly in the right brain hemisphere in behavioral variant frontotemporal dementia, and the 2nd joint component revealed greater atrophy relative to hypoperfusion affecting predominantly the left hemisphere in behavioral variant frontotemporal dementia. The patterns are consistent with the clinical symptoms of behavioral variant frontotemporal dementia that relate to asymmetric compromises of the left and right brain hemispheres. The joint components also revealed that that structural alterations can be associated with physiological alterations in spatially separated but potentially connected brain regions. Finally, jICA outperformed voxel-by-voxel unimodal tests significantly in terms of an effect size, separating the behavioral variant frontotemporal dementia patients from the controls. Taken together, the results demonstrate the benefit of multimodality MRI in conjunction with jICA for mapping

  1. Neurofilament light chain: a biomarker for genetic frontotemporal dementia.

    PubMed

    Meeter, Lieke H; Dopper, Elise G; Jiskoot, Lize C; Sanchez-Valle, Raquel; Graff, Caroline; Benussi, Luisa; Ghidoni, Roberta; Pijnenburg, Yolande A; Borroni, Barbara; Galimberti, Daniela; Laforce, Robert Jr; Masellis, Mario; Vandenberghe, Rik; Ber, Isabelle Le; Otto, Markus; van Minkelen, Rick; Papma, Janne M; Rombouts, Serge A; Balasa, Mircea; Öijerstedt, Linn; Jelic, Vesna; Dick, Katrina M; Cash, David M; Harding, Sophie R; Jorge Cardoso, M; Ourselin, Sebastien; Rossor, Martin N; Padovani, Alessandro; Scarpini, Elio; Fenoglio, Chiara; Tartaglia, Maria C; Lamari, Foudil; Barro, Christian; Kuhle, Jens; Rohrer, Jonathan D; Teunissen, Charlotte E; van Swieten, John C

    2016-08-01

    To evaluate cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia (FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptomatic stage. Additionally, to correlate NfL levels to clinical and neuroimaging parameters. In this multicenter case-control study, we investigated CSF NfL in 174 subjects (48 controls, 40 presymptomatic carriers and 86 patients with microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) mutations), and serum NfL in 118 subjects (39 controls, 44 presymptomatic carriers, 35 patients). In 55 subjects both CSF and serum was determined. In two subjects CSF was available before and after symptom onset (converters). Additionally, NfL levels were correlated with clinical parameters, survival, and regional brain atrophy. CSF NfL levels in patients (median 6762 pg/mL, interquartile range 3186-9309 pg/mL) were strongly elevated compared with presymptomatic carriers (804 pg/mL, 627-1173 pg/mL, P < 0.001), resulting in a good diagnostic performance to discriminate both groups. Serum NfL correlated highly with CSF NfL (r s = 0.87, P < 0.001) and was similarly elevated in patients. Longitudinal samples in the converters showed a three- to fourfold increase in CSF NfL after disease onset. Additionally, NfL levels in patients correlated with disease severity, brain atrophy, annualized brain atrophy rate and survival. NfL in both serum and CSF has the potential to serve as a biomarker for clinical disease onset and has a prognostic value in genetic FTD.

  2. Patterns of regional cerebellar atrophy in genetic frontotemporal dementia

    PubMed Central

    Bocchetta, Martina; Cardoso, M. Jorge; Cash, David M.; Ourselin, Sebastien; Warren, Jason D.; Rohrer, Jonathan D.

    2016-01-01

    Background Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with a strong genetic component. The cerebellum has not traditionally been felt to be involved in FTD but recent research has suggested a potential role. Methods We investigated the volumetry of the cerebellum and its subregions in a cohort of 44 patients with genetic FTD (20 MAPT, 7 GRN, and 17 C9orf72 mutation carriers) compared with 18 cognitively normal controls. All groups were matched for age and gender. On volumetric T1-weighted magnetic resonance brain images we used an atlas propagation and label fusion strategy of the Diedrichsen cerebellar atlas to automatically extract subregions including the cerebellar lobules, the vermis and the deep nuclei. Results The global cerebellar volume was significantly smaller in C9orf72 carriers (mean (SD): 99989 (8939) mm3) compared with controls (108136 (7407) mm3). However, no significant differences were seen in the MAPT and GRN carriers compared with controls (104191 (6491) mm3 and 107883 (6205) mm3 respectively). Investigating the individual subregions, C9orf72 carriers had a significantly lower volume than controls in lobule VIIa-Crus I (15% smaller, p < 0.0005), whilst MAPT mutation carriers had a significantly lower vermal volume (10% smaller, p = 0.001) than controls. All cerebellar subregion volumes were preserved in GRN carriers compared with controls. Conclusion There appears to be a differential pattern of cerebellar atrophy in the major genetic forms of FTD, being relatively spared in GRN, localized to the lobule VIIa-Crus I in the superior-posterior region of the cerebellum in C9orf72, the area connected via the thalamus to the prefrontal cortex and involved in cognitive function, and localized to the vermis in MAPT, the ‘limbic cerebellum’ involved in emotional processing. PMID:26977398

  3. Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications

    PubMed Central

    Sjogren, M; Folkesson, S; Blennow, K; Tarkowski, E

    2004-01-01

    Objective: Immunological mechanisms may be part of the pathophysiological mechanisms in frontotemporal dementia (FTD), but hitherto only vague evidence of such mechanisms has been presented. The aim of this study was to compare the cerebrospinal fluid (CSF) levels of the pro-inflammatory cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α, and the anti-inflammatory cytokine transforming growth factor (TGF)-ß in patients with FTD and normal controls. Furthermore, serum levels of TNF-α, TGF-ß, and IL-1ß were measured in FTD patients. Methods: The CSF levels of IL-1ß, TNFα, and TGF-ß were measured using ELISA in 19 patients with FTD and 24 sex and age matched healthy controls. Results: The CSF levels of TNF-α (FTD 0.6 pg/mL (median: lower, upper quartile 0.3, 0.7); controls: 0.0 pg/mL (0.0, 0.0); p = 0.008) and TGF-ß (FTD 266 pg/mL (157, 371), controls: 147 pg/mL (119, 156); p = 0.0001) were significantly increased in FTD patients compared with controls. No correlations were found between CSF and serum levels of the cytokines. In the controls, but not in the FTD patients, a positive correlation was found between the CSF levels of TGF-ß and age (r = 0.42, p<0.05). No correlation was found between any of the cytokines and degree of brain atrophy or white matter changes. No differences between the groups were found for age, gender, or CSF/serum albumin ratio. Conclusions: The results suggest an increased intrathecal production of both pro- and anti-inflammatory cytokines in FTD. As no correlations were found with the albumin ratio, and no correlations between CSF and serum levels of the cytokines were found, these changes in the CSF cannot be explained by a systemic overproduction of cytokines. PMID:15258209

  4. Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia.

    PubMed

    Dopper, Elise G P; Rombouts, Serge A R B; Jiskoot, Lize C; den Heijer, Tom; de Graaf, J Roos A; de Koning, Inge; Hammerschlag, Anke R; Seelaar, Harro; Seeley, William W; Veer, Ilya M; van Buchem, Mark A; Rizzu, Patrizia; van Swieten, John C

    2014-07-08

    We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of MAPT (microtubule-associated protein tau) or GRN (progranulin) mutations. In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk of frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, structural MRI, and fMRI. We used voxel-based morphometry and tract-based spatial statistics for voxel-wise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsular, anterior midcingulate, and posterior cingulate cortices. Carriers (n = 39) and noncarriers (n = 36) had similar neuropsychological performance, except for lower Letter Digit Substitution Test scores in carriers. Worse performance on Stroop III, Rivermead Behavioral Memory Test, and Happé Cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy in the right uncinate fasciculus was found in carriers compared with controls. Reductions in functional connectivity between anterior midcingulate cortex and frontoinsula and several other brain regions were found in carriers compared with controls and correlated with higher age in carriers, but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found, except for a small cluster of higher volume in the precentral gyrus in carriers. This study demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials. © 2014 American Academy of Neurology.

  5. The language profile of behavioral variant frontotemporal dementia

    PubMed Central

    Hardy, Chris J. D.; Buckley, Aisling H.; Downey, Laura E.; Lehmann, Manja; Zimmerer, Vitor C.; Varley, Rosemary A.; Crutch, Sebastian J.; Rohrer, Jonathan D.; Warrington, Elizabeth K; Warren, Jason D.

    2015-01-01

    Background The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. Objective We aimed to quantify the extent of language deficits in this patient group. Methods We assessed a cohort of patients with bvFTD (n=24) in relation to patents with semantic variant primary progressive aphasia (svPPA; n=14), nonfluent variant primary progressive aphasia (nfvPPA; n=18) and healthy age-matched individuals (n=24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients’ brain magnetic resonance images. Results Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. Conclusions bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker. PMID:26682693

  6. Glial fibrillar acidic protein in the cerebrospinal fluid of Alzheimer's disease, dementia with Lewy bodies, and frontotemporal lobar degeneration.

    PubMed

    Ishiki, Aiko; Kamada, Maki; Kawamura, Yuki; Terao, Chiaki; Shimoda, Fumiko; Tomita, Naoki; Arai, Hiroyuki; Furukawa, Katsutoshi

    2016-01-01

    Biomarkers in the cerebrospinal fluid (CSF) are currently regarded as indispensable indicators for accurate differential diagnosis of neurodegenerative disorders. Although high levels of astrocyte-secreted glial fibrillar acidic protein (GFAP) in the CSF of patients with Alzheimer's disease (AD) have been reported, the levels of GFAP in the CSF have not been fully investigated in other neurological disorders that cause dementia, such as dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). In this study, we determined the levels of GFAP in the CSF of healthy control subjects and AD, DLB, and FTLD patients to address two questions: (i) Do the levels of GFAP differ among these disorders? and (ii) Can GFAP be used as a biomarker for the differential diagnosis of these neurodegenerative disorders? The levels of GFAP in AD, DLB, and FTLD patients were significantly higher than those in the healthy control subjects. Although the levels of GFAP were not significantly different between AD and DLB patients, a higher level of GFAP was observed in FTLD patients than in AD and DLB patients. It is concluded that representative neurological disorders causing dementia were associated with higher levels of GFAP in the CSF. We propose the following mechanism concerning the amount of glial fibrillar acidic protein (GFAP) in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). The increase in the release of GFAP into CSF is considered to reflect the sum of degeneration of astrocytes and astrocytosis. The sum of degeneration and astrocytosis or the GFAP release could be in the order of FTLD > DLB > AD > normal condition.

  7. 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

  8. Metacognition in the behavioral variant of frontotemporal dementia and Alzheimer’s disease

    PubMed Central

    Rosen, Howard J.; Alcantar, Oscar; Zakrzewski, Jessica; Shimamura, Arthur P.; Neuhaus, John; Miller, Bruce L.

    2014-01-01

    Objective Impaired self-awareness is characteristic of nearly all dementias, including Alzheimer’s disease (AD), but the deficit is most severe in the behavioral variant of frontotemporal dementia (bvFTD). The prominence of frontal pathology in bvFTD suggests that failure of online monitoring, the process by which individuals monitor their own cognitive processing in real time, is an important contributor. Metacognitive research offers several approaches to measure self-assessment, some more and others less sensitive to online monitoring. The goal of this study was to assess metacognition in bvFTD using several approaches, and compare the results with those in AD. Methods We examined metacognition in 12 patients with bvFTD, 14 with AD and 35 healthy controls using Feeling of Knowing (FOK), Ease of Learning (EOL), Judgment of Learning (JOL), and Retrospective Confidence Rating (CR) tasks, as well as response to feedback about performance. Results BvFTD and AD were both impaired at FOK compared with controls, although AD showed some sparing. Both groups were similarly impaired at CR and neither group was impaired at JOL after accounting for memory performance. Most strikingly, bvFTD patients failed to appropriately adjust their predictions about future memory performance even after receiving explicit feedback that they had performed worse than they expected. Conclusions Both bvFTD and AD show deficits in online monitoring, although the deficit appears more severe in bvFTD. The insensitivity of bvFTD patients to overt feedback may point to unique mechanisms, possibly frontally mediated, that add to their severe lack of self-awareness. PMID:24548124

  9. 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.

  10. Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage

    PubMed Central

    Ranasinghe, Kamalini G.; Lobach, Iryna V.; Kramer, Joel H.; Sturm, Virginia E.; Bettcher, Brianne M.; Possin, Katherine; Christine You, S.; Lamarre, Amanda K.; Shany-Ur, Tal; Stephens, Melanie L.; Perry, David C.; Lee, Suzee E.; Miller, Zachary A.; Gorno-Tempini, Maria L.; Rosen, Howard J.; Boxer, Adam; Seeley, William W.; Rabinovici, Gil D.; Vossel, Keith A.; Miller, Bruce L.

    2016-01-01

    Objective: To characterize the cognitive and neuropsychiatric symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) over the natural course of the disease. Methods: We examined the initial and subsequent neuropsychological test performance and neuropsychiatric symptoms in a large cohort of patients with bvFTD (n = 204) across progressive stages of disease as measured by the Clinical Dementia Rating (CDR). We also compared cognitive and neuropsychiatric impairments of patients with bvFTD to those of an age-matched cohort with Alzheimer disease (AD) dementia (n = 674). Results: At the earliest stage (CDR = 0.5), patients with bvFTD had profound neuropsychiatric disturbances, insensitivity to errors, slower response times, and poor naming, with intact attention span, memory, and facial affect naming. Tests continuing to show progressive, statistically significant stepwise declines after the CDR = 1 stage included free recall, visuoconstruction, set-shifting, error insensitivity, semantic fluency, design fluency, emotion naming, calculations, confrontation naming, syntax comprehension, and verbal agility. At CDR = 0.5, patients with bvFTD significantly outperformed patients with AD in episodic memory and were faster in set-shifting, while scoring quantitatively worse in lexical fluency, emotion naming, and error sensitivity. The overall rate of disease progression in bvFTD was more rapid than in AD. Conclusion: There are distinct patterns of cognitive deficits differentiating the earlier and later disease stages in bvFTD, with the pattern of cognitive decline revealing in greater detail the natural history of the disease. These cognitive symptoms are readily apparent clinical markers of dysfunction in the principal brain networks known to undergo molecular and anatomical changes in bvFTD, thus are important indicators of the evolving pathology in individual patients. PMID:26802093

  11. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations

    PubMed Central

    Rollinson, Sara; Thompson, Jennifer C.; Harris, Jennifer M.; Stopford, Cheryl L.; Richardson, Anna M. T.; Jones, Matthew; Gerhard, Alex; Davidson, Yvonne S.; Robinson, Andrew; Gibbons, Linda; Hu, Quan; DuPlessis, Daniel; Neary, David; Pickering-Brown, Stuart M.

    2012-01-01

    The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients’ clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients’ delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all

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

    PubMed

    Lagarde, J; Sarazin, M

    2016-10-20

    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

  13. Hypersexual Behavior in Frontotemporal Dementia: A Comparison with Early-Onset Alzheimer’s Disease

    PubMed Central

    Mendez, Mario F.; Shapira, Jill S.

    2013-01-01

    The basis of hypersexual behavior among patients with dementia is not entirely clear. Hypersexual behavior may be a particular feature of behavioral variant frontotemporal dementia (bvFTD), which affects ventromedial frontal and adjacent anterior temporal regions specialized in interpersonal behavior. Recent efforts to define Hypersexual Disorder indicate an increasing awareness of heightened sexual activity as a source of personal distress and functional impairment, and clarification of hypersexuality in bvFTD could contribute to understanding the neurobiology of this behavior. This study reviewed 47 patients with bvFTD compared to 58 patients with Alzheimer’s disease (AD) for the presence of heightened sexual activity to the point of distress to caregivers and others. Hypersexual behavior occurred in 6 (13%) bvFTD patients compared to none of the AD patients. Caregivers judged all six bvFTD patients with hypersexual behavior as having a dramatic increase in sexual frequency from premorbid levels. All had general disinhibition, poor impulse control, and actively sought sexual stimulation. They had widened sexual interests and experienced sexual arousal from previously unexciting stimuli. One patient, with early and predominant right anterior temporal involvement, was easily aroused by slight stimuli, such as touching her palms. Although previously considered to be predominantly disinhibited sexual behavior as part of generalized disinhibition, these patients with dementia illustrate varying degrees of increased sexual desire. We conclude that bvFTD is uniquely associated with hypersexuality; it is more than just cognitive impairment with frontal disinhibition but also involves alterations in sexual drive, possibly from right anterior temporal-limbic involvement in this disease. PMID:23297146

  14. 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.

  15. 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…

  16. 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…

  17. 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…

  18. 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

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

    PubMed

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

    2014-06-01

    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. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Novel missense mutation in Charged Multivesicular body Protein 2B in a patient with Frontotemporal Dementia

    PubMed Central

    Ferrari, Raffaele; Kapogiannis, Dimitrios; Huey, Edward D.; Grafman, Jordan; Hardy, John; Momeni, Parastoo

    2010-01-01

    Frontotemporal Dementia (FTD) is the second major cause of dementia in persons under the age of 65 after Alzheimer’s disease (AD). FTD is clinically, pathologically and genetically heterogeneous and has been associated with mutations in different genes located on chromosomes 17, 9 and 3. In our study we report a novel heterozygous g.26218G>A variant in exon 6 of Charged Multivesicular body Protein 2B (CHMP2B), predicted to cause the amino acid change p.Ser187Asn, in one patient diagnosed with FTD. We were not able to determine the mode of inheritance of the mutation since we did not have access to the genetically informative family members of the proband; those who were screened did not carry the variant. We didn’t find this variant in 273 Caucasian controls while we did find it in 6 of 94 African American controls. Most of the mutations in CHMP2B which are considered pathogenic lead to partial deletion of the C-terminus region of CHMP2B protein. Based on previous reports and on our current data, missense mutations seem unlikely to be pathogenic. The pathogenicity of CHMP2B mutations requires further investigation. PMID:20592581

  1. 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

  2. Violation of Laws in Frontotemporal Dementia: A Multicenter Study in Japan.

    PubMed

    Shinagawa, Shunichiro; Shigenobu, Kazue; Tagai, Kenji; Fukuhara, Ryuji; Kamimura, Naoto; Mori, Takaaki; Yoshiyama, Kenji; Kazui, Hiroaki; Nakayama, Kazuhiko; Ikeda, Manabu

    2017-01-01

    Although violations of laws, such as shoplifting, are considered to be common in frontotemporal dementia (FTD) patients, there have been few studies on this subject and the frequencies and types of such violations have not been clarified. The objective of this study was to conduct a retrospective investigation of FTD patients in the psychiatry departments of multiple institutions to determine the types and frequencies of any law violations and compare them with those of AD patients. All patients were examined between January 2011 and December 2015 at the specialized dementia outpatient clinics of 10 facilities (5 psychiatry departments of university hospitals, 5 psychiatric hospitals). According to diagnostic criteria, 73 behavior variant FTD (bvFTD) patients, 84 semantic variant of primary progressive aphasia (svPPA) patients, and 255 age- and sex-matched AD subjects as the control group were selected. The findings revealed a higher rate of law violations in the bvFTD and svPPA patients before the initial consultation as compared to the AD group (bvFTD: 33%, svPPA: 21%, AD: 6%) and that many patients had been referred due to such violations. Laws had been broken 4 times or 5 or more times in several cases in the FTD group before the initial consultation. Regarding rates for different types of violation, in bvFTD subjects, the highest rate was for theft, followed by nuisance acts and hit and run. In svPPA, theft had the highest rate, followed by ignoring road signs. There was no gender difference in law violations but they were more frequent when the disease was severe at the initial consultation in the FTD group. As the rates of law violations after the initial consultation were lower than before it, interventions were considered to have been effective. These findings may be useful for future prevention as well as to the legal system.

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

    PubMed Central

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

    2016-01-01

    Background: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. Objective: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). Methods: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. Results: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. Conclusions: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia. PMID:27472884

  4. 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.

  5. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.

    PubMed

    Bannwarth, Sylvie; Ait-El-Mkadem, Samira; Chaussenot, Annabelle; Genin, Emmanuelle C; Lacas-Gervais, Sandra; Fragaki, Konstantina; Berg-Alonso, Laetitia; Kageyama, Yusuke; Serre, Valérie; Moore, David G; Verschueren, Annie; Rouzier, Cécile; Le Ber, Isabelle; Augé, Gaëlle; Cochaud, Charlotte; Lespinasse, Françoise; N'Guyen, Karine; de Septenville, Anne; Brice, Alexis; Yu-Wai-Man, Patrick; Sesaki, Hiromi; Pouget, Jean; Paquis-Flucklinger, Véronique

    2014-08-01

    Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these

  6. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement

    PubMed Central

    Bannwarth, Sylvie; Ait-El-Mkadem, Samira; Chaussenot, Annabelle; Genin, Emmanuelle C.; Lacas-Gervais, Sandra; Fragaki, Konstantina; Berg-Alonso, Laetitia; Kageyama, Yusuke; Serre, Valérie; Moore, David G.; Verschueren, Annie; Rouzier, Cécile; Le Ber, Isabelle; Augé, Gaëlle; Cochaud, Charlotte; Lespinasse, Françoise; N’Guyen, Karine; de Septenville, Anne; Brice, Alexis; Yu-Wai-Man, Patrick; Sesaki, Hiromi; Pouget, Jean

    2014-01-01

    Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these

  7. 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.

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

    PubMed

    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.

  9. 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

  10. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p.

    PubMed

    Hsiung, Ging-Yuek R; DeJesus-Hernandez, Mariely; Feldman, Howard H; Sengdy, Pheth; Bouchard-Kerr, Phoenix; Dwosh, Emily; Butler, Rachel; Leung, Bonnie; Fok, Alice; Rutherford, Nicola J; Baker, Matt; Rademakers, Rosa; Mackenzie, Ian R A

    2012-03-01

    Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34-74 years) and disease duration (mean = 5.3, range = 1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with M(r) 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor

  11. The impact of neurodegeneration on network connectivity: a study of change detection in frontotemporal dementia.

    PubMed

    Hughes, Laura E; Rowe, James B

    2013-05-01

    The neural response to unpredictable auditory events is suggested to depend on frontotemporal interactions. We used magnetoencephalography in patients with behavioral variant frontotemporal dementia to study change detection and to examine the impact of disease on macroscopic network connectivity underlying this core cognitive function. In patients, the amplitudes of auditory cortical responses to predictable standard tones were normal but were reduced for unpredictable deviant tones. Network connectivity, in terms of coherence among frontal, temporal, and parietal sources, was also abnormal in patients. In the beta frequency range, left frontotemporal coherence was reduced. In the gamma frequency range, frontal interhemispheric coherence was reduced whereas parietal interhemispheric coherence was enhanced. These results suggest impaired change detection resulting from dysfunctional frontotemporal interactions. They also provide evidence of a rostro-caudal reorganization of brain networks in disease. The sensitivity of magnetoencephalography to cortical network changes in behavioral variant frontotemporal dementia enriches the understanding of neurocognitive systems as well as showing potential for studies of experimental therapies for neurodegenerative disease.

  12. A Multiancestral Genome-Wide Exome Array Study of Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy

    PubMed Central

    Chen, Jason A.; Wang, Qing; Davis-Turak, Jeremy; Li, Yun; Karydas, Anna M.; Hsu, Sandy C.; Sears, Renee L.; Chatzopoulou, Doxa; Huang, Alden Y.; Wojta, Kevin J.; Klein, Eric; Lee, Jason; Beekly, Duane L.; Boxer, Adam; Faber, Kelley M.; Haase, Claudia M.; Miller, Josh; Poon, Wayne W.; Rosen, Ami; Rosen, Howard; Sapozhnikova, Anna; Shapira, Jill; Varpetian, Arousiak; Foroud, Tatiana M.; Levenson, Robert W.; Levey, Allan I.; Kukull, Walter A.; Mendez, Mario F.; Ringman, John; Chui, Helena; Cotman, Carl; DeCarli, Charles; Miller, Bruce L.; Geschwind, Daniel H.; Coppola, Giovanni

    2015-01-01

    IMPORTANCE Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. OBJECTIVE To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. DESIGN, SETTING, AND PARTICIPANTS We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005–2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. MAIN OUTCOMES AND MEASURES Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. RESULTS Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P = .0049, European P = .041, African American P = .043, and Asian P = .027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P = 5.53 × 10−5) and PAXIP1 (P = 2.26 × 10−4), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. CONCLUSIONS AND RELEVANCE Low

  13. A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy.

    PubMed

    Chen, Jason A; Wang, Qing; Davis-Turak, Jeremy; Li, Yun; Karydas, Anna M; Hsu, Sandy C; Sears, Renee L; Chatzopoulou, Doxa; Huang, Alden Y; Wojta, Kevin J; Klein, Eric; Lee, Jason; Beekly, Duane L; Boxer, Adam; Faber, Kelley M; Haase, Claudia M; Miller, Josh; Poon, Wayne W; Rosen, Ami; Rosen, Howard; Sapozhnikova, Anna; Shapira, Jill; Varpetian, Arousiak; Foroud, Tatiana M; Levenson, Robert W; Levey, Allan I; Kukull, Walter A; Mendez, Mario F; Ringman, John; Chui, Helena; Cotman, Carl; DeCarli, Charles; Miller, Bruce L; Geschwind, Daniel H; Coppola, Giovanni

    2015-04-01

    Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer's Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD

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

    PubMed Central

    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. PMID:27489543

  15. 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

  16. 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).

  17. 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

  18. Juvenile frontotemporal dementia with parkinsonism associated with tau mutation G389R.

    PubMed

    Chaunu, Marie-Pierre; Deramecourt, Vincent; Buée-Scherrer, Valérie; Le Ber, Isabelle; Brice, Alexis; Ehrle, Nathalie; El Hachimi, Khalid; Pluot, Michel; Maurage, Claude-Alain; Bakchine, Serge; Buée, Luc

    2013-01-01

    Frontotemporal lobe degeneration includes a large spectrum of neurodegenerative disorders. Patients with frontotemporal dementia with parkinsonism linked to chromosome 17 exhibit heterogeneity in both clinical and neuropathological features. Here, we report the case of a young patient with a G389R mutation. This teenager girl was 17 years old when she progressively developed severe behavioral disturbances. First, she was considered to be suffering from atypical depression. After 2 years, she was referred to the department of neurology. By this time, the patient exhibited typical frontotemporal dementia with mild extrapyramidal disorders. The main behavioral features included apathy and reduced speech output. MRI and SPECT showed a frontotemporal atrophy and hypofixation, respectively. She died 7 years after onset. Three relatives on her father side had also died after early onset dementia. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (Exon 13) of MAPT, the tau gene, resulting in a glycine to arginine substitution, in the patient and her non-affected father. Postmortem neuropathological and biochemical data indicate a Pick-like tau pathology but with phosphoserine 262-positive immunoreactivity. This case is remarkable because of the extremely early onset of the disease.

  19. 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.

  20. Assessment of Eating Behavior Disturbance and Associated Neural Networks in Frontotemporal Dementia.

    PubMed

    Ahmed, Rebekah M; Irish, Muireann; Henning, Elana; Dermody, Nadene; Bartley, Lauren; Kiernan, Matthew C; Piguet, Olivier; Farooqi, Sadaf; Hodges, John R

    2016-03-01

    Abnormal eating behaviors are common in patients with frontotemporal dementia (FTD), yet their exact prevalence, severity, and underlying biological mechanisms are not understood. To define the severity of abnormal eating behavior and sucrose preference and their neural correlates in patients with behavioral variant FTD (bvFTD) and semantic dementia. Forty-nine patients with dementia (19 with bvFTD, 15 with semantic dementia, and 15 with Alzheimer disease) were recruited, and their eating behavior was compared with that of 25 healthy controls. The study was conducted from November 1, 2013, through May 31, 2015, and data analyzed from June 1 to August 31, 2015. Patients participated in an ad libitum breakfast test meal, and their total caloric intake and food preferences were measured. Changes in eating behavior were also measured using the Appetite and Eating Habits Questionnaire (APEHQ) and the Cambridge Behavioral Inventory (CBI). Sucrose preference was tested by measuring liking ratings of 3 desserts of varying sucrose content (A: 26%, B: 39%, C: 60%). Voxel-based morphometry analysis of whole-brain 3-T high-resolution brain magnetic resonance imaging was used to determine the gray matter density changes across groups and their relations to eating behaviors. Mean (SD) ages of patients in all 4 groups ranged from 62 (8.3) to 66 (8.4) years. At the ad libitum breakfast test meal, all patients with bvFTD had increased total caloric intake (mean, 1344 calories) compared with the Alzheimer disease (mean, 710 calories), semantic dementia (mean, 573 calories), and control groups (mean, 603 calories) (P < .001). Patients with bvFTD and semantic dementia had a strong sucrose preference compared with the other groups. Increased caloric intake correlated with atrophy in discrete neural networks that differed between patients with bvFTD and semantic dementia but included the cingulate cortices, thalami, and cerebellum in patients with bvFTD, with the addition of the

  1. 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.

  2. 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.

  3. Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia.

    PubMed

    Hirano, Shigeki; Shinotoh, Hitoshi; Shimada, Hitoshi; Aotsuka, Akiyo; Tanaka, Noriko; Ota, Tsuneyoshi; Sato, Koichi; Ito, Hiroshi; Kuwabara, Satoshi; Fukushi, Kiyoshi; Irie, Toshiaki; Suhara, Tetsuya

    2010-07-01

    Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both

  4. Associations between APOE polymorphisms and seven diseases with cognitive impairment including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies in southeast China

    PubMed Central

    Chen, Ke-Liang; Sun, Yi-Min; Zhou, Yan; Zhao, Qian-Hua; Ding, Ding

    2016-01-01

    Objective To explore the effect of APOE polymorphisms on patients with cognitive impairments in The Chinese Han population. Materials and methods A total of 1027 cases with Alzheimer’s disease (AD), 40 cases with vascular dementia (VaD), 28 cases with behavioral variant frontotemporal dementia (bvFTD), 54 cases with semantic dementia (SD), 44 cases with dementia with Lewy bodies (DLB), 583 cases with mild cognitive impairment (MCI), and 32 cases with vascular cognitive impairment no dementia (VCIND) were recruited consecutively from memory disorders clinics in Huashan Hospital between January 2010 and December 2014. The 1149 cognitively normal controls were recruited from the community epidemiologic investigations. The APOE genotypes were determined using the TaqMan assay. Results The distribution of genotype and allele frequencies of APOE differed significantly between control and AD or MCI, with ε4 increasing the risk of AD and MCI in a dose-dependent pattern and ε2 decreasing the risk of AD, but not the risk of MCI. As for VaD, significant differences in the APOE genotype distribution were found compared with the controls. E4/4 increased the risk of VaD and ε4 increased the risk of VCIND in women. The allele distribution differed between bvFTD and controls, but genotype and allele frequencies of APOE did not affect the risk of bvFTD, SD, and DLB. Conclusion In The Chinese Han population, APOE ε4 increased the risk of AD and MCI in a dose-dependent manner and ε2 decreased the risk of AD as reported previously. APOE ε4 might increase risk in VaD and female patients with VCIND, but no effects of APOE on bvFTD, DLB, and SD were found. PMID:26981880

  5. Associations between APOE polymorphisms and seven diseases with cognitive impairment including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies in southeast China.

    PubMed

    Chen, Ke-Liang; Sun, Yi-Min; Zhou, Yan; Zhao, Qian-Hua; Ding, Ding; Guo, Qi-Hao

    2016-06-01

    To explore the effect of APOE polymorphisms on patients with cognitive impairments in The Chinese Han population. A total of 1027 cases with Alzheimer's disease (AD), 40 cases with vascular dementia (VaD), 28 cases with behavioral variant frontotemporal dementia (bvFTD), 54 cases with semantic dementia (SD), 44 cases with dementia with Lewy bodies (DLB), 583 cases with mild cognitive impairment (MCI), and 32 cases with vascular cognitive impairment no dementia (VCIND) were recruited consecutively from memory disorders clinics in Huashan Hospital between January 2010 and December 2014. The 1149 cognitively normal controls were recruited from the community epidemiologic investigations. The APOE genotypes were determined using the TaqMan assay. The distribution of genotype and allele frequencies of APOE differed significantly between control and AD or MCI, with ε4 increasing the risk of AD and MCI in a dose-dependent pattern and ε2 decreasing the risk of AD, but not the risk of MCI. As for VaD, significant differences in the APOE genotype distribution were found compared with the controls. E4/4 increased the risk of VaD and ε4 increased the risk of VCIND in women. The allele distribution differed between bvFTD and controls, but genotype and allele frequencies of APOE did not affect the risk of bvFTD, SD, and DLB. In The Chinese Han population, APOE ε4 increased the risk of AD and MCI in a dose-dependent manner and ε2 decreased the risk of AD as reported previously. APOE ε4 might increase risk in VaD and female patients with VCIND, but no effects of APOE on bvFTD, DLB, and SD were found.

  6. Autonomic dysfunction: A comparative study of patients with Alzheimer's and frontotemporal dementia – A pilot study

    PubMed Central

    Issac, Thomas Gregor; Chandra, Sadanandavalli Retnaswami; Gupta, Neelesh; Rukmani, Malligurki Raghurama; Deepika, S.; Sathyaprabha, T. N.

    2017-01-01

    Introduction: In frontotemporal dementia (FTD) and Alzheimer's disease (AD), central autonomic structures get affected early. An insight into autonomic functions in these patients is likely to be of diagnostic importance and thus help in prognosticating and also probably explain unexplained sudden death in some of these patients. Objectives: The objective of this study is to identify autonomic dysfunction prevailing in patients. Then, if there is dysfunction, is the pattern same or different in these two conditions. And if different it will serve as an additional biomarker for specific diagnosis. Patients and Methods: There were 25 patients and 25 controls and six patients and three controls in AD and FTD groups, respectively. The participants who were recruited were assessed for heart rate variability and conventional cardiac autonomic function testing. The parameters were analyzed using LabChart version 7 software and compared with control population using appropriate statistical methods using SPSS version 22 software. Results: The mean overall total power was low in the FTD group (P < 0.001), and there was significant reduction in the standard deviation of normal-to-normal intervals and root mean square of successive differences (P < 0.001) with elevated sympathovagal balance in the FTD group (P = 0.04). Patients with AD also showed sympathetic dominance, but there was in addition parasympathetic suppression unlike in the FTD group. Conclusion: This study reveals autonomic dysfunction in patients with FTD and AD. Both conditions show sympathetic dominance, probably consecutive to the involvement of central autonomic regulatory structures as a shared domain. It remains to be confirmed if these findings are the cause or effect of neurodegeneration and might open up newer territories of research based on the causal role of neurotransmitters in these regions and thus lead to novel therapeutic options such as yoga. The presence of parasympathetic suppression in AD in

  7. Differential putaminal morphology in Huntington's disease, Frontotemporal dementia and Alzheimer's disease

    PubMed Central

    Looi, Jeffrey C.L.; Rajagopalan, Priya; Walterfang, Mark; Madsen, Sarah K.; Thompson, Paul M.; Macfarlane, Matthew D.; Ching, Chris; Chua, Phyllis; Velakoulis, Dennis

    2014-01-01

    Objective Direct neuronal loss or deafferentation of the putamen, a critical hub in corticostriatal circuits, may result in diverse and distinct cognitive and motoric dysfunction in neurodegenerative disease. Differential putaminal morphology, as a quantitative measure of corticostriatal integrity, may thus be evident in Huntington disease (HD), Alzheimer Disease (AD) and Frontotemporal Dementia (FTD), diseases with differential clinical dysfunction. Method HD (n=17), FTD (n=33) and AD (n=13) patients were diagnosed according to international consensus criteria, and with healthy controls (n=17), were scanned on the same MRI scanner. Patients underwent brief cognitive testing using the Neuropsychiatry unit cognitive assessment tool (NUCOG). Ten MRI scans from this dataset were manually segmented as a training set for the Adaboost algorithm, which automatically segmented all remaining scans for the putamen, yielding the following subset of the data: 9 left and 12 right putamen segmentations for AD; 25 left and 26 right putamina for FTD; 16 left and 15 right putamina for HD; 12 left and 12 right putamina for controls. Shape analysis was performed at each point on the surface of each structure using a multiple regression controlling for age and sex to compare radial distance across diagnostic groups. Results Age, but not sex and ICV, were significantly different in the segmentation subgroups by diagnosis. The AD group showed significantly poorer performance on cognitive testing than FTD. Mean putaminal volumes were HDAD, with relevance to corticostriatal circuits, suggest the putamen may be a suitable clinical biomarker in neurodegenerative disease. PMID:22990433

  8. Environmental dependency behaviours in frontotemporal dementia: have we been underrating them?

    PubMed

    Ghosh, Amitabha; Dutt, Aparna; Bhargava, Pallavi; Snowden, Julie

    2013-03-01

    Environmental dependency (ED) behaviours, such as imitation behaviour (IB) and incidental utilization behaviour (UB), are considered pathognomonic of a frontal lesion and can play a unique role in diagnosing behavioural variant frontotemporal dementia (bvFTD). However, with only few focused observations of ED behaviour reported in earlier studies, their roles in the diagnosis of bvFTD have so far remained supportive. In this observational study, conducted in the cognitive clinic of a tertiary-care hospital, we explored the hypotheses that a focused and systematic search could uncover more ED behaviours in patients with bvFTD, and that the presence of ED behaviours such as incidental UB and IB should allow us to cleanly differentiate bvFTD from AD. Forty-one bvFTD patients and 75 probable AD patients, all diagnosed using accepted criteria, were seen by a neurologist and a neuropsychologist. Information regarding ED behaviour was obtained from the caregiver's history, observations for spontaneous behaviour and induction of the behaviour in the clinic. All ED behaviours were significantly more frequent in bvFTD compared with AD. UB (78 %; 66 % incidental) and IB (59 %) occurred exclusively in bvFTD. Multi-pronged and focused clinical assessment contributed to the high frequency of ED behaviours. Nearly two-thirds of bvFTD patients, but none with AD, showed three or more ED behaviours. We concluded that ED behaviours are more common in bvFTD than is currently recognized. UB, IB or three ED behaviours, if present, could clearly differentiate bvFTD from AD. A focused search should consistently uncover ED behaviours in bvFTD patients.

  9. 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.

  10. CHMP2B mutations are not a cause of dementia in Dutch patients with familial and sporadic frontotemporal dementia.

    PubMed

    Rizzu, Patrizia; van Mil, Saskia E; Anar, Burcu; Rosso, Sonia M; Donker Kaat, Laura; Heutink, Peter; van Swieten, John C

    2006-12-05

    Mutations in the CHMP2B gene have been recently identified in a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). We report the frequency of CHMP2B mutations in 162 FTD patients recruited from a large population-based study of FTD carried out in The Netherlands. Our results suggest that mutations in CHMP2B are a rare cause of FTD as compared to MAPT mutations. (c) 2006 Wiley-Liss, Inc.

  11. Neuropsychiatric characteristics of PiB-negative subcortical vascular dementia versus behavioral variant frontotemporal dementia.

    PubMed

    Jung, Na-Yeon; Kim, Hee Jin; Kim, Yeo Jin; Kim, Seonwoo; Seo, Sang Won; Kim, Eun-Joo; Na, Duk L

    2016-01-01

    Neuropsychiatric symptoms of subcortical vascular dementia (SVaD) are mainly associated with damage to frontal-subcortical circuits and may be similar to symptoms of behavioral variant frontotemporal dementia (bvFTD). The aim of this study was to determine whether the neuropsychiatric manifestations of the Pittsburgh compound B (PiB)-negative SVaD and bvFTD groups differ. We compared the Caregiver-Administered Neuropsychiatry Inventory (CGA-NPI) between 48 patients with PiB(-) SVaD and 31 patients with bvFTD. A stepwise logistic regression was applied to determine the best model to predict SVaD. The SVaD group showed a higher frequency of depression, whereas the bvFTD group had a higher frequency of elation, aberrant motor behavior and appetite/eating disorders. Regarding NPI subscores, the bvFTD group had greater severity of elation, apathy, disinhibition, aberrant motor behavior and appetite/eating disorders, whereas SVaD did not have significantly higher subscores in any domains. The most predictive models that tend to find suggestions of SVaD, as opposed to bvFTD, are as follows: (1) the presence of depression and the absence of appetite/eating disorders, (2) higher NPI subscores of depression and lower NPI subscores of irritability and aberrant motor behavior. Apart from apathy, SVaD differed from bvFTD in that negative symptoms were more common in SVaD than bvFTD, whereas positive symptoms were predominant in bvFTD compared to SVaD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. [Difference in sundowning of wandering behavior in patients with Alzheimer disease and frontotemporal dementia].

    PubMed

    Liao, Xiao-yan; Yamakawa, Miyae; Shigenobu, Kazue; Suto, Shunji; Makimoto, Kiyoko

    2012-01-17

    To delineate the difference in sundowning of wandering behavior between patient with Alzheimer Disease (AD) and frontotemporal dementia (FTD). The study was conducted in a dementia care unit at A hospital in Osaka, Japan from September 2008 to September 2009. Twenty-four-hour movements of 27 ambulatory inpatients with AD and 7 with FTD were coded consecutively by the IC tag monitoring system. Repeated measures ANOVA after the adjustment of Huynh-Feldt Epsilon (H-F) showed no significant difference in 24 h standardized activity level between two groups (F = 3.74, P = 0.06), and there was no interaction between diagnosis and time (F = 1.42, P > 0.05). The standardized activity levels gradually increased from late afternoon to evening and then reached the highest point at 18:00 in AD group and 19:00 in FTD group. Test of within-subjects contrasts for order 17 was significant (F = 5.24, P < 0.05) and for order 9 was a tendency of significant (F = 4.26; P = 0.05) between two groups. AD group was significant greater active at 5:00, 6:00 and 7:00 (0.75 ± 0.08 vs 0.35 ± 0.16, F = 4.91; 1.13 ± 0.13 vs 0.49 ± 0.26, F = 5.06; 1.24 ± 0.15 vs 0.56 ± 0.28, F = 4.47 respectively, P < 0.05), and less active at 16:00 (1.65 ± 0.11 vs 2.22 ± 0.22, P < 0.05) comparing to FTD group by Bonferroni's multiple comparison test. Meanwhile, the time of peak value of hourly distance moved per day (PV-time) was delayed in FTD group comparing to AD by circular χ² test (14:12 ± 5:12 vs 15:47 ± 4:19, χ² = 87.31, P < 0.01). The study suggests great possibility of sundowning of wandering behavior in both two subtypes with different temporal pattern of wandering behavior. Comparing to FTD patients, AD patients showed an advanced PV-time and prolonged active phase.

  13. Differential automatic diagnosis between Alzheimer's disease and frontotemporal dementia based on perfusion SPECT images.

    PubMed

    Horn, Jean-François; Habert, Marie-Odile; Kas, Aurélie; Malek, Zoulikha; Maksud, Philippe; Lacomblez, Lucette; Giron, Alain; Fertil, Bernard

    2009-10-01

    Alzheimer's disease (AD) and frontotemporal dementia (FTD) are among the most frequent neurodegenerative cognitive disorders, but their differential diagnosis is difficult. The aim of this study was to evaluate an automatic method returning the probability that a patient suffers from AD or FTD from the analysis of brain perfusion single photon emission computed tomography images. A set of 116 descriptors corresponding to the average activity in regions of interest was calculated from the images of 82 AD and 91 FTD patients. A set of linear (logistic regression and linear discriminant analysis) and non-linear (support vector machines, k-nearest neighbours, multilayer perceptron and kernel logistic PLS) classification methods was subsequently used to ascertain diagnoses. Validation was carried out by means of the leave-one-out protocol. Diagnoses by the classifier and by four physicians (visual assessment) were compared. Since images were acquired in different hospitals, the impact of the medical centre on the diagnosis of both the classifier and the physicians was investigated. Best results were obtained with support vector machine and partial least squares regression coupled with k-nearest neighbours methods (PLS+K-NN), with an overall accuracy of 88%. PLS+K-NN was however considered as the best method since performances obtained with leave-one-out cross-validation were closer to whole-database learning. The performances of the classifier were higher than those of experts (accuracy ranged from 65 to 72%). Physicians found it more difficult to diagnose the images from centres other than their own, and it affected their performances. The performances obtained by the classifier for the differential diagnosis of AD and FTD were found convincing. It could help physicians in daily practice, particularly when visual assessment is inconclusive, or when dealing with multicentre data.

  14. 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

  15. 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

  16. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.

    PubMed

    Skibinski, Gaia; Parkinson, Nicholas J; Brown, Jeremy M; Chakrabarti, Lisa; Lloyd, Sarah L; Hummerich, Holger; Nielsen, Jørgen E; Hodges, John R; Spillantini, Maria Grazia; Thusgaard, Tove; Brandner, Sebastian; Brun, Arne; Rossor, Martin N; Gade, Anders; Johannsen, Peter; Sørensen, Sven Asger; Gydesen, Susanne; Fisher, Elizabeth M C; Collinge, John

    2005-08-01

    We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

  17. Genetics Home Reference: CHMP2B-related frontotemporal dementia

    MedlinePlus

    ... DEMENTIA, CHROMOSOME 3-LINKED Sources for This Page Brown J, Ashworth A, Gydesen S, Sorensen A, Rossor M, ... Sep;4(9):1625-8. Citation on PubMed Brown J, Gydesen S, Johannsen P, Gade A, Skibinski G, ...

  18. C9orf72 repeat expansions that cause frontotemporal dementia are detectable among patients with psychosis.

    PubMed

    Watson, Annie; Pribadi, Mochtar; Chowdari, Kodavali; Clifton, Sue; Joel Wood; Miller, Bruce L; Coppola, Giovanni; Nimgaonkar, Vishwajit

    2016-01-30

    A pathologic hexanucleotide repeat expansion in C9orf72 causes frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). Behavioral abnormalities can also occur among mutation carriers with FTD, but it is uncertain whether such mutations occur among persons with psychoses per se. Among participants in a genetic study of psychoses (N=739), two pairs of related individuals had C9orf72 expansions, of whom three were diagnosed with schizophrenia (SZ) / schizoaffective disorder (SZA), but their clinical features did not suggest dementia or ALS. A few patients with SZ/SZA carry C9orf72 repeat expansions; such individuals are highly likely to develop FTD/ALS.

  19. Diffusion Tensor Tractography versus Volumetric Imaging in the Diagnosis of Behavioral Variant Frontotemporal Dementia

    PubMed Central

    Santillo, Alexander Frizell; Mårtensson, Johanna; Lindberg, Olof; Nilsson, Markus; Manzouri, Amir; Landqvist Waldö, Maria; van Westen, Danielle; Wahlund, Lars-Olof; Lätt, Jimmy; Nilsson, Christer

    2013-01-01

    MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p=0.031), and borderline significant for fractional anisotropy vs. VBM (p=0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls. PMID:23874403

  20. 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.

  1. Episodic future thinking is impaired in the behavioural variant of frontotemporal dementia.

    PubMed

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

    2013-10-01

    Remembering the past and imagining the future are complex endeavours proposed to rely on a core neurobiological brain system. In the behavioural variant of frontotemporal dementia (bvFTD), regional patterns of brain atrophy affect medial prefrontal and temporal cortices of this core network. While autobiographical memory impairments have been documented in bvFTD, it remains unknown whether the ability to imagine future events is also compromised. Here, we investigated episodic future thinking in 10 bvFTD patients and contrasted their performance with Alzheimer's disease (AD, n = 10) and healthy matched Control (n = 10) participants. Participants were asked to remember 3 events from the previous year and to envisage 3 possible events that could occur in the next year. Both patient groups showed equivalent episodic detail performance for the retrieval of past events and the simulation of possible future episodes. Patients with bvFTD, however, showed additional impairments for the generation of external (non-episodic) details irrespective of condition. Voxel-based morphometry analyses revealed divergent neural correlates of episodic past and future thinking performance specific to each patient group. Atrophy in the posterior cingulate cortex was implicated in the disruption of past and future thinking in AD. In contrast, in bvFTD, disruption of past retrieval correlated with atrophy in medial prefrontal regions, whereas future thinking deficits were associated with atrophy of frontopolar, medial temporal regions including the right hippocampus, and lateral temporal and occipital cortices. Our results point to the involvement of multiple brain regions in facilitating retrieval of past, and simulation of future, events. Damage to any of these key regions thus adversely affects the ability to engage in personally relevant mental time travel. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Multiparametric computer-aided differential diagnosis of Alzheimer's disease and frontotemporal dementia using structural and advanced MRI.

    PubMed

    Bron, Esther E; Smits, Marion; Papma, Janne M; Steketee, Rebecca M E; Meijboom, Rozanna; de Groot, Marius; van Swieten, John C; Niessen, Wiro J; Klein, Stefan

    2017-08-01

    To investigate the added diagnostic value of arterial spin labelling (ASL) and diffusion tensor imaging (DTI) to structural MRI for computer-aided classification of Alzheimer's disease (AD), frontotemporal dementia (FTD), and controls. This retrospective study used MRI data from 24 early-onset AD and 33 early-onset FTD patients and 34 controls (CN). Classification was based on voxel-wise feature maps derived from structural MRI, ASL, and DTI. Support vector machines (SVMs) were trained to classify AD versus CN (AD-CN), FTD-CN, AD-FTD, and AD-FTD-CN (multi-class). Classification performance was assessed by the area under the receiver-operating-characteristic curve (AUC) and accuracy. Using SVM significance maps, we analysed contributions of brain regions. Combining ASL and DTI with structural MRI resulted in higher classification performance for differential diagnosis of AD and FTD (AUC = 84%; p = 0.05) than using structural MRI by itself (AUC = 72%). The performance of ASL and DTI themselves did not improve over structural MRI. The classifications were driven by different brain regions for ASL and DTI than for structural MRI, suggesting complementary information. ASL and DTI are promising additions to structural MRI for classification of early-onset AD, early-onset FTD, and controls, and may improve the computer-aided differential diagnosis on a single-subject level. • Multiparametric MRI is promising for computer-aided diagnosis of early-onset AD and FTD. • Diagnosis is driven by different brain regions when using different MRI methods. • Combining structural MRI, ASL, and DTI may improve differential diagnosis of dementia.

  3. Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies.

    PubMed

    Mackenzie, Ian R A; Neumann, Manuela

    2016-08-01

    Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The past decade has seen the discovery of several new FTD-causing genetic mutations and the identification of many of the relevant pathological proteins. The current neuropathological classification is based on the predominant protein abnormality and allows most cases of FTD to be placed into one of three broad molecular subgroups; frontotemporal lobar degeneration with tau, TDP-43 or FET protein accumulation. This review will describe our current understanding of the molecular basis of FTD, focusing on insights gained from the study of human postmortem tissue, as well as some of the current controversies. Most cases of FTD can be subclassified into one of three broad molecular subgroups based on the predominant protein that accumulates as pathological cellular inclusions. Understanding the associated pathogenic mechanisms and recognizing these FTD molecular subtypes in vivo will likely be crucial for the development and use of targeted therapies. This article is part of the Frontotemporal Dementia special issue.

  4. A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3.

    PubMed

    Holm, Ida Elisabeth; Englund, Elisabet; Mackenzie, Ian R A; Johannsen, Peter; Isaacs, Adrian M

    2007-10-01

    A large Danish family has previously been reported in which autosomal dominant frontotemporal dementia (FTD) is genetically linked to chromosome 3 (FTD-3). A mutation was recently identified in the CHMP2B gene that is probably responsible for causing disease in this family. Because of its neuropathologic findings, FTD-3 was originally categorized as a subtype of frontotemporal lobar degeneration, termed "dementia lacking distinctive histopathology." We now report a reevaluation of the neuropathologic changes in this family. Postmortem material from 4 affected family members was available for examination. Gross examination revealed generalized cortical atrophy that was most severe in frontal and temporal cortices. Microscopy showed loss of cortical neurons, microvacuolation of layer II, mild gliosis, and demyelination of the deep white matter. Results of immunohistochemical staining for alpha-synuclein, prion protein, neurofilament, and tau protein were unremarkable. Variable numbers of small, round, ubiquitin-positive cytoplasmic inclusions were present in the dentate granule layer of the hippocampus in all 4 cases. Rare ubiquitin-positive inclusions were also found in frontal and temporal cortical neurons. These inclusions were also positive for p62 but not for TDP-43. The finding of ubiquitin- and p62-positive, TDP-43-negative cytoplasmic inclusions in the hippocampus and neocortex suggests reclassification of the neuropathology of FTD-3 as a unique subtype of frontotemporal lobar degeneration with ubiquitin-positive inclusions that are TDP-43-negative.

  5. 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.

  6. Improved discrimination of autopsy-confirmed Alzheimer's disease (AD) from non-AD dementias using CSF P-tau(181P).

    PubMed

    Koopman, Karen; Le Bastard, Nathalie; Martin, Jean-Jacques; Nagels, Guy; De Deyn, Peter P; Engelborghs, Sebastiaan

    2009-09-01

    To establish diagnostic accuracy (acc) and optimal cut-off levels of CSF tau phosphorylated at threonine 181 (P-tau(181P)) for discriminating Alzheimer's disease (AD) from non-AD dementias in autopsy-confirmed dementia patients, CSF levels of beta-amyloid peptide (Abeta(1-42)), total tau protein (T-tau) and P-tau(181P) from patients with definite AD (n=95) and non-AD dementias (n=50) were determined with single-parameter ELISA kits. Optimal P-tau(181P) cut-off levels for differentiating AD from pooled non-AD dementias, dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) were 50.4pg/mL (acc=0.73), 52.8pg/mL (acc=0.73) and 35.3pg/mL (acc=0.90), respectively. The optimal CSF P-tau(181P) cut-off level for discriminating AD from non-AD dementias was 50.4pg/mL. Optimal CSF P-tau(181P) cut-off levels differed between non-AD diagnostic dementia categories.

  7. Pure word deafness and pure anarthria in a patient with frontotemporal dementia.

    PubMed

    Iizuka, O; Suzuki, K; Endo, K; Fujii, T; Mori, E

    2007-04-01

    A 66-year-old right-handed man developed pure anarthria following pure word deafness. In addition to language disorders, his behavior gradually changed and finally included violence against his wife. Brain magnetic resonance imagings revealed atrophy of the left perisylvian area, which included the inferior half of the precentral gyrus and the upper portion of the superior temporal gyrus, consistent with frontotemporal dementia (FTD). It has been documented as either a disorder of expressive language or as an impaired understanding of word meaning. Unlike with pure anarthria, pure word deafness is not included in the clinical diagnostic current criteria for FTD. However, a large variety of language symptoms can appear in FTD according to the distribution of pathological changes in the frontotemporal cortices. This case suggests that pure word deafness could be a prodomal symptom of FTD.

  8. Predicting behavioral variant frontotemporal dementia with pattern classification in multi-center structural MRI data.

    PubMed

    Meyer, Sebastian; Mueller, Karsten; Stuke, Katharina; Bisenius, Sandrine; Diehl-Schmid, Janine; Jessen, Frank; Kassubek, Jan; Kornhuber, Johannes; Ludolph, Albert C; Prudlo, Johannes; Schneider, Anja; Schuemberg, Katharina; Yakushev, Igor; Otto, Markus; Schroeter, Matthias L

    2017-01-01

    Frontotemporal lobar degeneration (FTLD) is a common cause of early onset dementia. Behavioral variant frontotemporal dementia (bvFTD), its most common subtype, is characterized by deep alterations in behavior and personality. In 2011, new diagnostic criteria were suggested that incorporate imaging criteria into diagnostic algorithms. The study aimed at validating the potential of imaging criteria to individually predict diagnosis with machine learning algorithms. Brain atrophy was measured with structural magnetic resonance imaging (MRI) at 3 Tesla in a multi-centric cohort of 52 bvFTD patients and 52 healthy control subjects from the German FTLD Consortium's Study. Beside group comparisons, diagnosis bvFTD vs. controls was individually predicted in each subject with support vector machine classification in MRI data across the whole brain or in frontotemporal, insular regions, and basal ganglia known to be mainly affected based on recent meta-analyses. Multi-center effects were controlled for with a new method, "leave one center out" conjunction analyses, i.e. repeatedly excluding subjects from each center from the analysis. Group comparisons revealed atrophy in, most consistently, the frontal lobe in bvFTD beside alterations in the insula, basal ganglia and temporal lobe. Most remarkably, support vector machine classification enabled predicting diagnosis in single patients with a high accuracy of up to 84.6%, where accuracy was highest in a region-of-interest approach focusing on frontotemporal, insular regions, and basal ganglia in comparison with the whole brain approach. Our study demonstrates that MRI, a widespread imaging technology, can individually identify bvFTD with high accuracy in multi-center imaging data, paving the road to personalized diagnostic approaches in the future.

  9. Reversal of pathology in CHMP2B-mediated frontotemporal dementia patient cells using RNA interference.

    PubMed

    Nielsen, Troels Tolstrup; Mizielinska, Sarah; Hasholt, Lis; Isaacs, Adrian M; Nielsen, Jørgen E

    2012-08-01

    Frontotemporal dementia is the second most common form of young-onset dementia after Alzheimer's disease, and several genetic forms of frontotemporal dementia are known. A rare genetic variant is caused by a point mutation in the CHMP2B gene. CHMP2B is a component of the ESCRT-III complex, which is involved in endosomal trafficking of proteins targeted for degradation in lysosomes. Mutations in CHMP2B result in abnormal endosomal structures in patient fibroblasts and patient brains, probably through a gain-of-function mechanism, suggesting that the endosomal pathway plays a central role in the pathogenesis of the disease. In the present study, we used lentiviral vectors to efficiently knockdown CHMP2B by delivering microRNA embedded small hairpin RNAs. We show that CHMP2B can be efficiently knocked down in patient fibroblasts using an RNA interference approach and that the knockdown causes reversal of the abnormal endosomal phenotype observed in patient fibroblasts. This is the first description of a treatment that reverses the cellular pathology caused by mutant CHMP2B and suggests that RNA interference might be a feasible therapeutic strategy. Furthermore, it provides the first proof of a direct link between the disease-causing mutation and the cellular phenotype in cells originating from CHMP2B mutation patients. Copyright © 2012 John Wiley & Sons, Ltd.

  10. 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.

  11. Postmorbid learning of saxophone playing in a patient with frontotemporal dementia.

    PubMed

    Cho, Hanna; Chin, Juhee; Suh, Mee Kyung; Kim, Hee Jin; Kim, Yeo Jin; Ye, Byoung Seok; Lee, Na Kyung; Kim, Eun Joo; Seo, Sang Won; Na, Duk L

    2015-01-01

    Some patients with frontotemporal dementia (FTD) show an artistic enhancement of musical abilities. However, no patients with FTD, to date, have been reported to be able to learn how to play a musical instrument after disease onset. Herein we describe a patient (J. K.) who had never played any musical instruments premorbidly, but who learned to play the saxophone after being diagnosed with a behavioral variant of FTD. He mastered a repertoire that consisted of 10 pieces of Korean folk songs over a period of three years. Furthermore, his saxophone skills were high enough to outperform other students in his class.

  12. Relapsing-remitting behavioural variant of frontotemporal dementia in a bipolar patient

    PubMed Central

    Vorspan, Florence; Bertoux, Maxime; Brichant-Petitjean, Clara; Dubois, Bruno; Lépine, Jean-Pierre

    2012-01-01

    Summary We report the case of a bipolar I patient who was diagnosed with frontotemporal dementia at the age of 54 during a manic episode. Her neurological state improved when this episode ended. Each subsequent thymic relapse was associated with cognitive deficits which subsided when the patient became euthymic, even though SPECT continued to show the same frontal hypoperfusion. We here discuss the hypothesis that the cognitive reserve of this patient, a former journalist, may, except during her mood episodes, have provided her with sufficient resources to meet her life demands despite her underlying neurological disorder. PMID:23402681

  13. No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia.

    PubMed

    Schumacher, Axel; Friedrich, Patricia; Diehl-Schmid, Janine; Ibach, Bernd; Eisele, Tamara; Laws, Simon M; Förstl, Hans; Kurz, Alexander; Riemenschneider, Matthias

    2007-11-01

    Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.

  14. A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia

    PubMed Central

    Lashley, Tammaryn; Rohrer, Jonathan D; Mahoney, Colin; Gordon, Elizabeth; Beck, Jon; Mead, Simon; Warren, Jason; Rossor, Martin; Revesz, Tamas

    2014-01-01

    Aims Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease and is the second most common form of young onset dementia after Alzheimer's disease (AD). An autosomal dominant pattern of inheritance is present in around 25–50% of FTLD cases indicating a strong genetic component. Major pathogenic mutations of FTLD have been demonstrated independently in the progranulin (GRN) gene and the C9orf72 hexanucleotide expansion repeat. In this study we present a family that have been identified as carrying both a GRN Cys31fs mutation and the C9orf72 hexanucleotide expansion repeat. Methods In the present study we describe the clinical and genetic details of family members and pathological features of two family members that have come to post-mortem. Results The mean age at disease onset was 57 years (48–61 years) and mean duration 4 years (2–7 years). The most common presenting syndrome was behavioural variant frontotemporal dementia. Brain imaging from available cases showed a symmetrical pattern of atrophy particularly affecting the frontal and temporal lobes. Pathologically two cases were classified as FTLD-TDP type A with TDP-43 positive inclusions, with additional p62-positive ‘star-like’ inclusions found in the hippocampal formation and cerebellum. Conclusions The type and distribution of the pathological lesions in these two cases were in keeping with FTLD cases carrying only the C9orf72 hexanucleotide repeat. However the driving force of the pathological process may be either pathogenic mutation or a combination of both converging on a singular mechanism. PMID:24286341

  15. 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.

  16. The neuropsychology of frontal variant frontotemporal dementia and semantic dementia. Introduction to the special topic papers: Part II.

    PubMed

    Hodges, J R; Miller, B

    2001-01-01

    The second part of this review, which accompanies 10 special topic articles dedicated to frontotemporal dementia (FTD), describes some of the advances in understanding frontal variant FTD (fvFTD) and semantic dementia, and the theoretical insights gained into normal cognitive processes from the study of these syndromes. Recent work has clarified the neuropsychiatric features that distinguish fvFTD from Alzheimer's and has begun to spread light on the underlying deficits in social judgement, theory of mind, processing of emotional stimuli and decision making. With regard to central aspects of cognitive processing, such as memory, patients with fvFTD may have a distinctive profile of performance on tests of explicit and implicit memory, and contrary to current views some patients may even have a severe amnesic syndrome. There is also growing evidence that despite relatively well preserved general language skills, patients with fvFTD have particular problems with verb processing. Although there is agreement regarding the key features of semantic dementia, much controversy has surrounded the issue of whether the cognitive findings favour an explanation in terms of progressive breakdown of a central amodal semantic store or differential involvement of verbal and non-verbal systems. Other topics discussed include the impact of semantic breakdown on phonological processes and episodic memory. We also review recent structural and functional neuroimaging findings in semantic dementia.

  17. Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology.

    PubMed

    Ahmed, Rebekah M; Irish, Muireann; van Eersel, Janet; Ittner, Arne; Ke, Yazi D; Volkerling, Alexander; van der Hoven, Julia; Tanaka, Kimi; Karl, Tim; Kassiou, Michael; Kril, Jillian J; Piguet, Olivier; Götz, Jürgen; Kiernan, Matthew C; Halliday, Glenda M; Hodges, John R; Ittner, Lars M

    2017-03-01

    Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.

  18. Neuropsychiatric Symptoms in a Cohort of Patients with Frontotemporal Dementia: Our Experience

    PubMed Central

    Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Korada, Suresh Kumar; Teja, Karru Venkata Ravi; Philip, Mariamma

    2016-01-01

    Introduction: About 20–50% of relatively young onset dementia belongs to frontotemporal type. Most of these patients are diagnosed as psychiatric illness as their memory and instrumental activities of daily living remain unaltered till late and most of these patients do not qualify for dementia by the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. In this study, we analyzed the behavioral symptoms in our patients with radiologically and neuropsychologically proven as probable behavioral variant of frontotemporal dementia (FTD). Patients and Methods: Twenty patients qualifying the International Consensus Criteria were included and evaluated using National Institute of Mental Health and Neurosciences neuropsychological battery in addition to all mandatory dementia workup. Results: The mean age was 53.9 ± 9.9 years and the mean duration of illness was 2 ± 1.3 years. Sixty percent of them were <60 years. There were 9 males and 11 females. Most common heralding symptom noticed in 85% of the patients was irritability and aggression as against apathy in 100% in western studies. Memory impairment was found in only 11.1% as against 25% in western studies. Disinhibition, eating problems, stereotyped behavior, delusions, and paranoia were comparable between the study population and literature. Discussion and Conclusion: There are minor variations in the neuropsychological manifestations in our patients compared to western population. Agitation and aggression are more and memory impairment is very less making the diagnosis of FTD possible only if there is a high degree of suspicion. These symptoms are less amenable for pharmacotherapy and therefore, there is a need to explore the benefits of nonpharmacological treatment options such as yoga and meditation. PMID:27570344

  19. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration

    PubMed Central

    Xu, Zihui; Poidevin, Mickael; Li, Xuekun; Li, Yujing; Shu, Liqi; Nelson, David L.; Li, He; Hales, Chadwick M.; Gearing, Marla; Wingo, Thomas S.; Jin, Peng

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. PMID:23553836

  20. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration.

    PubMed

    Xu, Zihui; Poidevin, Mickael; Li, Xuekun; Li, Yujing; Shu, Liqi; Nelson, David L; Li, He; Hales, Chadwick M; Gearing, Marla; Wingo, Thomas S; Jin, Peng

    2013-05-07

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.

  1. Behavioural interventions for enhancing life participation in behavioural variant frontotemporal dementia and primary progressive aphasia.

    PubMed

    Kortte, Kathleen B; Rogalski, Emily J

    2013-04-01

    Primary progressive aphasia (PPA) and behavioural-variant frontotemporal dementia (bvFTD) are clinical syndromes under the umbrella term 'frontotemporal dementia' (FTD) and are caused by a neurodegenerative disease with an onset most typically in the productive years of adulthood. The cognitive and behavioural impairments associated with FTD interfere with successful engagement in typical life roles, such as parenting, working, and maintenance of interpersonal relationships. There are currently no treatments to stop or slow the degenerative process and there are only very limited medication options for the management of the cognitive-behavioural symptoms. However, alternative, non-pharmacological interventions may offer significant benefit to the quality of life of the diagnosed individual. The goal of this paper is to provide an overview of the approaches available through neurorehabilitation and community-based services that facilitate successful engagement in life activities and promote optimal quality of life for the individuals and families living with FTD. It is hoped that as medical providers become more familiar with behavioural interventions, referrals for services will increase thereby allowing individuals with FTD and their caregivers to learn ways to adapt, adjust, and participate in life to the fullest despite the impairments from this progressive disease.

  2. 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

  3. Clinical Studies in Familial VCP Myopathy Associated With Paget Disease of Bone and Frontotemporal Dementia

    PubMed Central

    Kimonis, Virginia. E.; Mehta, Sarju G.; Fulchiero, Erin C.; Thomasova, Dana; Pasquali, Marzia; Boycott, Kym; Neilan, Edward G.; Kartashov, Alex; Forman, Mark S.; Tucker, Stuart; Kimonis, Katerina; Mumm, Steven; Whyte, Michael P.; Smith, Charles D.; Watts, Giles D. J.

    2008-01-01

    Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9–60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy. PMID:18260132

  4. The role of CHMP2B(Intron5) in autophagy and frontotemporal dementia.

    PubMed

    Krasniak, Christopher S; Ahmad, S Tariq

    2016-10-15

    Charged multivesicular body protein 2B (CHMP2B) - a component of the endosomal complex required for transport-III (ESCRT-III) - is responsible for the vital membrane deformation functions in autophagy and endolysosomal trafficking. A dominant mutation in CHMP2B (CHMP2B(Intron5)) is associated with a subset of heritable frontotemporal dementia - frontotemporal dementia linked to chromosome 3 (FTD-3). ESCRT-III recruits Vps4, an AAA-ATPase that abscises the membrane during various cellular processes including autophagy and intraluminal vesicle formation. CHMP2B(Intron5) results in a C-terminus truncation removing an important Vps4 binding site as well as eliminating the normal autoinhibitory resting state of CHMP2B. CHMP2B is expressed in most cell types but seems to be especially vital for proper neuronal function. CHMP2B(Intron5)-mediated phenotypes include misregulation of transmembrane receptors, accumulation of multilamellar structures, abnormal lysosomal morphology, down regulation of a brain-specific micro RNA (miRNA-124), abnormal dendritic spine morphology, decrease in dendritic arborization, and cell death. Currently, transgenic-fly,-mouse, and -human cell lines are being used to better understand the diverse phenotypes and develop therapeutic approaches for the CHMP2B(Intron5)-induced FTD-3. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Progranulin Mutations Affects Brain Oscillatory Activity in Fronto-Temporal Dementia

    PubMed Central

    Moretti, Davide V.; Benussi, Luisa; Fostinelli, Silvia; Ciani, Miriam; Binetti, Giuliano; Ghidoni, Roberta

    2016-01-01

    Background: Mild cognitive impairment (MCI) is a clinical stage indicating a prodromal phase of dementia. This practical concept could be used also for fronto-temporal dementia (FTD). Progranulin (PGRN) has been recently recognized as a useful diagnostic biomarker for fronto-temporal lobe degeneration (FTLD) due to GRN null mutations. Electroencephalography (EEG) is a reliable tool in detecting brain networks changes. The working hypothesis of the present study is that EEG oscillations could detect different modifications among FTLD stages (FTD-MCI versus overt FTD) as well as differences between GRN mutation carriers versus non-carriers in patients with overt FTD. Materials and Methods: EEG in all patients and PGRN dosage in patients with a clear FTD were detected. The cognitive state has been investigated through mini mental state examination (MMSE). Results: MCI-FTD showed a significant lower spectral power in both alpha and theta oscillations as compared to overt FTD. GRN mutations carriers affected by FTLD show an increase in high alpha and decrease in theta oscillations as compared to non-carriers. Conclusion: EEG frequency rhythms are sensible to different stage of FTD and could detect changes in brain oscillatory activity affected by GRN mutations. PMID:26973510

  6. Non-pharmacological management for patients with frontotemporal dementia: a systematic review.

    PubMed

    Shinagawa, Shunichiro; Nakajima, Shinichiro; Plitman, Eric; Graff-Guerrero, Ariel; Mimura, Masaru; Nakayama, Kazuhiko; Miller, Bruce L

    2015-01-01

    Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by changes in behavior and language caused by focal degeneration of the frontal and anterior temporal lobes. The behavioral symptoms are distressing to patients and their caregivers. Non-pharmacological management is important as no disease-specific pharmacological treatment for FTD is currently available. The primary objective is to review the literature on non-pharmacological management for FTD and to propose directions for future research, with reference to findings. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included "frontotemporal dementia", and words related to non-pharmacological management, and it identified a total of 858 articles. Results revealed that very few randomized controlled trials exist on non-pharmacological management interventions for FTD. These interventions have been proposed by literature based on clinical experience. A small number of studies have supported behavioral management techniques that exploit disease-specific behaviors and preserved functions in patients with FTD, along with the management of caregivers' distress. These limitations warrant well-designed large-scale research to examine effects of non-pharmacological interventions on behavioral symptoms of FTD.

  7. 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.

  8. Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes.

    PubMed

    Thelen, Mathias; Razquin, Cristina; Hernández, Isabel; Gorostidi, Ana; Sánchez-Valle, Raquel; Ortega-Cubero, Sara; Wolfsgruber, Steffen; Drichel, Dmitriy; Fliessbach, Klaus; Duenkel, Tanja; Damian, Marinella; Heilmann, Stefanie; Slotosch, Anja; Lennarz, Martina; Seijo-Martínez, Manuel; Rene, Ramón; Kornhuber, Johannes; Peters, Oliver; Luckhaus, Christian; Jahn, Holger; Hüll, Michael; Rüther, Eckart; Wiltfang, Jens; Lorenzo, Elena; Gascon, Jordi; Lleó, Alberto; Lladó, Albert; Campdelacreu, Jaume; Moreno, Fermin; Ahmadzadehfar, Hojjat; Fortea, Juan; Indakoetxea, Begoña; Heneka, Michael T; Wetter, Axel; Pastor, Maria A; Riverol, Mario; Becker, Tim; Frölich, Lutz; Tárraga, Lluís; Boada, Mercè; Wagner, Michael; Jessen, Frank; Maier, Wolfgang; Clarimón, Jordi; López de Munain, Adolfo; Ruiz, Agustín; Pastor, Pau; Ramirez, Alfredo

    2014-11-01

    Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.

  9. In search of autobiographical memories: A PET study in the frontal variant of frontotemporal dementia.

    PubMed

    Piolino, Pascale; Chételat, Gaël; Matuszewski, Vanessa; Landeau, Brigitte; Mézenge, Florence; Viader, Fausto; de la Sayette, Vincent; Eustache, Francis; Desgranges, Béatrice

    2007-09-20

    Patients suffering from frontal variant of frontotemporal dementia (fv-FTD) undergo autobiographical amnesia encompassing all time periods. We previously demonstrated in a group of 20 fv-FTD patients that this impairment involved deficits in executive function and semantic memory for all periods as well as new episodic learning and behavioural changes for the most recent period covering the last 12 months [Matuszewski, V., Piolino, P., de la Sayette, V., Lalevée, C., Pélerin, A., Dupuy, B., et al. (2006). Retrieval mechanisms for autobiographical memories: Insights from the frontal variant of frontotemporal dementia, Neuropsychologia, 44, 2386-2397]. The aim of the present study was to unravel the neural bases of this impairment by mapping in a subgroup of patients correlations between resting-state brain glucose utilization measured by FDG-PET and measures of autobiographical memory (AM) using the TEMPau task which is designed to gauge personal event recollection across five life time periods. Like in our previous report, the group of patients was impaired regardless of time periods compared to healthy subjects providing generic memories instead of event specific sensory-perceptual-affective details, i.e., episodic memories. New data showed that the patients were also impaired in sense of reliving and self-perspective during retrieval. The cognitivo-metabolic correlations between the AM score and resting normalized FDG-Uptake were computed using statistical parametric mapping (SPM2) and controlling for age and dementia severity. They revealed that AM deficits were mainly subserved by the dysfunction of left-sided orbitofrontal and also temporal neocortical areas whatever the period. Additional analysis showed that specific memories were associated with left orbitofrontal areas whereas generic memories were mainly associated with the left temporal pole. This study supports the view that fv-FTD patients undergo a breakdown of generative processes which relies

  10. Malnutrition in Alzheimer’s Disease, Dementia with Lewy Bodies, and Frontotemporal Lobar Degeneration: Comparison Using Serum Albumin, Total Protein, and Hemoglobin Level

    PubMed Central

    Hashimoto, Mamoru; Tanaka, Hibiki; Fujise, Noboru; Matsushita, Masateru; Miyagawa, Yusuke; Hatada, Yutaka; Fukuhara, Ryuji; Hasegawa, Noriko; Todani, Shuji; Matsukuma, Kengo; Kawano, Michiyo; Ikeda, Manabu

    2016-01-01

    Malnutrition among dementia patients is an important issue. However, the biochemical markers of malnutrition have not been well studied in this population. The purpose of this study was to compare biochemical blood markers among patients with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). A total of 339 dementia outpatients and their family caregivers participated in this study. Low serum albumin was 7.2 times more prevalent among patients with DLB and 10.1 times more prevalent among those with FTLD than among those with AD, with adjustment for age. Low hemoglobin was 9.1 times more common in female DLB patients than in female AD patients, with adjustment for age. The levels of biochemical markers were not significantly correlated with cognitive function. Family caregivers of patients with low total protein, low albumin, or low hemoglobin were asked if the patients had loss of weight or appetite; 96.4% reported no loss of weight or appetite. In conclusion, nutritional status was worse in patients with DLB and FTLD than in those with AD. A multidimensional approach, including blood testing, is needed to assess malnutrition in patients with dementia. PMID:27336725

  11. Malnutrition in Alzheimer's Disease, Dementia with Lewy Bodies, and Frontotemporal Lobar Degeneration: Comparison Using Serum Albumin, Total Protein, and Hemoglobin Level.

    PubMed

    Koyama, Asuka; Hashimoto, Mamoru; Tanaka, Hibiki; Fujise, Noboru; Matsushita, Masateru; Miyagawa, Yusuke; Hatada, Yutaka; Fukuhara, Ryuji; Hasegawa, Noriko; Todani, Shuji; Matsukuma, Kengo; Kawano, Michiyo; Ikeda, Manabu

    2016-01-01

    Malnutrition among dementia patients is an important issue. However, the biochemical markers of malnutrition have not been well studied in this population. The purpose of this study was to compare biochemical blood markers among patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). A total of 339 dementia outpatients and their family caregivers participated in this study. Low serum albumin was 7.2 times more prevalent among patients with DLB and 10.1 times more prevalent among those with FTLD than among those with AD, with adjustment for age. Low hemoglobin was 9.1 times more common in female DLB patients than in female AD patients, with adjustment for age. The levels of biochemical markers were not significantly correlated with cognitive function. Family caregivers of patients with low total protein, low albumin, or low hemoglobin were asked if the patients had loss of weight or appetite; 96.4% reported no loss of weight or appetite. In conclusion, nutritional status was worse in patients with DLB and FTLD than in those with AD. A multidimensional approach, including blood testing, is needed to assess malnutrition in patients with dementia.

  12. 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.

  13. [Clinical and biomolecular classification of the frontotemporal dementias. A review of the literature].

    PubMed

    Toribio-Díaz, M E; Morera-Guitart, J

    The term 'frontotemporal lobar dementia' (FTLD) covers a group of neurodegenerative diseases that are very heterogeneous in their clinical expression, genetic component and histopathological features, and this has traditionally made it difficult to study and classify them. Patients usually present a progressive change in their behaviour associated with language disorders and loss of memory, which constitutes the second most important cause of dementia in persons under the age of 65. The most significant characteristic at the histopathological level is the presence of abnormal aggregates or accumulations of proteins in neurons or glial cells; their identification has, on the one hand, helped further our knowledge of the pathogenic mechanisms and, on the other hand, has allowed this type of dementia to be classified. In the last two decades a remarkable amount of progress has been made in our knowledge of this group of diseases, thanks to the genetic advances related to the discovery of the MAPT gene and the progranulin gene, as well as their mutations, which are responsible for a high percentage of cases of hereditary FTLD. Likewise, the development of new immunohistochemical techniques has made it possible to characterise some abnormal proteins, such as the protein TDP-43, as the main component of the neuronal inclusions in tau-negative FTLD. All this has led to a new classification of the FTLD. This work includes a thorough review of said advances and the possible clinical, histological, genetic and biomolecular correlations of the different subtypes of FTLD are also considered.

  14. Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD) in the FTD spectrum

    PubMed Central

    Steketee, Rebecca M.E.; Meijboom, Rozanna; Bron, Esther E.; Osse, Robert Jan; de Koning, Inge; Jiskoot, Lize C.; Klein, Stefan; de Jong, Frank Jan; van der Lugt, Aad; van Swieten, John C.; Smits, Marion

    2016-01-01

    Purpose ‘Phenocopy’ frontotemporal dementia (phFTD) patients may clinically mimic the behavioral variant of FTD (bvFTD), but do not show functional decline or abnormalities upon visual inspection of routine neuroimaging. We aimed to identify abnormalities in gray matter (GM) volume and perfusion in phFTD and to assess whether phFTD belongs to the FTD spectrum. We compared phFTD patients with both healthy controls and bvFTD patients. Materials & methods Seven phFTD and 11 bvFTD patients, and 20 age-matched controls underwent structural T1-weighted magnetic resonance imaging (MRI) and 3D pseudo-continuous arterial spin labeling (pCASL) at 3T. Normalized GM (nGM) volumes and perfusion, corrected for partial volume effects, were quantified regionally as well as in the entire supratentorial cortex, and compared between groups taking into account potential confounding effects of gender and scanner. Results PhFTD patients showed cortical atrophy, most prominently in the right temporal lobe. Apart from this regional atrophy, GM volume was generally not different from either controls or from bvFTD. BvFTD however showed extensive frontotemporal atrophy. Perfusion was increased in the left prefrontal cortex compared to bvFTD and to a lesser extent to controls. Conclusion PhFTD and bvFTD show overlapping cortical structural abnormalities indicating a continuum of changes especially in the frontotemporal regions. Together with functional changes suggestive of a compensatory response to incipient pathology in the left prefrontal regions, these findings are the first to support a possible neuropathological etiology of phFTD and suggest that phFTD may be a neurodegenerative disease on the FTD spectrum. PMID:27222795

  15. Differential neuropsychological patterns of frontal variant frontotemporal dementia and Alzheimer's disease in a study of diagnostic concordance.

    PubMed

    Giovagnoli, Anna R; Erbetta, Alessandra; Reati, Fabiola; Bugiani, Orso

    2008-04-01

    Although the pathological hallmarks of Alzheimer's disease (AD) and frontal variant frontotemporal dementia (fvFTD) predict different cognitive patterns, many comparative neuropsychological studies showed no difference in the expected cognitive domains. Inconsistencies in diagnostic criteria, small cohorts of patients, and neuropsychological assessment may account for such findings. Moreover, discrepancies in memory and executive dysfunctions that are expected to distinguish AD and fvFTD may reflect the basic brain organization. Adhering to a strict concordance of clinical and neuroradiological criteria, we compared many patients with AD and fvFTD using a large neuropsychological battery. One hundred and thirty-nine patients with AD (n=89) or fvFTD (n=50) were retrospectively considered in order to verify the diagnostic congruence of clinical and neuroradiological aspects. On this basis, 117 patients with AD (n=77) or fvFTD (n=40) with similar duration and severity of dementia were selected. Ninety-one healthy subjects were also controlled. Mean scores in tests for abstract reasoning, planning, set shifting, initiative, verbal fluency, immediate and episodic memory, constructive, ideomotor and orofacial praxis, selective and divided attention, visuomotor coordination, and visual perception were evaluated. Separate analyses of variance and post hoc Bonferroni tests showed that, with respect to controls, both patient groups were significantly impaired in all neuropsychological tests. Compared to fvFTD patients, AD patients were significantly impaired in episodic memory, selective attention, visual perception, visuomotor coordination, and constructive praxis, whereas no differences were found in executive, intellective, and linguistic abilities between the two patient groups. Logistic regression analyses revealed that episodic memory significantly predicted the diagnosis of AD while no executive deficit was able to predict the diagnosis of fvFTD. To conclude, memory

  16. Clinicopathological Study of Patients With C9ORF72-Associated Frontotemporal Dementia Presenting With Delusions.

    PubMed

    Shinagawa, Shunichiro; Naasan, Georges; Karydas, Anna M; Coppola, Giovanni; Pribadi, Mochtar; Seeley, William W; Trojanowski, John Q; Miller, Bruce L; Grinberg, Lea T

    2015-06-01

    Several clinical studies point to a high prevalence of psychotic symptoms in frontotemporal dementia associated with C9ORF72 mutations, but clinicopathological studies addressing the association between C9ORF72 mutations and delusions are lacking. Seventeen patients with pathologically proven frontotemporal lobar degeneration (FTLD) associated with C9ORF72 mutations were identified from Neurodegenerative Disease Brain Bank. Of the 17 cases with C9ORF72 mutation, 4 exhibited well-defined delusions. The clinical history, neurological examination, neuropsychological testing, neuroimaging analysis, and postmortem assessment of the patients with delusions were evaluated and compared with the other cases. The content of the delusions was mixed including persecution, infidelity, and grandiosity. All cases showed parkinsonism; voxel-based morphometry analysis showed greater precuneus atrophy in patients with delusions than those without delusions. All 4 had unclassifiable FTLD with TAR DNA-binding protein inclusions, with characteristics of both type A and type B. Three cases had additional τ pathology and another had α-synuclein pathology. C9ORF72 carriers with well-defined delusions likely associated with additional pathologies and parietal atrophy in neuroimaging. Patients presenting with middle-aged onset of delusions should be screened for C9ORF72 mutations, especially if family history and parkinsonism are present. © The Author(s) 2014.

  17. Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy.

    PubMed

    Guinto, Jake B; Ritson, Gillian P; Taylor, J Paul; Forman, Mark S

    2007-07-01

    Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions without VCP mutations. Yet, the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding protein, a feature that links this rare disease with the pathology associated with the majority of sporadic FTD as well as disease resulting from different genetic alterations. VCP, a member of the AAA-ATPase gene family, associates with a plethora of protein adaptors to perform a variety of cellular processes including Golgi assembly/disassembly and regulation of the ubiquitin-proteasome system. However, the mechanism whereby mutations in VCP lead to CNS, muscle, and bone disease is largely unknown. In this report, we review current literature on IBMPFD, focusing on the pathology of the disease and the biology of VCP with respect to IBMPFD.

  18. Presymptomatic generalized brain atrophy in frontotemporal dementia caused by CHMP2B mutation.

    PubMed

    Rohrer, Jonathan D; Ahsan, R Laila; Isaacs, Adrian M; Nielsen, Jorgen E; Ostergaard, Leif; Scahill, Rachael; Warren, Jason D; Rossor, Martin N; Fox, Nick C; Johannsen, Peter

    2009-01-01

    CHMP2B mutations are a rare cause of familial frontotemporal dementia (FTD). The clinical syndrome is dominated by personality change and behavioural symptoms, but language, memory, calculation and praxis impairments are also seen early in the course of the disease. There are no detailed studies of brain imaging in CHMP2B mutation-associated FTD. This study aimed to investigate whether there were early or presymptomatic changes in this group of patients. Subjects comprised 16 members of a Danish family with CHMP2B mutation-associated FTD. Nine subjects were presymptomatic mutation carriers with a control group of 7 mutation-negative family members. Volumetric MRI brain scans were performed on all subjects at two time points, and rates of volume change were compared between the two groups. We demonstrate that generalized atrophy occurs presymptomatically in CHMP2B gene mutation carriers. This finding suggests that mutations in CHMP2B have widespread effects throughout the brain, leading to a neuro-anatomical signature distinct from other diseases in the frontotemporal lobar degeneration spectrum. Copyright 2009 S. Karger AG, Basel.

  19. DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia

    PubMed Central

    Boutoleau-Bretonnière, Claire; Evrard, Christelle; Hardouin, Jean Benoît; Rocher, Laëtitia; Charriau, Tiphaine; Etcharry-Bouyx, Frédérique; Auriacombe, Sophie; Richard-Mornas, Aurélie; Lebert, Florence; Pasquier, Florence; Sauvaget, Anne; Bulteau, Samuel; Vercelletto, Martine; Derkinderen, Pascal; Bretonnière, Cédric; Thomas-Antérion, Catherine

    2015-01-01

    Background The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. Objective We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. Methods Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. Results DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. Conclusion We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD. PMID:26955383

  20. Effect of diagnostic criteria on prevalence of frontotemporal dementia in the elderly.

    PubMed

    Gislason, Thorsteinn B; Östling, Svante; Börjesson-Hanson, Anne; Sjögren, Magnus; Simoni, Michela; Pantoni, Leonardo; Skoog, Ingmar

    2015-04-01

    Frontotemporal dementia (FTD) is believed to be rare in the elderly, and the influence of different criteria on the prevalence of FTD is unclear. Population-based samples of 70- to 95-year-olds (n = 2462) in Gothenburg, Sweden, underwent neuropsychiatric examinations. Behavioral variant FTD (bvFTD) was diagnosed according to the International Behavioural Variant FTD Criteria Consortium (FTDC), the Frontotemporal Lobe Degeneration Consensus criteria, and the Lund-Manchester Research Criteria. A subset (n = 1074) underwent computerized tomography (CT) of the brain. The prevalence of bvFTD varied between 0.2% and 0.5% at age 70 to 79 years, between 2.5% and 3.6% at age 80 to 89 years, and between 1.7% and 2.2% at age 90 to 95 years. The agreement between different criteria was low to moderate (κ = 0.20-0.42). Among those with bvFTD according to FTDC, 93.3% had frontal and/or temporal lobar atrophy on CT, compared with 12.6% of those without bvFTD (P < .001). The prevalence of bvFTD was higher than expected in this population. To a large extent, different criteria captured different individuals. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  1. Augmented input reveals word deafness in a man with frontotemporal dementia

    PubMed Central

    Gibbons, Chris; Oken, Barry; Fried-Oken, Melanie

    2012-01-01

    We describe a 57 year old, right handed, English speaking man initially diagnosed with progressive aphasia. Language assessment revealed inconsistent performance in key areas. Expressive language was reduced to a few short, perseverative phrases. Speech was severely apraxic. Primary modes of communication included gesture, pointing, gaze, physical touch and leading. Responses were 100% accurate when he was provided with written words, with random or inaccurate responses for strictly auditory/verbal input. When instructions to subsequent neuropsychological tests were written instead of spoken, performance improved markedly. A comprehensive audiology assessment revealed no hearing impairment. Neuroimaging was unremarkable. Neurobehavioral evaluation utilizing written input led to diagnoses of word deafness and frontotemporal dementia, resulting in very different management. We highlight the need for alternative modes of language input for assessment and treatment of patients with language comprehension symptoms. PMID:22425725

  2. Augmented input reveals word deafness in a man with frontotemporal dementia.

    PubMed

    Gibbons, Chris; Oken, Barry; Fried-Oken, Melanie

    2012-01-01

    We describe a 57 year old, right handed, English speaking man initially diagnosed with progressive aphasia. Language assessment revealed inconsistent performance in key areas. Expressive language was reduced to a few short, perseverative phrases. Speech was severely apraxic. Primary modes of communication included gesture, pointing, gaze, physical touch and leading. Responses were 100% accurate when he was provided with written words, with random or inaccurate responses for strictly auditory/verbal input. When instructions to subsequent neuropsychological tests were written instead of spoken, performance improved markedly. A comprehensive audiology assessment revealed no hearing impairment. Neuroimaging was unremarkable. Neurobehavioral evaluation utilizing written input led to diagnoses of word deafness and frontotemporal dementia, resulting in very different management. We highlight the need for alternative modes of language input for assessment and treatment of patients with language comprehension symptoms.

  3. Skin conductance levels may reflect emotional blunting in behavioral variant frontotemporal dementia.

    PubMed

    Joshi, Aditi; Mendez, Mario F; Kaiser, Natalie; Jimenez, Elvira; Mather, Michelle; Shapira, Jill S

    2014-01-01

    Emotional blunting is a core diagnostic feature of behavioral variant frontotemporal dementia (bvFTD). The authors evaluated skin conductance as a measure of emotional blunting among 10 patients with bvFTD compared with 10 with Alzheimer's disease and 14 healthy control subjects. Despite responses to an auditory startle stimulus, skin conductance levels (SCLs) were lower in the patients with bvFTD compared with the other groups. The low SCLs significantly correlated with ratings of emotional blunting. The authors conclude that low SCLs in bvFTD indicate a low resting sympathetic state and low emotional arousal. The measurement of SCLs may be a useful noninvasive diagnostic test for bvFTD.

  4. Frontotemporal lobar dementia and amyotrophic lateral sclerosis associated with c9orf72 expansion.

    PubMed

    Le Ber, I

    2015-01-01

    An intronic GGGGCC repeat expansion in c9orf72 gene has been identified as the most common genetic cause of frontotemporal lobar dementia (FTLD), amyotrophic lateral sclerosis (ALS) and FTLD-ALS. The discovery of c9orf72 gene has led to important scientific progresses and has considerably changed our clinical practice over the last few years. This paper summarizes the common and less typical phenotypes associated with c9orf72 expansion, the complex pathological pattern characterized by p62/dipeptide repeat aggregates, as well as the pathological mechanisms by which the expansion might produce neurodegeneration implicating loss-of-function, RNA toxicity, RNA-binding protein sequestration and accumulation of dipeptide repeats. We also discuss the recommendations and limits for genetic testing and counseling in clinical practice. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Environmental control interventions for frontotemporal dementia with reversed sleep-wake cycles.

    PubMed

    Yamakawa, Miyae; Shigenobu, Kazue; Makimoto, Kiyoko; Zhu, Canqun; Ashida, Nobuyuki; Tabushi, Kaoru

    2008-01-01

    This study aimed to evaluate the effectiveness of environmental control interventions using an integrated chip tag monitoring system for a frontotemporal dementia (FTD) patient. The subject was a male FTD patient (Pick type) with reversed sleep-wake cycles. For a 2-week period, the doors to all patients' rooms in the unit were kept open as a form of environmental control, and in the following 2 weeks, all doors were kept closed (intervention A). To increase his activity levels, a staff walked with him for 2 weeks (intervention B), while all the doors to patients' rooms in the unit were kept closed. In intervention A, daytime ambulation increased, whereas nighttime ambulation decreased significantly. During intervention B, nighttime ambulation increased significantly. Environmental controls seem to be effective for restoring sleep-wake cycles in even an advanced-stage FTD patient, whereas exercise program by the staff aggravated the problem.

  6. Cognitive and Behavioral Challenges in Caring for Patients with Frontotemporal dementia and Amyotrophic Lateral Sclerosis

    PubMed Central

    Merrilees, Jennifer; Klapper, Jennifer; Murphy, Jennifer; Lomen-Hoerth, Catherine; Miller, Bruce L.

    2010-01-01

    Frontotemporal dementia (FTD) is a progressive neurological condition caused by degeneration of the frontal and/or anterior temporal lobes resulting in personality, behavioral, and cognitive changes. Amyotrophic lateral sclerosis (ALS) is caused by degeneration of lower motor and pyramidal neurons, leading to loss of voluntary muscle movement. The common molecular pathological and anatomical overlap between FTD and ALS, suggest that the two disorders are strongly linked. In some patients FTD precedes ALS, in others ALS occurs first, while in still others the two disorders begin simultaneously. The association between ALS and FTD create unique challenges for family caregivers. This paper provides a guide for healthcare providers caring for patients with FTD-ALS exhibiting behavioral, cognitive, and emotional symptoms. Strategies are suggested to help minimize the impact of negative symptoms. PMID:20222805

  7. Differential pharmacological responses of catatonia-like signs in frontotemporal dementia.

    PubMed

    Lauterbach, Edward C; Kuppuswamy, Preetha Sharone; Greenway, Lauren L

    2010-10-01

    Sequential therapeutic trials for catatonoid frontal signs in clinically-evident frontotemporal dementia (n = 2) revealed differential benefits for lorazepam, amantadine, memantine, pramipexole, aripiprazole, quetiapine, citalopram, and donepezil, although certain signs also worsened. Citalopram and donepezil were poorly tolerated. Ramelteon was without effect. While memantine appeared to improve cognition in case 1, this remains to be established by more reliable neuropsychological testing. Parkinsonism (case 2) responded to pramipexole, but not amantadine or levodopa. Possible relationships of catatonoid signs requiring future confirmation include insufficient GABA-A (multiple signs) and D2 (mutism) and excessive NMDA (immobility, rigidity), D2/D3 (mannerisms, verbal perseveration), and 5HT1a (staring) receptor stimulation. Low-dose lorazepam and quetiapine required close monitoring.

  8. Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia.

    PubMed

    Jovičić, Ana; Paul, Joseph W; Gitler, Aaron D

    2016-08-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of nucleocytoplasmic transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.

  9. The Ekman 60 Faces Test as a diagnostic instrument in frontotemporal dementia.

    PubMed

    Diehl-Schmid, Janine; Pohl, Corina; Ruprecht, Carolin; Wagenpfeil, Stefan; Foerstl, Hans; Kurz, Alexander

    2007-05-01

    Frontotemporal dementia (FTD) is characterized by dramatic changes of personality and behaviour. Impaired ability of emotional processing could contribute to these symptoms, as it may lead to misinterpretation of emotional cues that would normally guide behaviour. The aim of the present study was to investigate if the Ekman 60 Faces Test, an instrument to test the recognition of basic facial emotions, enables the differentiation between patients with mild FTD and cognitively healthy subjects (HC). We found that compared to 33 cognitively healthy subjects, 25 patients with mild FTD were impaired in the recognition of basic emotions. At a cut-off score from 46 out of 60 points, the Ekman 60 Faces Test discriminated between patients with mild FTD and HC with 97% diagnostic accuracy (sensitivity: 94%; specificity: 100%). The results of the present study were consistent with the findings of prior studies on smaller patient samples.

  10. 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

  11. Contrasting Prefrontal Cortex Contributions to Episodic Memory Dysfunction in Behavioural Variant Frontotemporal Dementia and Alzheimer’s Disease

    PubMed Central

    Wong, Stephanie; Flanagan, Emma; Savage, Greg; Hodges, John R.; Hornberger, Michael

    2014-01-01

    Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer’s disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures. PMID:24505314

  12. 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.

  13. DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia.

    PubMed

    Su, J H; Nichol, K E; Sitch, T; Sheu, P; Chubb, C; Miller, B L; Tomaselli, K J; Kim, R C; Cotman, C W

    2000-05-01

    Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly the frontal and anterior temporal cortex. It is associated with neuronal loss, gliosis, and microvacuolation of lamina I to III in these brain regions. In previous studies we have described neurons with DNA damage in the absence of tangle formation and suggested this may result in tangle-independent mechanisms of neurodegeneration in the AD brain. In the present study, we sought to examine DNA fragmentation and activated caspase-3 expression in FTD brain where tangle formation is largely absent. The results demonstrate that numerous nuclei were TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was detected in both neurons and astrocytes and was elevated in FTD cases as compared to control cases. A subset of activated caspase-3-positive cells were also TdT positive. In addition, the cell bodies of a subset of astrocytes showed enlarged, irregular shapes, and vacuolation and their processes appeared fragmented. These degenerating astrocytes were positive for activated caspase-3 and colocalized with robust TdT-labeled nuclei. These findings suggest that a subset of astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may contribute to neuronal cell death and astrocyte degeneration in the FTD brain. Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD (228).

  14. 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.

  15. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer’s and Parkinson’s diseases

    PubMed Central

    Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana; Guelfi, Sebastian; Witeolar, Aree; Karch, Celeste M; Schork, Andrew J; Fan, Chun C; Brewer, James B; Schellenberg, Gerard S; Dillon, William P; Sugrue, Leo P; Hess, Christopher P; Yokoyama, Jennifer S; Bonham, Luke W; Rabinovici, Gil D; Miller, Bruce L; Andreassen, Ole A; Dale, Anders M; Hardy, John; Desikan, Rahul S

    2016-01-01

    Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer’s disease (AD) and Parkinson’s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10−12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10−7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk. PMID:27899424

  16. Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer disease.

    PubMed

    Lee, Suzee E; Tartaglia, Maria C; Yener, Görsev; Genç, Sermin; Seeley, William W; Sanchez-Juan, Pascual; Moreno, Fermin; Mendez, Mario F; Klein, Eric; Rademakers, Rosa; López de Munain, Adolfo; Combarros, Onofre; Kramer, Joel H; Kenet, Robert O; Boxer, Adam L; Geschwind, Michael D; Gorno-Tempini, Maria-Luisa; Karydas, Anna M; Rabinovici, Gil D; Coppola, Giovanni; Geschwind, Daniel H; Miller, Bruce L

    2013-01-01

    Recently, Coppola and colleagues demonstrated that a rare microtubule-associated protein tau (MAPT) sequence variant, c.454G>A (p.A152T) significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer disease (AD) in a screen of 15,369 subjects. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (n=2); 2 patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathologic correlation to elucidate the influence of this genetic variant on neurodegenerative disease.

  17. 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.

  18. Cognitive function and psychiatric symptoms in early- and late-onset frontotemporal dementia.

    PubMed

    Shinagawa, Shunichiro; Toyota, Yasutaka; Ishikawa, Tomohisa; Fukuhara, Ryuji; Hokoishi, Kazuhiko; Komori, Kenjiro; Tanimukai, Satoshi; Ikeda, Manabu

    2008-01-01

    Some recent studies mentioned that late-onset frontotemporal dementia (FTD) is more common than previously assumed. Although much research has been done in the field, there are no systematic studies which have compared clinical characteristics of early- and late-onset FTD. The aim of this study was to compare cognitive function and psychiatric symptoms in patients with early- and late-onset FTD. Study participants were consecutive outpatients. There were 35 FTD patients; their mean age at onset was 63.0 years. We studied sex, education, duration from onset to consultation, Clinical Dementia Rating (CDR) scores, Mini-Mental State Examination (MMSE) scores, Raven's Coloured Progressive Matrices (RCPM) scores, and Neuropsychiatric Inventory (NPI) scores at first consultation of early- and late-onset FTD patients. There were no significant differences in sex ratio, education, CDR scores, and duration from onset to consultation. There were significant differences in the total MMSE scores, 'three-word recall task', 'construction task', and RCPM scores; late-onset groups scored significantly lower than early-onset groups. There were significant differences in the apathy domain of NPI and total NPI scores; late-onset groups scored significantly higher than early-onset groups. Late-onset FTD patients may have memory and visuospatial deficits in addition to their behavioural changes, even if they are clinically diagnosed according to consensus diagnostic criteria. They also present more apathy, and they may have a different histolopathological background. (c) 2008 S. Karger AG, Basel

  19. Reorganisation of brain networks in frontotemporal dementia and progressive supranuclear palsy☆

    PubMed Central

    Hughes, Laura E.; Ghosh, Boyd C.P.; Rowe, James B.

    2013-01-01

    The disruption of large-scale brain networks is increasingly recognised as a consequence of neurodegenerative dementias. We assessed adults with behavioural variant frontotemporal dementia and progressive supranuclear palsy using magnetoencephalography during an auditory oddball paradigm. Network connectivity among bilateral temporal, frontal and parietal sources was examined using dynamic causal modelling. We found evidence for a systematic change in effective connectivity in both diseases. Compared with healthy subjects, who had focal modulation of intrahemispheric frontal–temporal connections, the patient groups showed abnormally extensive and inefficient networks. The changes in connectivity were accompanied by impaired responses of the auditory cortex to unexpected deviant tones (MMNm), despite normal responses to standard stimuli. Together, these results suggest that neurodegeneration in two distinct clinical syndromes with overlapping profiles of prefrontal atrophy, causes a similar pattern of reorganisation of large-scale networks. We discuss this network reorganisation in the context of other focal brain disorders and the specific vulnerability of functional brain networks to neurodegenerative disease. PMID:23853762

  20. 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.

  1. Novel missense mutation in charged multivesicular body protein 2B in a patient with frontotemporal dementia.

    PubMed

    Ferrari, Raffaele; Kapogiannis, Dimitrios; Huey, Edward D; Grafman, Jordan; Hardy, John; Momeni, Parastoo

    2010-01-01

    Frontotemporal dementia (FTD) is the second major cause of dementia in persons below the age of 65 years after Alzheimer disease. FTD is clinically, pathologically, and genetically heterogeneous and has been associated with mutations in different genes located on chromosomes 17, 9, and 3. In our study we report a novel heterozygous g.26218G>A variant in exon 6 of charged multivesicular body protein 2B (CHMP2B), predicted to cause the amino acid change p.Ser187Asn, in one patient diagnosed with FTD. We were not able to determine the mode of inheritance of the mutation as we did not have access to the genetically informative family members of the proband; those who were screened did not carry the variant. We did not find this variant in 273 White controls although we did find it in 6 of 94 African-American controls. Most of the mutations in CHMP2B which are considered pathogenic lead to partial deletion of the C-terminus region of CHMP2B protein. Based on previous reports and on our current data, missense mutations in this gene seem unlikely to be pathogenic. The pathogenicity of CHMP2B mutations requires further investigation.

  2. Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

    PubMed

    Kimura, Takemi; Hayashida, Hideki; Murata, Masako; Takamatsu, Junichi

    2011-07-01

    The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies. We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test. Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data. Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies. © 2011 Japan Geriatrics Society.

  3. 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

  4. 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 Central

    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. PMID:22207423

  5. An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer's disease.

    PubMed

    Daianu, Madelaine; Mendez, Mario F; Baboyan, Vatche G; Jin, Yan; Melrose, Rebecca J; Jimenez, Elvira E; Thompson, Paul M

    2016-12-01

    Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer's disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics - fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter - the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally

  6. Differential diagnosis of behavioral variant of fronto-temporal dementia (bvFTD)

    PubMed Central

    Pąchalska, Maria; Bidzan, Leszek; Łukowicz, Małgorzata; Bidzan, Mariola; Markiewicz, Katarzyna; Jastrzębowska, Grażyna; Talar, Jan

    2011-01-01

    Summary Background The aim of the paper is the differential diagnosis of various types of Fronto-Temporal Dementia (FTD), with the focus on its behavioural variant (bvFTD). Material/Method Material and Method. Screening was done in order to assess the depth of dementia with the short version of MMSE, while evaluation of various variants of FTD was performed with the use of such neuropsychological tests as Newcomb and Chicago Fluency Tests, Wechsler Memory Scale - III (WMS-III), Western Aphasia Battery (WAB-R), and the Boston Naming Test (BNT). Behaviour was evaluated with a Polish version of the Frontal Behavioral Inventory (FBInv). The inventory consists of 24 questions which enable an evaluation of social behaviour disorders. The study included 112 patients - 68 men and 46 women treated in the Reintegrative -Training Centre of the Foundation for Persons with Brain Dysfunctions in Kraków and in the Clinic for Developmental Psychiatry, Psychotic Disorders and Old Age Psychiatry, of the Medical University at Gdańsk, who were suffering from various types of dementia. Results It was found that FTD patients scored the highest, while the VAD patients scored somewhat lower in the FBInv. At the same time the scores obtained by PPA patients were higher in comparison to the control groups, but not as high as in the case of patients with FTD. In the process of the neurotherapy of FTD patients we found a reduction of the behavioral disturbances, despite the progression of the illness. Conclusions The results obtained in the present study confirmed the diagnostic value of FBInv in the differential diagnosis of various types of FTD and in the evaluation of neurotherapy efficacy. PMID:21629185

  7. Longitudinal change in everyday function and behavioral symptoms in frontotemporal dementia

    PubMed Central

    O'Connor, Claire M.; Clemson, Lindy; Hornberger, Michael; Leyton, Cristian E.; Hodges, John R.; Piguet, Olivier

    2016-01-01

    Abstract Background: The relationship between behavioral changes and functional decline in frontotemporal dementia (FTD) is not well understood. Methods: Thirty-nine patients (21 behavioral variant FTD [bvFTD], 18 semantic variant primary progressive aphasia [svPPA]) were followed up longitudinally (2–4 years follow-up). Functional (Disability Assessment for Dementia) and behavioral (Cambridge Behavioural Inventory Revised) assessments were included for between-group (pairwise comparisons, mixed model analysis) and within-group analyses (bivariate correlations). Results: Functionally, patients with bvFTD were more impaired than patients with svPPA at baseline and continued to be at follow-up, despite similar disease duration. By contrast, behavioral impairments differed between patient groups at baseline and at follow-up. At baseline, patients with bvFTD exhibited higher levels of apathy and changes in eating than patients with svPPA; disinhibited and stereotypical behaviors were similar. Over the years, patients with bvFTD showed reduction in disinhibition and stereotypical behavior while apathy and eating changes increased. By contrast, all measured behaviors increased in patients with svPPA over time. Finally, only apathy made longitudinal contributions to functional disability in patients with svPPA, whereas apathy and stereotypical behavior were associated with increased disability in patients with bvFTD. Conclusions: Despite shared overlapping baseline behavioral symptoms, patients with bvFTD are more functionally impaired than patients with svPPA. Apathy has a strong role in disability for both bvFTD and svPPA, but stereotypical behaviors only contributed to functional deficits in patients with bvFTD. Our findings suggest that rigid/compulsive behaviors may in fact support activity engagement in patients with svPPA. Taken together, our results indicate that interventions to reduce disability in the FTD spectrum require an alternative rationale in

  8. 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

  9. Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD)

    PubMed Central

    Grossman, Murray; Robinson, John L.; Toledo, Jon B.; Fang, Lubin; Van Deerlin, Vivianna M.; Ludolph, Albert C.; Lee, Virginia M.-Y.; Braak, Heiko; Trojanowski, John Q.

    2014-01-01

    We examined regional distribution patterns of phosphorylated 43-kDa TAr DNA-binding protein (pTDP-43) intraneuronal inclusions in frontotemporal lobar degeneration (FTLD). Immunohistochemistry was performed on 70 μm sections from FTLD-TDP autopsy cases (n = 39) presenting with behavioral variant frontotemporal dementia. Two main types of cortical pTDP-43 pathology emerged, characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD). Cortical involvement in nFTLD was extensive and frequently reached occipital areas, whereas cases with cFTLD often involved bulbar somatomotor neurons and the spinal cord. We observed four patterns indicative of potentially sequential dissemination of pTDP-43: cases with the lowest burden of pathology (pattern I) were characterized by widespread pTDP-43 lesions in the orbital gyri, gyrus rectus, and amygdala. With increasing burden of pathology (pattern II) pTDP-43 lesions emerged in the middle frontal and anterior cingulate gyrus as well as in anteromedial temporal lobe areas, the superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei. More advanced cases showed a third pattern (III) with involvement of the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn, whereas cases with the highest burden of pathology (pattern IV) were characterized by pTDP-43 lesions in the visual cortex. We interpret the four neuropathological patterns in bvFTD to be consistent with the hypothesis that pTDP-43 pathology can spread sequentially and may propagate along axonal pathways. PMID:24407427

  10. 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

  11. Clinic, neuropathology and molecular genetics of frontotemporal dementia: a mini-review.

    PubMed

    Pan, Xiao-Dong; Chen, Xiao-Chun

    2013-04-19

    Frontotemporal lobar degeneration (FTLD) represents a group of clinically, neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype. FTLD is pathologically characterized by the frontal and temporal lobar atrophy. Frontotemporal dementia (FTD) clinically presents with abnormalities of behavior and personality and language impairments variants. The clinical spectrum of FTD encompasses distinct canonical syndromes: behavioural variant of FTD (bvFTD) and primary progressive aphasia. The later includes nonfluent/agrammatic variant PPA (nfvPPA or PNFA), semantic variant PPA (svPPA or SD) and logopenic variant PPA (lvPPA). In addition, there is also overlap of FTD with motor neuron disease (FTD-MND or FTD-ALS), as well as the parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The FTLD spectrum disorders are based upon the predominant neuropathological proteins (containing inclusions of hyperphosphorylated tau or ubiquitin protein, e.g transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and fusedin-sarcoma protein in neurons and glial cells) into three main categories: (1) microtubule-associated protein tau (FTLD-Tau); (2) TAR DNA-binding protein-43 (FTLD-TDP); and (3) fused in sarcoma protein (FTLD-FUS). There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies, which are chromosome 9 open reading frame 72 (C9ORF72) gene, granulin (GRN) gene, microtubule associated protein tau gene (MAPT), the gene encoding valosin-containing protein (VCP) and the charged multivesicular body protein 2B (CHMP2B). In this review, recent advances on the different clinic variants, neuroimaging, genetics, pathological subtypes and clinicopathological associations of FTD will be discussed.

  12. Clinic, neuropathology and molecular genetics of frontotemporal dementia: a mini-review

    PubMed Central

    2013-01-01

    Frontotemporal lobar degeneration (FTLD) represents a group of clinically, neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype. FTLD is pathologically characterized by the frontal and temporal lobar atrophy. Frontotemporal dementia (FTD) clinically presents with abnormalities of behavior and personality and language impairments variants. The clinical spectrum of FTD encompasses distinct canonical syndromes: behavioural variant of FTD (bvFTD) and primary progressive aphasia. The later includes nonfluent/agrammatic variant PPA (nfvPPA or PNFA), semantic variant PPA (svPPA or SD) and logopenic variant PPA (lvPPA). In addition, there is also overlap of FTD with motor neuron disease (FTD-MND or FTD-ALS), as well as the parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The FTLD spectrum disorders are based upon the predominant neuropathological proteins (containing inclusions of hyperphosphorylated tau or ubiquitin protein, e.g transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and fusedin-sarcoma protein in neurons and glial cells) into three main categories: (1) microtubule-associated protein tau (FTLD-Tau); (2) TAR DNA-binding protein-43 (FTLD-TDP); and (3) fused in sarcoma protein (FTLD-FUS). There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies, which are chromosome 9 open reading frame 72 (C9ORF72) gene, granulin (GRN) gene, microtubule associated protein tau gene (MAPT), the gene encoding valosin-containing protein (VCP) and the charged multivesicular body protein 2B (CHMP2B). In this review, recent advances on the different clinic variants, neuroimaging, genetics, pathological subtypes and clinicopathological associations of FTD will be discussed. PMID:23597030

  13. The behavioral variant of frontotemporal dementia: An analysis of the literature and a case report.

    PubMed

    Birkhoff, Jutta Maria; Garberi, Cesare; Re, Laura

    2016-01-01

    The aim of this case report is to underline the importance of possible legal consequences of the behavioral variant of frontotemporal dementia (bvFTD). This disease is associated with antisocial behavior, impulse control disorder and cognitive and personality impairment, which are often the earliest manifestations of the bvFTD. One of the antisocial behaviors possibly associated with this neurodegenerative disease is pathological stealing. This case report is about a 50-year-old Italian man who had a regular life until 2010. In 2010 and 2011, some critical events occurred: he lost his job, his father-in-law, to whom he was particularly close, died, and his wife had a serious illness. He began to show symptoms of depression, a significant weight loss, apathy, poor self-care, and lack of interest in the activities of his family. He became disengaged from his prior activities, emotionally detached from his family and developed compulsive hoarding. Moreover, he had uninhibited behaviors, a memory retrieval deficit, executive dysfunctions and impulsive behaviors. In January 2012, the subject began stealing objects, particularly components of computer, without premeditation or concern for resulting legal actions. He was then diagnosed affected by bvFTD. He was charged with theft and attempted theft and the Court asked for a psychiatric evaluation, in order to analyze the effect of the neurodegenerative disease on his behavior. To answer to the Court, the Authors analyzed his history of life and made a mental examination. The subject was considered mentally insane at the time of his crimes. This is an example of the practical application in judicial cases of the latest knowledge and evidence in the literature about the frontotemporal dementia, a disease associated with antisocial behaviors that could create tensions with the criminal law. The focus of the paper is to explain how the behavioral symptoms of bvFTD can have legal implications and how to deal with legal

  14. 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

  15. NREM sleep transient events in fronto-temporal dementia: beyond sleep stage architecture.

    PubMed

    Maestri, Michelangelo; Carnicelli, Luca; Economou, Nicholas-Tiberio; Bonakis, Anastasios; Paparrigopoulos, Thomas; Papageorgiou, Sokratis T; Giorgi, Filippo Sean; Di Coscio, Elisa; Tognoni, Gloria; Ferri, Raffaele; Bonuccelli, Ubaldo; Bonanni, Enrica

    2015-01-01

    Frontotemporal dementia (FTD) is increasingly becoming recognized as a major cause of early onset (<65 years) neurodegenerative dementia. Although sleep disorders significantly impair patients' and caregivers' quality of life in neurodegenerative diseases, polysomnographic data in FTD patients are scarce in literature. Aim of our study was to investigate sleep microstructure in FTD, by means of Cyclic Alternating Pattern (CAP), in a group of ten behavioral variant FTD patients (6 M, 4 F; mean age 61.2±7.3 years; disease duration: 1.4±0.7 years) and to compare them with cognitively intact healthy elderly. Sleep in FTD patients was altered at different levels, involving not only the conventional sleep stage architecture parameters (total sleep time, single stage percentage, NREM/REM cycle organization), but also microstructure. FTD subjects showed CAP disruption with decreased slow wave activity related phases (A1 index, n/h:14.5±6.8 vs 38.8±6.6; p<.001) and increased arousal-related fast CAP components (A2 index 22.9±8.2 vs 11.6±3.7; p=.006; A3 index 41.9±20.7 vs 13.0±6.5; p=.002). Several correlations between sleep variables and neuropsychological tests were found. Sleep impairment in FTD may be specifically related to the specific frontal lobe involvement in the neurodegenerative process. The pattern of alterations seems somewhat peculiar, probably due to the anatomical distribution of the neurodegenerative process with a major impact on frontal lobe generated sleep transients, and a substantial sparing of phenomena related to the posterior cortex.

  16. Brain perfusion SPECT with Brodmann areas analysis in differentiating frontotemporal dementia subtypes.

    PubMed

    Valotassiou, Varvara; Papatriantafyllou, John; Sifakis, Nikolaos; Tzavara, Chara; Tsougos, Ioannis; Psimadas, Dimitrios; Kapsalaki, Eftychia; Fezoulidis, Ioannis; Hadjigeorgiou, George; Georgoulias, Panagiotis

    2014-01-01

    Despite the known validity of clinical diagnostic criteria, significant overlap of clinical symptoms between Frontotemporal dementia (FTD) subtypes exists in several cases, resulting in great uncertainty of the diagnostic boundaries. We evaluated the perfusion between FTD subtypes using brain perfusion (99m)Tc-HMPAO SPECT with Brodmann areas (BA) mapping. NeuroGam software was applied on single photon emission computed tomographic (SPECT) studies for the semi-quantitative evaluation of perfusion in BA and the comparison with the software's normal database. We studied 91 consecutive FTD patients: 21 with behavioural variants (bvFTD), 39 with language variants (lvFTD) [12 with progressive non-fluent aphasia (PNFA), 27 with semantic dementia (SD)], and 31 patients with progressive supranuclear palsy (PSP)/corticobasal degeneration (CBD). Stepwise logistic regression analyses showed that the BA 28L and 32R could independently differentiate bvFTD from lvFTD, while the BA 8R and 25R could discriminate bvFTD from SD and PNFA, respectively. Additionally, BA 7R and 32R were found to discriminate bvFTD from CBD/PSP. The only BA that could differentiate SD from PNFA was 6L. BA 6R and 20L were found to independently differentiate CBD/PSP from lvFTD. Moreover, BA 20L and 22R could discriminate CBD/PSP from PNFA, while BA 6R, 20L and 45R were found to independently discriminate CBD/PSP from SD. Brain perfusion SPECT with BA mapping can be a useful additional tool in differentiating FTD variants by improving the definition of brain areas that are specifically implicated, resulting in a more accurate differential diagnosis in atypical or uncertain forms of FTD.

  17. 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

  18. Impulse control disorders in frontotemporal dementia: spectrum of symptoms and response to treatment.

    PubMed

    Pompanin, Sara; Jelcic, Nela; Cecchin, Diego; Cagnin, Annachiara

    2014-01-01

    To describe a patient with behavioral variant frontotemporal dementia (bvFTD) presenting with impulse control disorders (ICDs) which responded to fluvoxamine and topiramate. A 64-year-old woman was affected by several ICDs. At disease onset, she suffered from impulsive smoking and overeating which caused a body weight increase of 20 kg in 6 months. Later on she manifested binge-eating behavior and skin-picking compulsion. Presence of progressive frontal cognitive impairment (Mini Mental State Examination 24/30) and evidence of hypoperfusion of the anterior cingulate and dorsolateral frontal cortex with brain single-photon emission computed tomography scan contributed to the diagnosis of bvFTD. Use of combination treatment with selective serotonin reuptake inhibitor drugs and topiramate improved all these symptoms. This case extends the clinical phenotype of repetitive and compulsive habits in bvFTD to encompass symptoms suggestive of ICDs. It is proposed that fluvoxamine and topiramate may be considered as treatment options in these conditions. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. The acoustic cortex in frontotemporal dementia: a Golgi and electron microscope study.

    PubMed

    Baloyannis, Stavros J; Mauroudis, Ioannis; Manolides, Spyros L; Manolides, Leonidas S

    2011-04-01

    The neuronal loss and the alteration of the synapses in the acoustic cortex in frontotemporal dementia (FTD) may be related to the impairment of communication and symbolic sound perception, which is noticed in the majority of the cases. FTD is a heterogeneous neurodegenerative disorder, causing progressive decline of intellectual faculties, impairment of behavior and social performance, and impairment of speech eloquence, associated with various neurological manifestations based on a variable neuropathological background. We attempted to determine the morphological alterations of the dendrites and the dendritic spines in the acoustic cortex of 10 cases who fulfilled the diagnostic criteria for FTD. For the histological study we applied (a) routine neuropathological techniques and (b) rapid Golgi method. We proceeded to electron microscopy for the ultrastructural study of the synapses and the morphological and morphometric study of the organelles, the dendrites, and the dendritic spines. The morphological and morphometric analysis revealed substantial neuronal loss and synaptic alterations in the acoustic cortex in all the cases of FTD and particularly in Pick disease and in primary progressive aphasia. Mitochondria alterations and changes of the Golgi apparatus were seen mostly in Pick disease.

  20. Impaired emotion processing from vocal and facial cues in frontotemporal dementia compared to right hemisphere stroke.

    PubMed

    Dara, Chinar; Kirsch-Darrow, Lindsey; Ochfeld, E; Slenz, Jamie; Agranovich, Anna; Vasconcellos-Faria, Andreia; Ross, Elliott; Hillis, Argye E; Kortte, Kathleen B

    2013-01-01

    To advance our understanding about the emotional and cognitive deficits of patients with frontotemporal dementia with behavioral variant (bvFTD), the current study examined comprehension and expression of emotions from prosodic and facial cues in a 66-year-old woman. The patient diagnosed with bvFTD is compared to six patients with acute right hemisphere stroke. Recognition of emotion from prosodic cues was assessed using an identification task in four conditions with decreasing verbal demands (neutral sentences, language-like pseudo sentences, monosyllables, and asyllabic vowel sounds). Repetition of utterances with emotional connotations and self-generated conversations were analyzed to measure relative changes in mean fundamental frequency (f0), f0 variance, speech rate, and intensity along with the facial musculature pattern. The patient showed a marked deficit in identifying emotions in all four prosody conditions; and she did not show much variation in modulating mean f0, f0 variance, speech rate and intensity for all emotion categories when compared to neutral utterances. In addition, this patient demonstrated little to no facial expressions during emotionally provoking tasks, but demonstrated no difficulty recognizing emotions from facial expressions or verbal scenarios. Results show that the patient seems to have selective impairment in recognition of emotions from prosody and expression of emotions using both prosodic and facial features. Impaired processing of emotional prosody and facial expressions could be important for detecting bvFTD with greater right hemisphere atrophy.

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

    PubMed

    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.

  2. Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia

    PubMed Central

    West, Ryan J.H.; Lu, Yubing; Marie, Bruno; Gao, Fen-Biao

    2015-01-01

    Mutations in genes essential for protein homeostasis have been identified in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Why mature neurons should be particularly sensitive to such perturbations is unclear. We identified mutations in Rab8 in a genetic screen for enhancement of an FTD phenotype associated with ESCRT-III dysfunction. Examination of Rab8 mutants or motor neurons expressing a mutant ESCRT-III subunit, CHMP2BIntron5, at the Drosophila melanogaster neuromuscular junction synapse revealed synaptic overgrowth and endosomal dysfunction. Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2BIntron5. In Rab8 mutant synapses, c-Jun N-terminal kinase (JNK)/activator protein-1 and TGF-β signaling were overactivated and acted synergistically to potentiate synaptic growth. We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants. Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes. PMID:25800055

  3. 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

  4. Abhorring the vacuum: use of Alzheimer’s disease medications in frontotemporal dementia

    PubMed Central

    Kerchner, Geoffrey A; Tartaglia, Maria Carmela; Boxer, Adam L

    2011-01-01

    There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer’s disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development. PMID:21728274

  5. Olfactory deficits in frontotemporal dementia as measured by the Alberta Smell Test.

    PubMed

    Heyanka, Daniel J; Golden, Charles J; McCue, Robert B; Scarisbrick, David M; Linck, John F; Zlatkin, Nancy I

    2014-01-01

    The study of olfaction in neurodegeneration has primarily focused on Alzheimer's disease. Research of olfaction in frontotemporal dementia (FTD) has generally not been empirically studied. The current study compared olfaction in FTD to major depressive disorder (MDD) using the Alberta Smell Test (AST). Independent-samples t test results suggested olfaction in FTD was impaired when compared with participants diagnosed with MDD. The AST Total score (out of 20 trials) significantly predicted the diagnostic group and accounted for 40% of the variance in diagnostic group status with an odds ratio of 20.08. Results suggested that a cutoff of ≤2/20 differentiated FTD from MDD with 94% accuracy (91% sensitivity, 97% specificity) and a cutoff of ≤1/20 differentiated the groups with a 95.5% hit rate (91% sensitivity, 100% specificity). Results confirmed olfactory identification deficits in FTD and suggested that the AST is an effective tool for the demarcation of FTD from MDD. This is especially important due to the potential for significant overlap in the behavioral/emotional phenotype and cognitive deficits between the two disorders when presented with early stages of FTD.

  6. 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.

  7. 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.

  8. Atypical Huntington's disease with the clinical presentation of behavioural variant of frontotemporal dementia.

    PubMed

    Sutovsky, Stanislav; Smolek, Tomas; Alafuzoff, Irina; Blaho, Andrej; Parrak, Vojtech; Turcani, Peter; Palkovic, Michal; Petrovic, Robert; Novak, Michal; Zilka, Norbert

    2016-12-01

    Huntington's disease is an incurable, adult-onset, autosomal dominant inherited disorder caused by an expanded trinucleotide repeat (CAG). In this study, we describe a Huntington's disease patient displaying clinical symptoms of the behavioural variant of frontotemporal dementia in the absence of tremor and ataxia. The clinical onset was at the age of 36 years and the disease progressed slowly (18 years). Genetic testing revealed expanded trinucleotide CAG repeats in the Huntingtin gene, together with a Glu318Gly polymorphism in presenilin 1. Neuropathological assessment revealed extensive amyloid β (Aβ) aggregates in all cortical regions. No inclusions displaying hyperphosphorylated tau or phosphorylated transactive response DNA-binding protein 43 (TDP43) were found. A high number of p62 (sequestosome 1) immunopositive intranuclear inclusions were seen mainly in the cortex, while subcortical areas were affected to a lesser extent. Confocal microscopy revealed that the majority of p62 intranuclear lesions co-localised with the fused-in-sarcoma protein (FUS) immunostaining. The morphology of the inclusions resembled intranuclear aggregates in Huntington's disease. The presented proband suffered from Huntington's disease showed atypical distribution of FUS positive intranuclear aggregates in the cortical areas with concomitant Alzheimer's disease pathology.

  9. The role of social cognition in moral judgment in frontotemporal dementia.

    PubMed

    Gleichgerrcht, Ezequiel; Torralva, Teresa; Roca, María; Pose, Máriangeles; Manes, Facundo

    2011-01-01

    Patients with behavioral variant frontotemporal dementia (bvFTD) exhibit a set of behavioral disturbances that have been strongly associated with involvement of the prefrontal cortex (PFC). Many such disturbances have been linked to impaired moral behavior, especially in regard to "personal" or "emotionally driven" moral dilemmatic judgment, which has been demonstrated to also depend on the integrity of the PFC. In this study, we administered a personal moral dilemma (the footbridge dilemma) and social cognition measures to patients with early bvFTD, who were also assessed with an extensive neuropsychological battery, including moral knowledge, cognitive and emotional empathy, and affective decision-making. BvFTD patients who would push a man off a footbridge (knowing this would kill him) to save the life of five workers who would have been otherwise killed by the train showed significantly lower scores on affective Theory of Mind (ToM) relative to those bvFTD patients who responded negatively. No significant differences were found on other sociodemographic, neuropsychological or social cognition variables. This study reveals that altered dilemmatic judgment may be related to impaired affective ToM, which has important clinical and theoretical implications.

  10. Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies.

    PubMed

    Gazzina, S; Manes, M A; Padovani, A; Borroni, B

    2017-06-01

    Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. 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.

  12. Methylphenidate ('Ritalin') can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia.

    PubMed

    Rahman, Shibley; Robbins, Trevor W; Hodges, John R; Mehta, Mitul A; Nestor, Peter J; Clark, Luke; Sahakian, Barbara J

    2006-03-01

    The frontal variant of frontotemporal dementia is a significant neurological condition worldwide. There exist few treatments available for the cognitive and behavioural sequelae of fvFTD. Previous research has shown that these patients display risky decision-making, and numerous studies have now demonstrated pathology affecting the orbitofrontal cortex. The present study uses a within-subjects, double-blind, placebo-controlled procedure to investigate the effects of a single dose of methylphenidate (40 mg) upon a range of different cognitive processes including those assessing prefrontal cortex integrity. Methylphenidate was effective in 'normalizing' the decision-making behavior of patients, such that they became less risk taking on medication, although there were no significant effects on other aspects of cognitive function, including working memory, attentional set shifting, and reversal learning. Moreover, there was an absence of the normal subjective and autonomic responses to methylphenidate seen in elderly subjects. The results are discussed in terms of the 'somatic marker' hypothesis of impaired decision-making following orbitofrontal dysfunction.

  13. Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology.

    PubMed

    Clayton, Emma L; Mizielinska, Sarah; Edgar, James R; Nielsen, Troels Tolstrup; Marshall, Sarah; Norona, Frances E; Robbins, Miranda; Damirji, Hana; Holm, Ida E; Johannsen, Peter; Nielsen, Jørgen E; Asante, Emmanuel A; Collinge, John; Isaacs, Adrian M

    2015-10-01

    Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal system. Consistent with these findings, CHMP2B mutation patient brains contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD.

  14. Relationships between Environmental Dependency and Closing-in in Patients with Fronto-temporal Dementia.

    PubMed

    Grossi, Dario; De Lucia, Natascia; Milan, Graziella; Trojano, Luigi

    2015-01-01

    Environmental dependency (ED) phenomena, including utilization behavior and imitation behavior, are clinical manifestations typically observed in patients with the behavioral variant of fronto-temporal dementia (bvFTD), who may also show the closing-in (CI) phenomenon. Here, we explored the neuropsychological correlates of ED and CI in bvFTD, and the association of ED with CI to clarify the mechanisms underlying these clinical manifestations. Thirty-one bvFTD patients underwent a wide cognitive assessment in addition to special tasks to detect occurrence of CI and ED phenomena. Both ED and CI phenomena were present in more than half of the sample. Logistic regression analyses revealed that both ED and CI phenomena were significantly associated with poor scores on frontal neuropsychological tests. Although ED and CI often co-occurred, 3/12 patients with CI did not show ED, and 5/18 patients with ED did not show CI. A logistic regression model showed that the presence of ED was not significantly associated to CI. CI and ED are associated to progressive derangement of frontal functions in bvFTD. However, specific frontal dysfunctions might explain the occurrence of either phenomenon in isolation.

  15. 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

  16. Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum.

    PubMed

    Ji, Ai-Ling; Zhang, Xia; Chen, Wei-Wei; Huang, Wen-Juan

    2017-03-01

    Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future.

  17. Tau protein in frontotemporal dementia linked to chromosome 3 (FTD-3).

    PubMed

    Yancopoulou, Despina; Crowther, R Anthony; Chakrabarti, Lisa; Gydesen, Susanne; Brown, Jeremy M; Spillantini, Maria Grazia

    2003-08-01

    Recent work on frontotemporal dementia (FTD) has revealed the existence of at least 3 genetically distinct groups of inherited FTD: FTDP-17, FTD and motor neuron disease linked to chromosome 9, and FTD linked to chromosome 3 (FTD-3). Tau, on chromosome 17, is the only gene where mutations have been identified and its involvement in FTD has been firmly established. The genes on chromosome 9 and chromosome 3 associated with familial forms of FTD remain to be identified. Abnormal aggregates of tau protein characterize the brain lesions of FTDP-17 patients and ubiquitin inclusions have been found in FTD with motor neuron disease linked to chromosome 9. In this study the frontal cortices of 3 FTD-3 patients from a unique Danish family were examined for characteristic neuropathological features. In these brains tau inclusions were present in neurons and some glial cells in the absence of beta-amyloid deposits. The presence of filamentous tau protein in the frontal cortex of these patients suggests a possible link between tau and the genetic defect present on chromosome 3 and associated with FTD-3, although the limited amount of tau deposits observed makes it difficult to define this as a tauopathy.

  18. 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.

  19. CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines.

    PubMed

    Belly, Agnès; Bodon, Gilles; Blot, Béatrice; Bouron, Alexandre; Sadoul, Rémy; Goldberg, Yves

    2010-09-01

    The highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2B(intron5) and CHMP2B(Delta10) in cultured hippocampal neurons modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2B(Delta10) induced a drop in frequency and amplitude of spontaneous excitatory postsynaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development.

  20. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

    PubMed Central

    Urwin, Hazel; Authier, Astrid; Nielsen, Jorgen E.; Metcalf, Daniel; Powell, Caroline; Froud, Kristina; Malcolm, Denise S.; Holm, Ida; Johannsen, Peter; Brown, Jeremy; Fisher, Elizabeth M.C.; van der Zee, Julie; Bruyland, Marc; Van Broeckhoven, Christine; Collinge, John; Brandner, Sebastian; Futter, Clare; Isaacs, Adrian M.

    2010-01-01

    Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. We report a novel endosomal pathology in CHMP2B mutation-positive patient brains and also identify and characterize abnormal endosomes in patient fibroblasts. Functional studies demonstrate a specific disruption of endosome–lysosome fusion but not protein sorting by the MVB. We provide evidence for a mechanism for impaired endosome–lysosome fusion whereby mutant CHMP2B constitutively binds to MVBs and prevents recruitment of proteins necessary for fusion to occur, such as Rab7. The fusion of endosomes with lysosomes is required for neuronal function and the data presented therefore suggest a pathogenic mechanism for FTD caused by CHMP2B mutations. PMID:20223751

  1. Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia.

    PubMed

    West, Ryan J H; Lu, Yubing; Marie, Bruno; Gao, Fen-Biao; Sweeney, Sean T

    2015-03-30

    Mutations in genes essential for protein homeostasis have been identified in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Why mature neurons should be particularly sensitive to such perturbations is unclear. We identified mutations in Rab8 in a genetic screen for enhancement of an FTD phenotype associated with ESCRT-III dysfunction. Examination of Rab8 mutants or motor neurons expressing a mutant ESCRT-III subunit, CHMP2B(Intron5), at the Drosophila melanogaster neuromuscular junction synapse revealed synaptic overgrowth and endosomal dysfunction. Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2B(Intron5). In Rab8 mutant synapses, c-Jun N-terminal kinase (JNK)/activator protein-1 and TGF-β signaling were overactivated and acted synergistically to potentiate synaptic growth. We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants. Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes. © 2015 West et al.

  2. CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines

    PubMed Central

    Belly, Agnès; Bodon, Gilles; Blot, Béatrice; Bouron, Alexandre; Sadoul, Rémy; Goldberg, Yves

    2010-01-01

    Summary The highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause fronto-temporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2Bintron5 and CHMP2BΔ10 in cultured hippocampal neurones modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2BΔ10 induced a drop in frequency and amplitude of spontaneous excitatory post-synaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development. PMID:20699355

  3. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations.

    PubMed

    Urwin, Hazel; Authier, Astrid; Nielsen, Jorgen E; Metcalf, Daniel; Powell, Caroline; Froud, Kristina; Malcolm, Denise S; Holm, Ida; Johannsen, Peter; Brown, Jeremy; Fisher, Elizabeth M C; van der Zee, Julie; Bruyland, Marc; Van Broeckhoven, Christine; Collinge, John; Brandner, Sebastian; Futter, Clare; Isaacs, Adrian M

    2010-06-01

    Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. We report a novel endosomal pathology in CHMP2B mutation-positive patient brains and also identify and characterize abnormal endosomes in patient fibroblasts. Functional studies demonstrate a specific disruption of endosome-lysosome fusion but not protein sorting by the MVB. We provide evidence for a mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B constitutively binds to MVBs and prevents recruitment of proteins necessary for fusion to occur, such as Rab7. The fusion of endosomes with lysosomes is required for neuronal function and the data presented therefore suggest a pathogenic mechanism for FTD caused by CHMP2B mutations.

  4. 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.

  5. Early-onset Alzheimer’s disease versus frontotemporal dementia: resolution with genetic diagnoses?

    PubMed Central

    Sha, Sharon J.; Khazenzon, Anna M.; Ghosh, Pia M.; Rankin, Katherine P.; Pribadi, Mochtar; Coppola, Giovanni; Geschwind, Daniel H.; Rabinovici, Gil D.; Miller, Bruce L.; Lee, Suzee E.

    2015-01-01

    We report a diagnostically challenging case of a 64-year-old man with a history of remote head trauma who developed mild behavioral changes and dyscalculia. He was diagnosed with clinical Alzheimer’s disease, with additional features consistent with behavioral variant frontotemporal dementia. Structural MRI revealed atrophy in bilateral frontal and parietal cortices and hippocampi on visual inspection and left frontal pole and bilateral anterior temporal encephalomalacia, suspected to be due to head trauma. Consistent with a diagnosis of Alzheimer’s pathology, positron emission tomography (PET) with Pittsburgh compound B suggested the presence of beta-amyloid. Fluorodeoxyglucose PET demonstrated hypometabolism in bilateral frontal and temporoparietal cortices. Voxel-based morphometry showed atrophy predominant in ventral frontal regions (bilateral orbitofrontal cortex, pregenual anterior cingulate/medial superior frontal gyrus), bilateral mid cingulate, bilateral lateral temporal cortex, and posterior insula. Bilateral caudate, thalamus, hippocampi and cerebellum were prominently atrophied. Unexpectedly, a pathologic hexanucleotide repeat expansion in C9ORF72 was identified in this patient. This report underscores the clinical variability in C9ORF72 expansion carriers and the need to consider mixed pathologies, particularly when imaging studies are inconsistent with a single syndrome or pathology. PMID:26304661

  6. Terra incognita—cerebellar contributions to neuropsychiatric and cognitive dysfunction in behavioral variant frontotemporal dementia

    PubMed Central

    Tan, Rachel H.; Devenney, Emma; Kiernan, Matthew C.; Halliday, Glenda M.; Hodges, John R.; Hornberger, Michael

    2015-01-01

    Although converging evidence has positioned the human cerebellum as an important relay for intact cognitive and neuropsychiatric processing, changes in this large structure remain mostly overlooked in behavioral variant frontotemporal dementia (bvFTD), a disease which is characterized by cognitive and neuropsychiatric deficits. The present study assessed whether degeneration in specific cerebellar subregions associate with indices of cognition and neuropsychiatric performance in bvFTD. Our results demonstrate a relationship between cognitive and neuropsychiatric decline across various domains of memory, language, emotion, executive, visuospatial function, and motivation and the degree of gray matter degeneration in cerebellar lobules V–VII. Most notably, bilateral cerebellar lobule VII and the posterior vermis emerged as distinct for memory processes, the right cerebellar hemisphere underpinned emotion, and the posterior vermis was highlighted in language dysfunction in bvFTD. Based on cortico-cerebellar connectivity maps, these findings in the cerebellum are consistent with the neural connections with the cortices involved in these domains in patients with bvFTD. Overall, the present study underscores the significance of cortical-cerebellar networks associated with cognition and neuropsychiatric dysfunction in bvFTD. PMID:26191000

  7. Frontotemporal dementia and language networks: cortical thickness reduction is driven by dyslexia susceptibility genes

    PubMed Central

    Paternicó, Donata; Manes, Marta; Premi, Enrico; Cosseddu, Maura; Gazzina, Stefano; Alberici, Antonella; Archetti, Silvana; Bonomi, Elisa; Cotelli, Maria Sofia; Cotelli, Maria; Turla, Marinella; Micheli, Anna; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara

    2016-01-01

    Variations within genes associated with dyslexia result in a language network vulnerability, and in patients with Frontotemporal Dementia (FTD), language disturbances represent a disease core feature. Here we explored whether variations within three related-dyslexia genes, namely KIAA0319, DCDC2, and CNTNAP, might affect cortical thickness measures in FTD patients. 112 FTD patients underwent clinical and neuropsychological examination, genetic analyses and brain Magnetic Resonance Imaging (MRI). KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G and CNTNAP2 rs17236239 A/G genetic variations were assessed. Cortical thickness was analysed by Freesurfer. Patients carrying KIAA0319 A*(AG or AA) carriers showed greater cortical thickness atrophy in the left fusiform and inferior temporal gyri, compared to KIAA0319 GG (p ≤ 0.001). Patients carrying CNTNAP2 G*(GA or GG) showed reduced cortical thickness in the left insula thenCNTNAP2 AA carriers (p≤0.001). When patients with both at-risk polymorphisms were considered (KIAA0319 A* and CNTNAP2 G*), greater and addictive cortical thickness atrophy of the left insula and the inferior temporal gyrus was demonstrated (p ≤ 0.001). No significant effect of DCDC2 was found. In FTD, variations of KIAA0319 and CNTNAP2 genes were related to cortical thickness abnormalities in those brain areas involved in language abilities. These findings shed light on genetic predisposition in defining phenotypic variability in FTD. PMID:27484312

  8. Network-selective vulnerability of the human cerebellum to Alzheimer's disease and frontotemporal dementia.

    PubMed

    Guo, Christine C; Tan, Rachel; Hodges, John R; Hu, Xintao; Sami, Saber; Hornberger, Michael

    2016-05-01

    SEE SCHMAHMANN DOI101093/BRAIN/AWW064 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Neurodegenerative diseases are associated with distinct and distributed patterns of atrophy in the cerebral cortex. Emerging evidence suggests that these atrophy patterns resemble intrinsic connectivity networks in the healthy brain, supporting the network-based degeneration framework where neuropathology spreads across connectivity networks. An intriguing yet untested possibility is that the cerebellar circuits, which share extensive connections with the cerebral cortex, could be selectively targeted by major neurodegenerative diseases. Here we examined the structural atrophy in the cerebellum across common types of neurodegenerative diseases, and characterized the functional connectivity patterns of these cerebellar atrophy regions. Our results showed that Alzheimer's disease and frontotemporal dementia are associated with distinct and circumscribed atrophy in the cerebellum. These cerebellar atrophied regions share robust and selective intrinsic connectivity with the atrophied regions in the cerebral cortex. These findings for the first time demonstrated the selective vulnerability of the cerebellum to common neurodegenerative disease, extending the network-based degeneration framework to the cerebellum. Our work also has direct implications on the cerebellar contribution to the cognitive and affective processes that are compromised in neurodegeneration as well as the practice of using the cerebellum as reference region for ligand neuroimaging studies. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. A Study of Cortical Excitability, Central Motor Conduction, and Cortical Inhibition Using Single Pulse Transcranial Magnetic Stimulation in Patients with Early Frontotemporal and Alzheimer's Dementia.

    PubMed

    Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Nagaraju, B C; Philip, Mariamma

    2016-01-01

    Degenerative cortical dementias affect several million people worldwide. Early diagnosis and categorization are essential for initiating appropriate pharmacological and nonpharmacological treatment so that deterioration can be postponed, and disability adjusted life years can be saved both for the patient and for the caregiver. Therefore, an early, simple, noninvasive biomarker will serve as a boon. Patients who satisfied probable Alzheimer's disease (AD) or frontotemporal dementia (FTD) using international consensus criteria for FTD and National Institute of Neurological Disorders and Stroke-AD and Related Disorders Association criteria for AD were evaluated using single pulse transcranial magnetic stimulation with figure of eight coil and motor evoked potential from right first dorsal interossei. Resting threshold (MT), central motor conduction time (CMCT), and silent period (SP) were evaluated. Resting MT and SP are reduced in patients with Alzheimer's disease whereas CMCT is prolonged in patients with FTD and SP is in the lower limit of normal in both conditions. The patterns of central motor conduction and MT are distinctly different in patients with early Alzheimer's disease (AD) and FTD.

  10. A Study of Cortical Excitability, Central Motor Conduction, and Cortical Inhibition Using Single Pulse Transcranial Magnetic Stimulation in Patients with Early Frontotemporal and Alzheimer's Dementia

    PubMed Central

    Chandra, Sadanandavalli Retnaswami; Issac, Thomas Gregor; Nagaraju, B. C.; Philip, Mariamma

    2016-01-01

    Introduction: Degenerative cortical dementias affect several million people worldwide. Early diagnosis and categorization are essential for initiating appropriate pharmacological and nonpharmacological treatment so that deterioration can be postponed, and disability adjusted life years can be saved both for the patient and for the caregiver. Therefore, an early, simple, noninvasive biomarker will serve as a boon. Patients and Methods: Patients who satisfied probable Alzheimer's disease (AD) or frontotemporal dementia (FTD) using international consensus criteria for FTD and National Institute of Neurological Disorders and Stroke-AD and Related Disorders Association criteria for AD were evaluated using single pulse transcranial magnetic stimulation with figure of eight coil and motor evoked potential from right first dorsal interossei. Resting threshold (MT), central motor conduction time (CMCT), and silent period (SP) were evaluated. Results: Resting MT and SP are reduced in patients with Alzheimer's disease whereas CMCT is prolonged in patients with FTD and SP is in the lower limit of normal in both conditions. Conclusion: The patterns of central motor conduction and MT are distinctly different in patients with early Alzheimer's disease (AD) and FTD. PMID:27011398

  11. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia

    PubMed Central

    van Blitterswijk, Marka; Mullen, Bianca; Nicholson, Alexandra M.; Bieniek, Kevin F.; Heckman, Michael G.; Baker, Matthew C.; DeJesus-Hernandez, Mariely; Finch, NiCole A.; Brown, Patricia H.; Murray, Melissa E.; Hsiung, Ging-Yuek R.; Stewart, Heather; Karydas, Anna M.; Finger, Elizabeth; Kertesz, Andrew; Bigio, Eileen H.; Weintraub, Sandra; Mesulam, Marsel; Hatanpaa, Kimmo J.; White, Charles L.; Strong, Michael J.; Beach, Thomas G.; Wszolek, Zbigniew K.; Lippa, Carol; Caselli, Richard; Petrucelli, Leonard; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Mackenzie, Ian R.; Seeley, William W.; Grinberg, Lea T.; Miller, Bruce L.; Boylan, Kevin B.; Graff-Radford, Neill R.; Boeve, Bradley F.; Dickson, Dennis W.; Rademakers, Rosa

    2014-01-01

    Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions (with or without motor neuron disease [MND]; cohort 2), and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls (11.9% versus 19.1%, odds ratio (OR): 0.57, p=0.014; same direction as carriers of GRN mutations). The strongest evidence was provided by FTD patients (OR: 0.33, p=0.009) followed by FTD/MND patients (OR: 0.38, p=0.017), whereas no significant difference was observed in MND patients (OR: 0.85, p=0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR: 0.77, p=0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR: 0.26, p<0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations, and might be relevant for prognostic testing, and as a promising

  12. 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

  13. 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.

  14. So Close Yet So Far: Executive Contribution to Memory Processing in Behavioral Variant Frontotemporal Dementia.

    PubMed

    Bertoux, Maxime; Ramanan, Siddharth; Slachevsky, Andrea; Wong, Stephanie; Henriquez, Fernando; Musa, Gada; Delgado, Carolina; Flanagan, Emma; Bottlaender, Michel; Sarazin, Marie; Hornberger, Michael; Dubois, Bruno

    2016-10-04

    Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties. This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach. Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls (among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n = 33) and non-amnestic (n = 38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling. Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4% - 12.7%) predicted by EF. These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD.

  15. Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort

    PubMed Central

    Gijselinck, Ilse; Van Mossevelde, Sara; van der Zee, Julie; Sieben, Anne; Philtjens, Stéphanie; Heeman, Bavo; Engelborghs, Sebastiaan; Vandenbulcke, Mathieu; De Baets, Greet; Bäumer, Veerle; Cuijt, Ivy; Van den Broeck, Marleen; Peeters, Karin; Mattheijssens, Maria; Rousseau, Frederic; Vandenberghe, Rik; De Jonghe, Peter; Cras, Patrick; De Deyn, Peter P.; Martin, Jean-Jacques

    2015-01-01

    Objective: To assess the genetic contribution of TBK1, a gene implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and FTD-ALS, in Belgian FTD and ALS patient cohorts containing a significant part of genetically unresolved patients. Methods: We sequenced TBK1 in a hospital-based cohort of 482 unrelated patients with FTD and FTD-ALS and 147 patients with ALS and an extended Belgian FTD-ALS family DR158. We followed up mutation carriers by segregation studies, transcript and protein expression analysis, and immunohistochemistry. Results: We identified 11 patients carrying a loss-of-function (LOF) mutation resulting in an overall mutation frequency of 1.7% (11/629), 1.1% in patients with FTD (5/460), 3.4% in patients with ALS (5/147), and 4.5% in patients with FTD-ALS (1/22). We found 1 LOF mutation, p.Glu643del, in 6 unrelated patients segregating with disease in family DR158. Of 2 mutation carriers, brain and spinal cord was characterized by TDP-43-positive pathology. The LOF mutations including the p.Glu643del mutation led to loss of transcript or protein in blood and brain. Conclusions: TBK1 LOF mutations are the third most frequent cause of clinical FTD in the Belgian clinically based patient cohort, after C9orf72 and GRN, and the second most common cause of clinical ALS after C9orf72. These findings reinforce that FTD and ALS belong to the same disease continuum. PMID:26581300

  16. 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

  17. 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.

  18. Damage to left frontal regulatory circuits produces greater positive emotional reactivity in frontotemporal dementia.

    PubMed

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

    2015-03-01

    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 (FTD), a neurodegenerative disease that targets emotion-relevant neural systems and causes alterations in positive emotion (i.e., euphoria and jocularity), and in 34 healthy controls. Participants watched a film clip designed to elicit happiness and a comparison film clip designed to elicit sadness while their facial behavior, physiological reactivity, and self-reported emotional experience were monitored. Whole-brain voxel-based morphometry (VBM) analyses revealed that atrophy in predominantly left hemisphere fronto-striatal emotion regulation systems including left ventrolateral prefrontal cortex, orbitofrontal cortex, anterior insula, and striatum was associated with greater happiness facial behavior during the film (pFWE < .05). Atrophy in left anterior insula and bilateral frontopolar cortex was also associated with higher cardiovascular reactivity (i.e., heart rate and blood pressure) but not self-reported positive emotional experience during the happy film (p < .005, uncorrected). No regions emerged as being associated with greater sadness reactivity, which suggests that left-lateralized fronto-striatal atrophy is selectively associated with happiness dysregulation. Whereas previous models have proposed that left frontal injury decreases positive emotional responding, we argue that

  19. 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

  20. Tackling variability: A multicenter study to provide a gold-standard network approach for frontotemporal dementia.

    PubMed

    Sedeño, Lucas; Piguet, Olivier; Abrevaya, Sofía; Desmaras, Horacio; García-Cordero, Indira; Baez, Sandra; Alethia de la Fuente, Laura; Reyes, Pablo; Tu, Sicong; Moguilner, Sebastian; Lori, Nicolas; Landin-Romero, Ramon; Matallana, Diana; Slachevsky, Andrea; Torralva, Teresa; Chialvo, Dante; Kumfor, Fiona; García, Adolfo M; Manes, Facundo; Hodges, John R; Ibanez, Agustin

    2017-08-01

    Biomarkers represent a critical research area in neurodegeneration disease as they can contribute to studying potential disease-modifying agents, fostering timely therapeutic interventions, and alleviating associated financial costs. Functional connectivity (FC) analysis represents a promising approach to identify early biomarkers in specific diseases. Yet, virtually no study has tested whether potential FC biomarkers prove to be reliable and reproducible across different centers. As such, their implementation remains uncertain due to multiple sources of variability across studies: the numerous international centers capable conducting FC research vary in their scanning equipment and their samples' socio-cultural background, and, more troublingly still, no gold-standard method exists to analyze FC. In this unprecedented study, we aim to address both issues by performing the first multicenter FC research in the behavioral-variant frontotemporal dementia (bvFTD), and by assessing multiple FC approaches to propose a gold-standard method for analysis. We enrolled 52 bvFTD patients and 60 controls from three international clinics (with different fMRI recording parameters), and three additional neurological patient groups. To evaluate FC, we focused on seed analysis, inter-regional connectivity, and several graph-theory approaches. Only graph-theory analysis, based on weighted-matrices, yielded consistent differences between bvFTD and controls across centers. Also, graph metrics robustly discriminated bvFTD from the other neurological conditions. The consistency of our findings across heterogeneous contexts highlights graph-theory as a potential gold-standard approach for brain network analysis in bvFTD. Hum Brain Mapp 38:3804-3822, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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

    PubMed

    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

    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. 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. 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. 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.

  2. 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

  3. Neuronal loss in familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.

    PubMed

    Cairns, N J; Brännström, T; Khan, M N; Rossor, M N; Lantos, P L

    2003-06-01

    The neuronal density in the frontal, temporal, and parietal lobes was determined in nine cases of familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions (FTDU). The mean age at onset was 56.9 +/- 2.2 years and the duration of disease was 6.7 +/- 0.5 years. The mean age at death was 63.6 +/- 2.2 years. There was substantial loss (34%) of brain weight (877 +/- 73 g) in the familial cases in comparison with 10 normal aged controls (1326 +/- 50 g, P < 0.001). All of the familial FTDU cases showed atrophy of the frontal, temporal, and parietal lobes; neuronal loss; vacuolation in superficial laminae; reactive astrocytosis; and ubiquitin-positive, tau-negative intracytoplasmic and intranuclear inclusions and dystrophic neurites in varying sites and numbers. Neuronal loss was estimated in nine cases of familial FTDU and in 10 aged controls using a stereological probe, the optical "disector," and a computerized stereology system (CAST-Grid, Olympus, Denmark). There was a significant reduction in neuronal density in the frontal lobe (22.3 +/- 3.8 x 10(3)/mm(3)) of familial FTDU in comparison to aged controls (33.1 +/- 1.7 x 10(3) per mm(3), P < 0.05). An estimate of the relative numbers of neurons was calculated by multiplying the numerical density by the cortical thickness, which showed a striking loss of neurons of 56% in the frontal lobe, 52% loss in the temporal lobe, and a 49% loss in the parietal lobe of familial FTDU when compared to controls. This study shows that familial FTDU has profound focal neuronal loss in multiple association areas that relate to the clinical symptoms characteristic of the disease.

  4. Grey and White Matter Changes across the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Continuum

    PubMed Central

    Lillo, Patricia; Mioshi, Eneida; Burrell, James R.; Kiernan, Matthew C.; Hodges, John R.; Hornberger, Michael

    2012-01-01

    There is increasing evidence that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a clinical, pathological and genetic continuum with patients of one disease exhibiting features of the other. Nevertheless, to date, the underlying grey matter and white matter changes across the ALS-FTD disease continuum have not been explored. In this study fifty-three participants with ALS (n = 10), ALS-FTD (n = 10) and behavioural variant FTD (bvFTD; n = 15) as well as controls (n = 18), underwent detailed clinical assessment plus structural imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis of magnetic resonance brain imaging to examine grey and white matter differences and commonalities across the continuum. Importantly, patient groups were matched for age, education, gender and disease duration. VBM and DTI results showed that changes in the ALS group were confined mainly to the motor cortex and anterior cingulate as well as their underlying white matter tracts. ALS-FTD and bvFTD showed widespread grey matter and white matter changes involving frontal and temporal lobes. Extensive prefrontal cortex changes emerged as a marker for bvFTD compared to other subtypes, while ALS-FTD could be distinguished from ALS by additional temporal lobe grey and white matter changes. Finally, ALS could be mainly distinguished from the other two groups by corticospinal tract degeneration. The present study shows for the first time that FTD and ALS overlap in anterior cingulate, motor cortex and related white matter tract changes across the whole continuum. Nevertheless, frontal and temporal atrophy as well as corticospinal tract degeneration emerged as marker for subtype classification, which will inform future diagnosis and target disease management across the continuum. PMID:22952843

  5. Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia

    PubMed Central

    McMillan, Corey T.; Suh, EunRan; Powers, John; Rascovsky, Katya; Wood, Elisabeth M.; Toledo, Jon B.; Arnold, Steven E.; Lee, Virginia M.-Y.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grossman, Murray

    2014-01-01

    Objective: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD). Methods: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37). Results: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p = 0.04) but not with TDP-43 proteinopathies (p > 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p < 0.01). MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p < 0.01). Conclusions: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings. PMID:24994843

  6. Detailed volumetric analysis of the hypothalamus in behavioral variant frontotemporal dementia.

    PubMed

    Bocchetta, Martina; Gordon, Elizabeth; Manning, Emily; Barnes, Josephine; Cash, David M; Espak, Miklos; Thomas, David L; Modat, Marc; Rossor, Martin N; Warren, Jason D; Ourselin, Sebastien; Frisoni, Giovanni B; Rohrer, Jonathan D

    2015-12-01

    Abnormal eating behaviors are frequently reported in behavioral variant frontotemporal dementia (bvFTD). The hypothalamus is the regulatory center for feeding and satiety but its involvement in bvFTD has not been fully clarified, partly due to its difficult identification on MR images. We measured hypothalamic volume in 18 patients with bvFTD (including 9 MAPT and 6 C9orf72 mutation carriers) and 18 cognitively normal controls using a novel optimized multimodal segmentation protocol, combining 3D T1 and T2-weighted 3T MRIs (intrarater intraclass correlation coefficients ≥0.93). The whole hypothalamus was subsequently segmented into five subunits: the anterior (superior and inferior), tuberal (superior and inferior), and posterior regions. The presence of abnormal eating behavior was assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R). The bvFTD group showed a 17% lower hypothalamic volume compared with controls (p < 0.001): mean 783 (standard deviation 113) versus 944 (73) mm(3) (corrected for total intracranial volume). In the hypothalamic subunit analysis, the superior parts of the anterior and tuberal regions and the posterior region were significantly smaller in the bvFTD group compared with controls. There was a trend for a smaller hypothalamic volume, particularly in the superior tuberal region, in those with severe eating disturbance scores on the CBI-R. Differences were seen between the two genetic subgroups with significantly smaller volumes in the MAPT but not the C9orf72 group compared with controls. In summary, bvFTD patients had lower hypothalamic volumes compared with controls. Different genetic mutations may have a differential impact on the hypothalamus.

  7. 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

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

    PubMed Central

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

    2015-01-01

    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. PMID:25556536

  9. Neuropsychological, behavioral, and anatomical evolution in right temporal variant frontotemporal dementia: a longitudinal and post-mortem single case analysis.

    PubMed

    Henry, Maya L; Wilson, Stephen M; Ogar, Jennifer M; Sidhu, Manu S; Rankin, Katherine P; Cattaruzza, Tatiana; Miller, Bruce L; Gorno-Tempini, Maria Luisa; Seeley, William W

    2014-01-01

    We describe a patient with semantic variant of frontotemporal dementia who received longitudinal clinical evaluations and structural MRI scans and subsequently came to autopsy. She presented with early behavior changes and semantic loss for foods and people and ultimately developed a pervasive semantic impairment affecting social-emotional as well as linguistic domains. Imaging revealed predominant atrophy of the right temporal lobe, with later involvement of the left, and pathology confirmed bilateral temporal involvement. Findings support the view that left and right anterior temporal lobes serve as semantic hubs that may be affected differentially in semantic variant by early, relatively unilateral damage.

  10. Neuropsychological, behavioral, and anatomical evolution in right temporal variant frontotemporal dementia: A longitudinal and post-mortem single case analysis

    PubMed Central

    Henry, Maya L.; Wilson, Stephen M.; Ogar, Jennifer M.; Sidhu, Manu S.; Rankin, Katherine P.; Cattaruzza, Tatiana; Miller, Bruce L.; Gorno-Tempini, Maria Luisa; Seeley, William W.

    2013-01-01

    We describe a patient with semantic variant of frontotemporal dementia who received longitudinal clinical evaluations and structural MRI scans and subsequently came to autopsy. She presented with early behavior changes and semantic loss for foods and people and ultimately developed a pervasive semantic impairment affecting social-emotional as well as linguistic domains. Imaging revealed predominant atrophy of the right temporal lobe, with later involvement of the left, and pathology confirmed bilateral temporal involvement. Findings support the view that left and right anterior temporal lobes serve as semantic hubs that may be affected differentially in semantic variant by early, relatively unilateral damage. PMID:23171151

  11. The overlap of symptomatic dimensions between frontotemporal dementia and several psychiatric disorders that appear in late adulthood.

    PubMed

    Pose, Mariangeles; Cetkovich, Marcelo; Gleichgerrcht, Ezequiel; Ibáñez, Agustin; Torralva, Teresa; Manes, Facundo

    2013-04-01

    Several factors make diagnosis of a possible behavioural variant of frontotemporal dementia (bvFTD) particularly challenging, especially the overlap of certain symptomatic dimensions such as apathy, disinhibition, depression, anhedonia, stereotyped behaviour, and psychosis between bvFTD and several psychiatric disorders that appear in late adulthood. We discuss the most frequent psychiatric conditions that can simulate early bvFTD symptoms, including late onset bipolar disorder, late onset schizophrenia-like psychosis, late onset depression, and attention deficit hyperactivity disorder in middle and older age.

  12. 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

  13. The role of the orbitofrontal cortex in regulation of interpersonal space: evidence from frontal lesion and frontotemporal dementia patients.

    PubMed

    Perry, Anat; Lwi, Sandy J; Verstaen, Alice; Dewar, Callum; Levenson, Robert W; Knight, Robert T

    2016-12-01

    Interpersonal distance is central to communication and complex social behaviors but the neural correlates of interpersonal distance preferences are not defined. Previous studies suggest that damage to the orbitofrontal cortex (OFC) is associated with impaired interpersonal behavior. To examine whether the OFC is critical for maintaining appropriate interpersonal distance, we tested two groups of patients with OFC damage: Patients with OFC lesions and patients with behavioral variant frontotemporal dementia. These two groups were compared to healthy controls and to patients with lesions restricted to the dorsolateral prefrontal cortex. Only patients with OFC damage showed abnormal interpersonal distance preferences, which were significantly different from both controls and patients with dorsolateral prefrontal damage. The comfortable distances these patients chose with strangers were significantly closer than the other groups and resembled distances normally used with close others. These results shed light on the role of the OFC in regulating social behavior and may serve as a simple diagnostic tool for dementia or lesion patients.

  14. 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

  15. 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.

  16. Behavioural and neuropsychiatric disturbance in three clinical subtypes of frontotemporal dementia: A Clinical Research Center for Dementia of South Korea-FTD Study.

    PubMed

    Park, Moon Ho; Kim, Eun-Joo; Park, Kyung Won; Kwon, Jae Cheol; Ku, Bon D; Han, Seol-Heui; Kim, SangYun; Yang, Dong Won; Na, Duk L; Choi, Seong Hye

    2017-03-01

    To characterise the behavioural and neuropsychiatric disturbances of patients with three clinical subtypes of frontotemporal dementia (FTD): behavioural variant FTD (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA). Consecutive series of 66 patients with bvFTD, 58 patients with SD and 21 patients with PNFA were compared using the Frontal Behavioural Inventory (FBI) and the Neuropsychiatric Inventory (NPI). Patients with bvFTD had more behavioural and neuropsychiatric disturbances than patients with PNFA based on the total scores of FBI and NPI. When comparing subtotal and item scores of FBI and NPI, there were some significant differences among three clinical subtypes of FTD. There are some distinct patterns of behavioural and neuropsychiatric disturbance among three clinical subtypes of FTD. © 2017 AJA Inc.

  17. Inhibition of p25/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia.

    PubMed

    Seo, Jinsoo; Kritskiy, Oleg; Watson, L Ashley; Barker, Scarlett J; Dey, Dilip; Raja, Waseem K; Lin, Yuan-Ta; Ko, Tak; Cho, Sukhee; Penney, Jay; Silva, M Catarina; Sheridan, Steven D; Lucente, Diane; Gusella, James F; Dickerson, Bradford C; Haggarty, Stephen J; Tsai, Li-Huei

    2017-09-14

    Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders including Alzheimer's disease (AD). Previously, we showed that replacing endogenous p35 with the non-cleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial AD mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared to the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we utilized frontotemporal dementia (FTD) patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENTAccumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes such as neuroinflammation, synaptic loss, Aβ accumulation and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δp35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we utilized this

  18. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia

    PubMed Central

    Woollacott, Ione O.C.; Dick, Katrina M.; Brotherhood, Emilie; Gordon, Elizabeth; Fellows, Alexander; Toombs, Jamie; Druyeh, Ronald; Cardoso, M. Jorge; Ourselin, Sebastien; Nicholas, Jennifer M.; Norgren, Niklas; Mead, Simon; Andreasson, Ulf; Blennow, Kaj; Schott, Jonathan M.; Fox, Nick C.; Warren, Jason D.; Zetterberg, Henrik

    2016-01-01

    Objective: To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease. Methods: Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume. Results: Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL [SD 51.3 pg/mL]) than controls (19.6 pg/mL [SD 8.2 pg/mL]; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL [SD 33.1 pg/mL]) and both the semantic and nonfluent variants of PPA (95.9 and 82.5 pg/mL [SD 33.0 and 33.8 pg/mL], respectively) compared with controls and in semantic variant PPA compared with logopenic variant PPA. Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL [SD 48.2 and 20.9 pg/mL], respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL [SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003). Conclusions: Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes. PMID:27581216

  19. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking

    PubMed Central

    Farg, Manal A.; Sundaramoorthy, Vinod; Sultana, Jessica M.; Yang, Shu; Atkinson, Rachel A.K.; Levina, Vita; Halloran, Mark A.; Gleeson, Paul A.; Blair, Ian P.; Soo, Kai Y.; King, Anna E.; Atkin, Julie D.

    2014-01-01

    Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking. PMID:24549040

  20. 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

  1. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia.

    PubMed

    Radford, Helois; Moreno, Julie A; Verity, Nicholas; Halliday, Mark; Mallucci, Giovanna R

    2015-11-01

    The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates the transient shutdown of translation in response to rising levels of misfolded proteins in the endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer's disease, the tauopathies and prion disorders. These are all characterised by the accumulation of misfolded disease-specific proteins in the brain in association with specific patterns of neuronal loss, but the role of UPR activation in their pathogenesis is unclear. In prion-diseased mice, overactivation of PERK-P/eIF2α-P signalling results in the sustained reduction in global protein synthesis, leading to synaptic failure, neuronal loss and clinical disease. Critically, restoring vital neuronal protein synthesis rates by inhibiting the PERK-eIF2α pathway, both genetically and pharmacologically, prevents prion neurodegeneration downstream of misfolded prion protein accumulation. Here we show that PERK-eIF2α-mediated translational failure is a key process leading to neuronal loss in a mouse model of frontotemporal dementia, where the misfolded protein is a form of mutant tau. rTg4510 mice, which overexpress the P301L tau mutation, show dysregulated PERK signalling and sustained repression of protein synthesis by 6 months of age, associated with onset of neurodegeneration. Treatment with the PERK inhibitor, GSK2606414, from this time point in mutant tau-expressing mice restores protein synthesis rates, protecting against further neuronal loss, reducing brain atrophy and abrogating the appearance of clinical signs. Further, we show that PERK-eIF2α activation also contributes to the pathological phosphorylation of tau in rTg4510 mice, and that levels of phospho-tau are lowered by PERK inhibitor treatment, providing a second mechanism of protection. The data support UPR-mediated translational failure as a generic pathogenic mechanism in

  2. 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.…

  3. 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.…

  4. A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia

    PubMed Central

    Ferrari, Raffaele; Grassi, Mario; Salvi, Erika; Borroni, Barbara; Palluzzi, Fernando; Pepe, Daniele; D'Avila, Francesca; Padovani, Alessandro; Archetti, Silvana; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Galimberti, Daniela; Scarpini, Elio; Serpente, Maria; Rossi, Giacomina; Giaccone, Giorgio; Tagliavini, Fabrizio; Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia; Bruni, Amalia C.; Maletta, Raffaele G.; Bernardi, Livia; Postiglione, Alfredo; Milan, Graziella; Franceschi, Massimo; Puca, Annibale A.; Novelli, Valeria; Barlassina, Cristina; Glorioso, Nicola; Manunta, Paolo; Singleton, Andrew; Cusi, Daniele; Hardy, John; Momeni, Parastoo

    2015-01-01

    Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10−7 and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of –cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD–genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis. PMID:26154020

  5. Medical and environmental risk factors associated with frontotemporal dementia: a case-control study in a veteran population.

    PubMed

    Kalkonde, Yogeshwar V; Jawaid, Ali; Qureshi, Salah U; Shirani, Peyman; Wheaton, Michael; Pinto-Patarroyo, Gineth P; Schulz, Paul E

    2012-05-01

    Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population. The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias. The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P < .05). The FTD group also had a lower prevalence of heart disease (19.0% vs 36.7%; P < .05) and cerebrovascular diseases (12.7% vs 26.1%; P < .05), although the prevalence of vascular risk factors was comparable between FTD and non-FTD dementia groups: hypertension (65.1% vs 68.2%), diabetes (31.7% vs 26.9%), hyperlipidemia (42.9% vs 48.9%), and tobacco use (7.9% vs 8.8%; P > .05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6-11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3-0.96). In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms. Copyright © 2012. Published by Elsevier Inc.

  6. 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.

  7. 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

  8. 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.

  9. A Comparison of Magnetic Resonance Imaging and Neuropsychological Examination in the Diagnostic Distinction of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia

    PubMed Central

    Wang, Jingjing; Redmond, Stephen J.; Bertoux, Maxime; Hodges, John R.; Hornberger, Michael

    2016-01-01

    The clinical distinction between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) remains challenging and largely dependent on the experience of the clinician. This study investigates whether objective machine learning algorithms using supportive neuroimaging and neuropsychological clinical features can aid the distinction between both diseases. Retrospective neuroimaging and neuropsychological data of 166 participants (54 AD; 55 bvFTD; 57 healthy controls) was analyzed via a Naïve Bayes classification model. A subgroup of patients (n = 22) had pathologically-confirmed diagnoses. Results show that a combination of gray matter atrophy and neuropsychological features allowed a correct classification of 61.47% of cases at clinical presentation. More importantly, there was a clear dissociation between imaging and neuropsychological features, with the latter having the greater diagnostic accuracy (respectively 51.38 vs. 62.39%). These findings indicate that, at presentation, machine learning classification of bvFTD and AD is mostly based on cognitive and not imaging features. This clearly highlights the urgent need to develop better biomarkers for both diseases, but also emphasizes the value of machine learning in determining the predictive diagnostic features in neurodegeneration. PMID:27378905

  10. A Comparison of Magnetic Resonance Imaging and Neuropsychological Examination in the Diagnostic Distinction of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia.

    PubMed

    Wang, Jingjing; Redmond, Stephen J; Bertoux, Maxime; Hodges, John R; Hornberger, Michael

    2016-01-01

    The clinical distinction between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) remains challenging and largely dependent on the experience of the clinician. This study investigates whether objective machine learning algorithms using supportive neuroimaging and neuropsychological clinical features can aid the distinction between both diseases. Retrospective neuroimaging and neuropsychological data of 166 participants (54 AD; 55 bvFTD; 57 healthy controls) was analyzed via a Naïve Bayes classification model. A subgroup of patients (n = 22) had pathologically-confirmed diagnoses. Results show that a combination of gray matter atrophy and neuropsychological features allowed a correct classification of 61.47% of cases at clinical presentation. More importantly, there was a clear dissociation between imaging and neuropsychological features, with the latter having the greater diagnostic accuracy (respectively 51.38 vs. 62.39%). These findings indicate that, at presentation, machine learning classification of bvFTD and AD is mostly based on cognitive and not imaging features. This clearly highlights the urgent need to develop better biomarkers for both diseases, but also emphasizes the value of machine learning in determining the predictive diagnostic features in neurodegeneration.

  11. Emotion, social functioning and activities of daily living in frontotemporal dementia.

    PubMed

    Kipps, Christopher M; Mioshi, Eneida; Hodges, John R

    2009-06-01

    Social functioning in FTD is profoundly affected, and forms the basis for the clinical diagnosis of the behavioural variant of the disease (bv-FTD). In particular, there are deficits in emotional processing, but the inter-relationship of such deficits to other aspects of social functioning remains unclear. We studied patients with bv-FTD (n = 14) and AD (n = 14), and compared their performance on a test of emotion recognition with their scores on two carer-based assessments: the Disability Assessment for Dementia (DAD) of activities in daily living (ADL), and the Cambridge Behavioural Inventory (CBI). The bv-FTD group had significantly greater impairments in ADLs, and had higher scores on the CBI, compared to the AD group. Despite a deficit in emotion recognition, particularly involving negative emotions, in the FTD group relative to AD and controls, performance on this task did not correlate with ADL ratings which instead, correlated highly with carer-rated apathy levels on the CBI. The study highlights the multifactorial nature of social dysfunction in FTD which is important in the management of these patients and in designing effective behavioural and therapeutic interventions. The relationship of emotional processing to other aspects of social cognition in FTD is reviewed.

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

    PubMed Central

    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. PMID:27632209

  13. Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia.

    PubMed

    Takeuchi, Ryoko; Toyoshima, Yasuko; Tada, Mari; Tanaka, Hidetomo; Shimizu, Hiroshi; Shiga, Atsushi; Miura, Takeshi; Aoki, Kenju; Aikawa, Akane; Ishizawa, Shin; Ikeuchi, Takeshi; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) may be accompanied by frontotemporal dementia (FTD). We report a case of glial mixed tau and TDP-43 proteinopathies in a Japanese patient diagnosed clinically as having ALS-D. Autopsy revealed loss of lower motor neurons and degeneration of the pyramidal tracts in the spinal cord and brain stem. The brain showed frontotemporal lobar degeneration (FTLD), the most severe neuronal loss and gliosis being evident in the precentral gyrus. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. AT8 immunostaining revealed that predominant occurrence of astrocytic tau lesions termed globular astrocytic inclusions (GAIs) was a feature of the affected regions. These GAIs were Gallyas-Braak negative. Neuronal and oligodendrocytic tau lesions were comparatively scarce. pS409/410 immunostaining also revealed similar neuronal and glial TDP-43 lesions. Interestingly, occasional co-localization of tau and TDP-43 was evident in the GAIs. Immunoblot analyses revealed band patterns characteristic of a 4-repeat (4R) tauopathy, corticobasal degeneration and a TDP-43 proteinopathy, ALS/FTLD-TDP Type B. No mutations were found in the MAPT or TDP-43 genes. We consider that this patient harbored a distinct, sporadic globular glial mixed 4R tau and TDP-43 proteinopathy associated with motor neuron disease and FTD.

  14. Studying social cognition in patients with schizophrenia and patients with frontotemporal dementia: theory of mind and the perception of sarcasm.

    PubMed

    Kosmidis, Mary H; Aretouli, Eleni; Bozikas, Vassilis P; Giannakou, Maria; Ioannidis, Panayiotis

    2008-01-01

    We investigated social cognition and theory of mind in patients with schizophrenia and in patients with frontotemporal dementia in order to elucidate the cognitive mechanisms involved in the breakdown of these skills in psychiatric and neurological patients. Our tasks included videotaped scenarios of social interactions depicting sincere, sarcastic and paradoxical remarks, as well as lies. We found impaired performance of the schizophrenia group on all theory of mind conditions despite their intact understanding of sincere statements. In contrast, the FTD group performed poorly only when they had to rely on paralinguistic cues indicating sarcasm or lies, and not on paradoxical remarks or sarcasm when given additional verbal cues. Our findings suggest that, while current deficits in social and interpersonal functioning in patients with FTD may reflect a decrement in previously acquired skills, similar deficits in patients with schizophrenia may reflect an altogether inadequately learned process.

  15. A decade of genetic counseling in frontotemporal dementia affected families: few counseling requests and much familial opposition to testing.

    PubMed

    Riedijk, S R; Niermeijer, M F N; Dooijes, D; Tibben, A

    2009-08-01

    A decade of genetic counseling of frontotemporal dementia (FTD) affected families has generated two important observations. First, the uptake rate for presymptomatic testing for FTD is low in our department of Clinical Genetics at the Erasmus Medical Center in the Netherlands. Second, FTD at-risk counselees reported substantial familial opposition to genetic testing, which is distinct from the attitude in Huntington Disease affected families. We hypothesize that the low acceptance for FTD genetic counseling is consequential to the familial opposition and explain this within the theoretical framework of separation-individuation. Furthermore, we hypothesize that separation-individuation problems do not similarly influence the acceptance of HD genetic counseling, due to the educative role of the well-organised patient organization for HD in the Netherlands. We offer counseling recommendations that serve to facilitate the individuation of the counselee with respect to the FTD genetic test.

  16. Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia.

    PubMed

    Lee, Jin-A; Gao, Fen-Biao

    2009-07-01

    Autophagy is a conserved lysosomal protein degradation pathway whose precise roles in age-dependent neurodegenerative diseases remain largely unknown. Here we show that the autophagy inhibitor 3-methyladenine delays neuronal cell loss caused by dysfunctional endosomal sorting complex required for transport III (ESCRT-III), either through loss of its essential component mSnf7-2 or ectopic expression of the disease protein CHMP2B(Intron5), which is associated with frontotemporal dementia linked to chromosome 3. Neuronal loss was also delayed by reduced activity of the autophagy genes atg5 and atg7. However, the endosomal accumulation of ubiquitinated proteins induced by dysfunctional ESCRT-III was not significantly affected, further confirming the essential contribution of dysregulated autophagy pathway in neurodegeneration. These findings show that autophagic stress by excess accumulation of autophagosomes is detrimental to neuronal survival under certain neurodegenerative conditions.

  17. What is known about the subjective needs of people with behavioural variant frontotemporal dementia? A scoping review.

    PubMed

    Dinand, Claudia; Nover, Sabine Ursula; Holle, Daniela; Zischka, Matthias; Halek, Margareta

    2016-07-01

    Behavioural variant frontotemporal dementia (bvFTD) is an early-onset and progressive neurodegenerative disease associated with strong changes in judgement, behaviour, personality and emotions. These changes can cause significant problems in everyday life for people with bvFTD and their families, and have implications for health and society. Currently, there are no suitable evidence-based specific interventions for people with bvFTD. This scoping review aims to identify the self-expressed needs, demands and coping strategies of people with bvFTD. Identifying these issues is the first step towards the development of need-based psycho-social interventions for people with bvFTD. A comprehensive literature research was conducted of German and English scientific articles published between January 2000 and October 2014 using the databases MEDLINE, CINAHL, PsycINFO, PSYNDEX, SocINDEX, GeroLit, the Cochrane Library, ProQuest, the German National Library and additional search strategies in terms of a scoping review. Articles were identified by combining search terms related to 'frontotemporal dementia' with terms related to 'self-expressions', 'needs/demands' and 'coping'. After excluding duplicates, two independent reviewers screened the titles and abstracts of 2317 records for eligibility. Because eligibility could not be assessed from the titles or abstracts of 28 articles, those articles were assessed using the full text. One poster abstract met our research question and a few articles were related, but no article met all of the inclusion criteria. This lack of scientifically based knowledge concerning the perspective of people with bvFTD is discussed with reference to the search strategy and the research questions, disease-related aspects such as changes in behaviour or language and emotions and the difficulties in researching this topic. Recommendations are formulated for future research considering the perspective of people with bvFTD and that will involve the

  18. Experiences and needs of spouses of persons with young-onset frontotemporal lobe dementia during the progression of the disease.

    PubMed

    Johannessen, Aud; Helvik, Anne-Sofie; Engedal, Knut; Thorsen, Kirsten

    2017-03-09

    Two of the most common types of young-onset dementia (<65 years old) are Alzheimer's disease and frontotemporal lobe dementia (FTLD). A limited amount of research that focuses on the needs of spouses of persons with young-onset FTLD (yo-FTLD) has been published. Thus, we have carried out a study aiming to examine the spouses of yo-FTLD experiences and needs for assistance in daily life. Qualitative interviews with 16 informants (aged 51-69 years; nine wives, six husbands and one male cohabitant) were conducted in 2014 and 2015. The data were analysed by reformulated and modified method of Grounded Theory. From the interviews, three main themes with subthemes emerged: The first main theme that appeared is sneaking signs at the early stage of dementia. It covers two subthemes: incomprehensible early signs and lack of self-insight. The second main theme that appeared is other relations, and it covers three subthemes: the torment, interference with work and vanishing social relations. The third main theme: needs for assistance through all stages of dementia, are described under three subthemes: Relief of the diagnosis, support at home and the path to the nursing home. The interviews showed that spouses and the whole family of yo-FTLD need interdisciplinary, individualised and specialised support throughout the progression of the disorder. Furthermore, there is a need for more knowledge about yo-FTLD among health personnel, including general practitioners. IT-solutions can contribute to developing such services and support to the entire family. © 2017 Nordic College of Caring Science.

  19. 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.

  20. Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

    PubMed Central

    Krabbe, Grietje; Minami, S. Sakura; Etchegaray, Jon I.; Taneja, Praveen; Djukic, Biljana; Davalos, Dimitrios; Le, David; Lo, Iris; Zhan, Lihong; Reichert, Meredith C.; Sayed, Faten; Merlini, Mario; Ward, Michael E.; Perry, David C.; Lee, Suzee E.; Sias, Ana; Parkhurst, Christopher N.; Gan, Wen-biao; Akassoglou, Katerina; Miller, Bruce L.; Farese, Robert V.; Gan, Li

    2017-01-01

    Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior. PMID:28438992

  1. Early onset behavioral variant frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations.

    PubMed

    Arighi, Andrea; Fumagalli, Giorgio G; Jacini, Francesca; Fenoglio, Chiara; Ghezzi, Laura; Pietroboni, Anna M; De Riz, Milena; Serpente, Maria; Ridolfi, Elisa; Bonsi, Rossana; Bresolin, Nereo; Scarpini, Elio; Galimberti, Daniela

    2012-01-01

    A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration with or without concomitant motor neuron disease phenotype and TDP-43 based pathology. Here, we report on three cases carrying the hexanucleotide repeat expansion with an atypical presentation consisting in the development of psychiatric symptoms. Patient #1, a 53 year old man with positive family history for dementia, presented with mood deflection, characterized by apathy, social withdraw, and irritability in the last two years. He was diagnosed with "mild cognitive impairment due to depressive syndrome" six months later and subsequently with Alzheimer's disease. Patient #2, a woman with positive family history for dementia, developed behavioral disturbances, aggressiveness, and swearing at 57 years of age. Patient #3 presented, in the absence of brain atrophy, with mystical delirium with auditory hallucinations at 44 years of age, and did not present neurological symptoms over a 7-year follow up. The description of these cases underlines that the hexanucleotide repeat expansion in chromosome 9 could be associated with early onset psychiatric presentations.

  2. Personality Traits in the Siblings and Children of Patients with Frontotemporal Dementia: A Questionnaire-based Study.

    PubMed

    Korada, Suresh Kumar; Chandra, Sadanandavalli Retnaswami; Benegal, Vivek; Purushothaman, Meera; Philip, Mariamma

    2017-01-01

    Frontotemporal dementias (FLD) form a group of relatively young onset, male dominant dementias with significant behavioral abnormalities early in the course of the disease. Routine assessment suggested preexisting traits such as lack of empathy, self-directedness, and persistence in most of these persons even before the onset of disease. Hence, we decided the study, the siblings and children of patients for any specific traits and correlation with hexanucleotide expansion repeats if any traits were identified. A total of 35 age- and gender-matched cases and controls were included for the study as per criteria. They were screened for mental illness and cognitive dysfunction using Hindi Mental State Examination and Mini-mental State Examination. Eligible persons were given temperament and character inventory (TCI) scores for the recommended parameters. Hexanucleotide expansion was also studied in the patients, cases and controls. No specific personality trait was found to have an increased correlation with siblings and children of patients with FLD in this small group using TCI scores. 7% of cases showed Hexanucleotide expansion suggesting a possible risk. The role of self reporting bias resulting in normal personality trait needs to be addressed in future studies.

  3. Presymptomatic cerebral blood flow changes in CHMP2B mutation carriers of familial frontotemporal dementia (FTD-3), measured with MRI

    PubMed Central

    Lunau, Line; Mouridsen, Kim; Rodell, Anders; Østergaard, Leif; Nielsen, Jørgen Erik; Isaacs, Adrian

    2012-01-01

    Objectives To assess functional changes measured by cerebral blood flow (CBF) in the presymptomatic stage of frontotemporal dementia linked to chromosome 3 (FTD-3) caused by a truncating mutation in CHMP2B. Design Case–control study. Setting A memory clinic and tertiary referrals centre for dementia and inherited neurodegenerative disorders. Participants The authors included 11 presymptomatic CHMP2B mutation carriers and seven first-degree-related family non-carriers. Participants were MRI scanned twice with an interval of 15 months. Primary and secondary outcome measures Local functional changes in brain tissue perfusion were measured as CBF with two different MR techniques, gradient echo (GRE) and spin echo (SE), focusing on CBF in all cerebral vessels (GRE) and cerebral capillaries (SE), respectively. As planned, data analysis included co-registration of perfusion images to structural T1 images. Perfusion data were then extracted from seven regions-of-interest, normalised to white matter and statistically compared between carriers and non-carriers. Results For SE, contrasts between carriers and non-carriers showed significant differences in temporal, occipital and parietal lobes and in hippocampus. There was no evidence of changes from baseline to follow-up. For GRE, there were no significant differences between carriers and non-carriers. Conclusions Significantly decreased CBF was found in presymptomatic CHMP2B mutation carriers in occipital-and parietal lobes. Comparing SE with GRE, data indicate that FTD-3 vascular pathology might primarily affect brain capillaries. PMID:22422914

  4. Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease.

    PubMed

    Talbot, Kevin; Ansorge, Olaf

    2006-10-15

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease classically defined by the impairment of the voluntary motor system and ubiquitin-positive intraneuronal aggregates in anterior horn cells. Frontotemporal dementia (FTD) is a common form of neurodegenerative dementia and presents with personality change associated in a significant subgroup of patients with cortical ubiquitin-only neuropathology (FTD-U). Careful study of ALS as well as FTD patient cohorts suggests clinical as well as pathological overlap of ALS with FTD. The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of ALS and FTD. The identification of two further genetic causes of FTD-U with (rare) ALS (PGRN) or without ALS (VCP) also provides a starting point for exploring the pathways associated with ubiquitin-mediated protein mishandling in FTD-U and ALS. Pure ALS, through ALS with cognitive impairment and ALS-FTD to pure FTD-U, may represent a continuous spectrum of ubiquitin-associated neurodegenerative disease.

  5. Presymptomatic cerebral blood flow changes in CHMP2B mutation carriers of familial frontotemporal dementia (FTD-3), measured with MRI.

    PubMed

    Lunau, Line; Mouridsen, Kim; Rodell, Anders; Ostergaard, Leif; Nielsen, Jørgen Erik; Isaacs, Adrian; Johannsen, Peter

    2012-01-01

    To assess functional changes measured by cerebral blood flow (CBF) in the presymptomatic stage of frontotemporal dementia linked to chromosome 3 (FTD-3) caused by a truncating mutation in CHMP2B. Case-control study. A memory clinic and tertiary referrals centre for dementia and inherited neurodegenerative disorders. The authors included 11 presymptomatic CHMP2B mutation carriers and seven first-degree-related family non-carriers. Participants were MRI scanned twice with an interval of 15 months. Local functional changes in brain tissue perfusion were measured as CBF with two different MR techniques, gradient echo (GRE) and spin echo (SE), focusing on CBF in all cerebral vessels (GRE) and cerebral capillaries (SE), respectively. As planned, data analysis included co-registration of perfusion images to structural T1 images. Perfusion data were then extracted from seven regions-of-interest, normalised to white matter and statistically compared between carriers and non-carriers. For SE, contrasts between carriers and non-carriers showed significant differences in temporal, occipital and parietal lobes and in hippocampus. There was no evidence of changes from baseline to follow-up. For GRE, there were no significant differences between carriers and non-carriers. Significantly decreased CBF was found in presymptomatic CHMP2B mutation carriers in occipital-and parietal lobes. Comparing SE with GRE, data indicate that FTD-3 vascular pathology might primarily affect brain capillaries.

  6. Personality Traits in the Siblings and Children of Patients with Frontotemporal Dementia: A Questionnaire-based Study

    PubMed Central

    Korada, Suresh Kumar; Chandra, Sadanandavalli Retnaswami; Benegal, Vivek; Purushothaman, Meera; Philip, Mariamma

    2017-01-01

    Introduction: Frontotemporal dementias (FLD) form a group of relatively young onset, male dominant dementias with significant behavioral abnormalities early in the course of the disease. Routine assessment suggested preexisting traits such as lack of empathy, self-directedness, and persistence in most of these persons even before the onset of disease. Hence, we decided the study, the siblings and children of patients for any specific traits and correlation with hexanucleotide expansion repeats if any traits were identified. Patients and Methods: A total of 35 age- and gender-matched cases and controls were included for the study as per criteria. They were screened for mental illness and cognitive dysfunction using Hindi Mental State Examination and Mini-mental State Examination. Eligible persons were given temperament and character inventory (TCI) scores for the recommended parameters. Hexanucleotide expansion was also studied in the patients, cases and controls. Results: No specific personality trait was found to have an increased correlation with siblings and children of patients with FLD in this small group using TCI scores. Conclusions: 7% of cases showed Hexanucleotide expansion suggesting a possible risk. The role of self reporting bias resulting in normal personality trait needs to be addressed in future studies. PMID:28250555

  7. Behavioral-variant frontotemporal dementia with corticobasal degeneration pathology: Phenotypic comparison to bvFTD with Pick’s disease

    PubMed Central

    Rankin, Katherine P.; Mayo, Mary Catherine; Seeley, William W.; Lee, Suzee; Rabinovici, Gil; Gorno-Tempini, Maria Luisa; Boxer, Adam L.; Weiner, Michael W.; Trojanowski, John Q.; DeArmond, Stephen J.; Miller, Bruce L.

    2011-01-01

    Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer’s-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed phenotypic characterization. All patients with CBD pathology and clinical assessment were reviewed (N=17) and selected if they initially met criteria for bvFTD [bvFTD(CBD): N=5]. Available bvFTD patients with Pick’s [bvFTD(Pick’s): N=5] were selected as controls. Patients were also compared to healthy older controls [N=53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick’s). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick’s) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal > ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick’s) patients. Despite remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick’s disease neuropathology. PMID:21881831

  8. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

    PubMed Central

    van der Zee, Julie; Gijselinck, Ilse; Van Mossevelde, Sara; Perrone, Federica; Dillen, Lubina; Heeman, Bavo; Bäumer, Veerle; Engelborghs, Sebastiaan; De Bleecker, Jan; Baets, Jonathan; Gelpi, Ellen; Rojas‐García, Ricardo; Clarimón, Jordi; Lleó, Alberto; Diehl‐Schmid, Janine; Alexopoulos, Panagiotis; Perneczky, Robert; Synofzik, Matthis; Just, Jennifer; Schöls, Ludger; Graff, Caroline; Thonberg, Håkan; Borroni, Barbara; Padovani, Alessandro; Jordanova, Albena; Sarafov, Stayko; Tournev, Ivailo; de Mendonça, Alexandre; Miltenberger‐Miltényi, Gabriel; Simões do Couto, Frederico; Ramirez, Alfredo; Jessen, Frank; Heneka, Michael T.; Gómez‐Tortosa, Estrella; Danek, Adrian; Cras, Patrick; Vandenberghe, Rik; De Jonghe, Peter; De Deyn, Peter P.; Sleegers, Kristel; Cruts, Marc; Goeman, Johan; Nuytten, Dirk; Smets, Katrien; Robberecht, Wim; Damme, Philip Van; Bleecker, Jan De; Santens, Patrick; Dermaut, Bart; Versijpt, Jan; Michotte, Alex; Ivanoiu, Adrian; Deryck, Olivier; Bergmans, Bruno; Delbeck, Jean; Bruyland, Marc; Willems, Christiana; Salmon, Eric; Pastor, Pau; Ortega‐Cubero, Sara; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Hernández, Isabel; Boada, Mercè; Ruiz, Agustín; Sorbi, Sandro; Nacmias, Benedetta; Bagnoli, Silvia; Sorbi, Sandro; Sanchez‐Valle, Raquel; Llado, Albert; Santana, Isabel; Rosário Almeida, Maria; Frisoni, Giovanni B; Maetzler, Walter; Matej, Radoslav; Fraidakis, Matthew J.; Kovacs, Gabor G.; Fabrizi, Gian Maria; Testi, Silvia

    2017-01-01

    ABSTRACT We investigated the mutation spectrum of the TANK‐Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early‐Onset Dementia Consortium. We assessed pathogenicity of predicted protein‐truncating mutations by measuring loss of RNA expression. Functional effect of in‐frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB‐induced luciferase reporter assay and measuring phosphorylated TBK1. The protein‐truncating mutations led to the loss of transcript through nonsense‐mediated mRNA decay. For the in‐frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high‐risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD‐ALS. PMID:28008748

  9. 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.

  10. Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17

    PubMed Central

    Varani, Luca; Hasegawa, Masato; Spillantini, Maria Grazia; Smith, Michael J.; Murrell, Jill R.; Ghetti, Bernardino; Klug, Aaron; Goedert, Michel; Varani, Gabriele

    1999-01-01

    Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Intronic mutations and some missense mutations increase splicing in of exon 10, leading to an increased ratio of four-repeat to three-repeat tau isoforms. Secondary structure predictions have led to the proposal that intronic mutations and one missense mutation destabilize a putative RNA stem-loop structure located close to the splice-donor site of the intron after exon 10. We have determined the three-dimensional structure of this tau exon 10 splicing regulatory element RNA by NMR spectroscopy. We show that it forms a stable, folded stem-loop structure whose thermodynamic stability is reduced by frontotemporal dementia and parkinsonism linked to chromosome 17 mutations and increased by compensatory mutations. By exon trapping, the reduction in thermodynamic stability is correlated with increased splicing in of exon 10. PMID:10393977

  11. Clinical, genetic and neuropathological features of frontotemporal dementia: an update and guide.

    PubMed

    Pelicano Paulos, Jorge; Massano, João

    2013-01-01

    Introdução: A Degenerescência Lobar Frontotemporal engloba um conjunto de situações heterogéneas que partilham sintomas cognitivos e comportamentais, bem como características patológicas macroscópicas. As bases genéticas e características histopatológicas são bastante diversas e formam a base da classificação molecular das várias doenças, sendo difícil fazer uma correlação com os achados clínicos e síndromas. A investigação científica trouxe um conjunto vasto de conhecimentos, nem sempre fáceis de acompanhar,especialmente nos últimos anos em relação à genética e histopatologia.Material e Métodos: Os autores fizeram uma pesquisa de literatura neste tema, escolheram referências relevantes, extraíram e sistematizaram os dados.Resultados e Conclusão: o texto apresenta uma revisão atualizada dos aspetos clínicos, genéticos e histopatológicos da Degenerescência Lobar Frontotemporal, com ênfase especial na Demência Frontotemporal, a doença mais comum. O tratamento é também revisto e são propostas pelos autores estratégias relativamente à escolha dos testes genéticos na prática clínica. Deveriam serpromovidos a atenção e conhecimento públicos sobre este grupo de doenças.

  12. 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

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

    PubMed

    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.

  14. 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

  15. Frontotemporal dementia linked to chromosome 3 (FTD-3)--current concepts and the detection of a previously unknown branch of the Danish FTD-3 family.

    PubMed

    Lindquist, S G; Braedgaard, H; Svenstrup, K; Isaacs, A M; Nielsen, J E

    2008-07-01

    Among patients with onset of dementia below the age of 65 years, frontotemporal dementia (FTD) is the second most prevalent cause, secondary only to Alzheimer's disease. Recent advances in understanding the heterogeneous genetic background for different clinical and neuropathological entities of FTD have involved identification of several new causative genes. We report the finding of a truncating mutation in the CHMP2B gene (c.532-1G>C) in a patient with early onset dementia. The patient was previously not known to be related to the single Danish pedigree known to have this specific mutation. Subsequently he has turned out to represent a new branch of the family with several affected individuals. Our findings highlight the need for awareness of the CHMP2B mutation and associated clinical phenotype for neurological assessment in Denmark. Further, we discuss recent advances and current concepts in the understanding of CHMP2B-related dementia.

  16. Rapidly progressive Fronto-temporal dementia (FTD) associated with Frontotemporal lobar degeneration (FTLD) in the presence of Fused in Sarcoma (FUS) protein: a rare, sporadic, and aggressive form of FTD.

    PubMed

    Bradfield, Nicholas I; McLean, Catriona; Drago, John; Darby, David G; Ames, David

    2017-10-01

    Fronto-temporal dementia (FTD) associated with Fused in Sarcoma (FUS) protein accumulation is an uncommon cause of FTD with a distinct syndrome of young age onset behavioral variant FTD, without a family history of FTD and caudate atrophy. We present a sporadic case of a 61-year-old patient with mixed features of both behavioral variant FTD with later semantic language dissolution associated with pathologically proven FUS. He was older than usual for FUS pathology, his course was rapidly progressive, and he had atypical language features. This case broadens the clinical spectrum caused by FUS-protein-related FTD.

  17. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72

    PubMed Central

    Boylan, Kevin B.; Graff-Radford, Neill R.; DeJesus-Hernandez, Mariely; Knopman, David S.; Pedraza, Otto; Vemuri, Prashanthi; Jones, David; Lowe, Val; Murray, Melissa E.; Dickson, Dennis W.; Josephs, Keith A.; Rush, Beth K.; Machulda, Mary M.; Fields, Julie A.; Ferman, Tanis J.; Baker, Matthew; Rutherford, Nicola J.; Adamson, Jennifer; Wszolek, Zbigniew K.; Adeli, Anahita; Savica, Rodolfo; Boot, Brendon; Kuntz, Karen M.; Gavrilova, Ralitza; Reeves, Andrew; Whitwell, Jennifer; Kantarci, Kejal; Jack, Clifford R.; Parisi, Joseph E.; Lucas, John A.; Petersen, Ronald C.; Rademakers, Rosa

    2012-01-01

    Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral

  18. 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

  19. When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians

    PubMed Central

    Shinagawa, Shunichiro; Catindig, Joseree Ann; Block, Nikolas R.; Miller, Bruce L.; Rankin, Katherine P.

    2016-01-01

    Background Accurate diagnosis of behavioral variant frontotemporal dementia (bvFTD) is important as patients’ behavioral symptoms have profound implications for their families and communities. Since the diagnosis of bvFTD derives from behavioral features, accurate identification of patients can be difficult for non-specialists. Concrete rates of diagnostic accuracy among non-specialists are unavailable. Methods To examine the accuracy of community clinicians’ diagnoses of bvFTD and to identify patient characteristics leading to misdiagnosis, we reviewed the charts and referral letters of 3,578 patients who were seen at our specialized center. Referral diagnosis and reasons, manifesting symptoms, demographic data, Mini-Mental State Examination score, Clinical Dementia Rating score and Neuropsychiatric Inventory score were extracted. Results 60% of patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists. Compared to specialist-confirmed bvFTD patients, false bvFTD patients were more likely to be depressed and to be non-Caucasian, showed less euphoria, apathy, disinhibition and abnormal eating behaviors, had milder disease severity and better overall cognition. bvFTD was mentioned by referring clinicians in 86% of specialist-confirmed bvFTD cases, but missed cases were called Alzheimer’s, Parkinson’s or Huntington’s disease, or progressive aphasia. Conclusion These results revealed a widespread lack of familiarity with core diagnostic symptoms among non-specialists and suggest that community clinicians require specialized diagnostic support before providing a definitive diagnosis of bvFTD. PMID:26741499

  20. When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians.

    PubMed

    Shinagawa, Shunichiro; Catindig, Joseree Ann; Block, Nikolas R; Miller, Bruce L; Rankin, Katherine P

    2016-01-01

    Accurate diagnosis of behavioral variant frontotemporal dementia (bvFTD) is important as patients' behavioral symptoms have profound implications for their families and communities. Since the diagnosis of bvFTD derives from behavioral features, accurate identification of patients can be difficult for non-specialists. Concrete rates of diagnostic accuracy among non-specialists are unavailable. To examine the accuracy of community clinicians' diagnoses of bvFTD and to identify patient characteristics leading to misdiagnosis, we reviewed the charts and referral letters of 3,578 patients who were seen at our specialized center. Referral diagnosis and reasons, manifesting symptoms, demographic data, Mini-Mental State Examination score, Clinical Dementia Rating score and Neuropsychiatric Inventory score were extracted. 60% of patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists. Compared to specialist-confirmed bvFTD patients, false bvFTD patients were more likely to be depressed and to be non-Caucasian, showed less euphoria, apathy, disinhibition and abnormal eating behaviors, had milder disease severity and better overall cognition. bvFTD was mentioned by referring clinicians in 86% of specialist-confirmed bvFTD cases, but missed cases were called Alzheimer's, Parkinson's or Huntington's disease, or progressive aphasia. These results revealed a widespread lack of familiarity with core diagnostic symptoms among non-specialists and suggest that community clinicians require specialized diagnostic support before providing a definitive diagnosis of bvFTD. © 2016 S. Karger AG, Basel.

  1. 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.

  2. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

    PubMed

    van der Zee, Julie; Gijselinck, Ilse; Van Mossevelde, Sara; Perrone, Federica; Dillen, Lubina; Heeman, Bavo; Bäumer, Veerle; Engelborghs, Sebastiaan; De Bleecker, Jan; Baets, Jonathan; Gelpi, Ellen; Rojas-García, Ricardo; Clarimón, Jordi; Lleó, Alberto; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Perneczky, Robert; Synofzik, Matthis; Just, Jennifer; Schöls, Ludger; Graff, Caroline; Thonberg, Håkan; Borroni, Barbara; Padovani, Alessandro; Jordanova, Albena; Sarafov, Stayko; Tournev, Ivailo; de Mendonça, Alexandre; Miltenberger-Miltényi, Gabriel; Simões do Couto, Frederico; Ramirez, Alfredo; Jessen, Frank; Heneka, Michael T; Gómez-Tortosa, Estrella; Danek, Adrian; Cras, Patrick; Vandenberghe, Rik; De Jonghe, Peter; De Deyn, Peter P; Sleegers, Kristel; Cruts, Marc; Van Broeckhoven, Christine; Goeman, Johan; Nuytten, Dirk; Smets, Katrien; Robberecht, Wim; Damme, Philip Van; Bleecker, Jan De; Santens, Patrick; Dermaut, Bart; Versijpt, Jan; Michotte, Alex; Ivanoiu, Adrian; Deryck, Olivier; Bergmans, Bruno; Delbeck, Jean; Bruyland, Marc; Willems, Christiana; Salmon, Eric; Pastor, Pau; Ortega-Cubero, Sara; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Hernández, Isabel; Boada, Mercè; Ruiz, Agustín; Sorbi, Sandro; Nacmias, Benedetta; Bagnoli, Silvia; Sorbi, Sandro; Sanchez-Valle, Raquel; Llado, Albert; Santana, Isabel; Rosário Almeida, Maria; Frisoni, Giovanni B; Maetzler, Walter; Matej, Radoslav; Fraidakis, Matthew J; Kovacs, Gabor G; Fabrizi, Gian Maria; Testi, Silvia

    2017-03-01

    We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affectin