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Frontotemporal dementia: a bridge between dementia and neuromuscular disease.

ABSTRACT: 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 that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (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 the 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, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.

SUBMITTER: Ng AS

PROVIDER: S-EPMC4399703 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Frontotemporal dementia: a bridge between dementia and neuromuscular disease.

Ng Adeline S L AS Rademakers Rosa R Miller Bruce L BL

Annals of the New York Academy of Sciences 20141230

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 that the C9ORF72 locus is responsible ...[more]

PMID: 25557955

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Project description: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 ?² 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 with those in the AD group, who commonly committed traffic violations, often related to cognitive impairment. CONCLUSIONS AND RELEVANCE:Criminal behavior is more common in patients with bvFTD and semantic variant of primary progressive aphasia than in those with AD and is more likely to be an early manifestation of the disorder. Judicial evaluations of criminality in the demented individual might require different criteria than the classic "insanity defense" used in the American legal system; these individuals should be treated differently by the law. The appearance of new-onset criminal behavior in an adult should elicit a search for frontal and anterior temporal brain disease and for dementing disorders.

Project description: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 anti-epileptics, 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 small percentage of patients may experience improvement with a trial of carbidopa-levodopa. Physical and occupational therapy remain an important corner stone of motor symptom management in FTD. Speech therapy may also help patients manage symptoms associated with aphasia, apraxia, and dysarthria. Recent advances in the understanding of FTLD pathophysiology and genetics have led to development of potentially disease-modifying therapies as well as symptomatic therapies aimed at ameliorating social and behavioral deficits.

Project description:BackgroundAlzheimer's disease (AD) and frontotemporal dementia (FTD) are the two main types of dementia. We investigated the electroencephalogram (EEG) difference and clinical correlation in early-onset Alzheimer's disease (EOAD), and FTD using multimodal EEG analyses. EOAD had more severe EEG abnormalities than late-onset AD (LOAD). Group comparisons between EOAD and LOAD were also performed.MethodsThirty patients diagnosed with EOAD, nine patients with LOAD, and 14 patients with FTD (≤65 y) were recruited (2008.1-2020.2), along with 24 healthy controls (≤65 y, n = 18; >65 y, n = 6). Clinical data were reviewed. Visual EEG, EEG microstate, and spectral analyses were performed.ResultsCompared to controls, markedly increased mean microstate duration, reduced mean occurrence, and reduced global field power (GFP) peaks per second were observed in EOAD and FTD. We found increased durations of class B in EOAD and class A in FTD. EOAD had reduced occurrences in classes A, B, and C, while only class C occurrence was reduced in FTD. The visual EEG results did not differ between AD and FTD. Microstate B showed correlations with activities of daily living score (r = 0.780, p = 0.008) and cerebrospinal fluid (CSF) Aβ42 (r = -0.833, p = 0.010) in EOAD. Microstate D occurrence was correlated with the CSF Aβ42 level in FTD (r = 0.786, p = 0.021). Spectral analysis revealed a general slowing EEG, which may contribute to microstate dynamic loss. Power in delta was significantly higher in EOAD than in FTD all over the head. In addition, EOAD had a marked increased duration and decreased occurrence than late-onset AD (LOAD), with no group differences in visual EEG results.ConclusionThe current study found that EOAD and FTD had different EEG changes, and microstate had an association with clinical severity and CSF biomarkers. EEG microstate is more sensitive than visual EEG and may be useful for the differentiation between AD and FTD. The observations support that EEG can be a potential biomarker for the diagnosis and assessment of early-onset dementias.

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Frontotemporal dementia: a bridge between dementia and neuromuscular disease.

Publications

Frontotemporal dementia: a bridge between dementia and neuromuscular disease.

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