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Brain : a Journal of Neurology Sep 2011Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant...
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 and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
Topics: Aged; Behavior; Female; Frontotemporal Dementia; Guidelines as Topic; Humans; Male; Middle Aged; Neuropsychological Tests; Reproducibility of Results; Sensitivity and Specificity
PubMed: 21810890
DOI: 10.1093/brain/awr179 -
Continuum (Minneapolis, Minn.) Apr 2016This article reviews the common behavioral and cognitive features of frontotemporal dementia (FTD) and related disorders as well as the distinguishing clinical, genetic,... (Review)
Review
PURPOSE OF REVIEW
This article reviews the common behavioral and cognitive features of frontotemporal dementia (FTD) and related disorders as well as the distinguishing clinical, genetic, and pathologic features of the most common subtypes.
RECENT FINDINGS
Advances in clinical phenotyping, genetics, and biomarkers have enabled improved predictions of the specific underlying molecular pathology associated with different presentations of FTD. Evaluation of large international cohorts has led to recent refinements in diagnostic criteria for several of the FTD subtypes.
SUMMARY
The FTDs are a group of neurodegenerative disorders featuring progressive deterioration of behavior or language and associated pathology in the frontal or temporal lobes. Based on anatomic, genetic, and neuropathologic categorizations, the six clinical subtypes of FTD or related disorders are: (1) behavioral variant of FTD, (2) semantic variant primary progressive aphasia, (3) nonfluent agrammatic variant primary progressive aphasia, (4) corticobasal syndrome, (5) progressive supranuclear palsy, and (6) FTD associated with motor neuron disease. Recognition and accurate diagnoses of FTD subtypes will aid the neurologist in the management of patients with FTD.
Topics: Cognition Disorders; Frontotemporal Dementia; Humans; Mental Disorders; Neuroimaging; Neuropsychological Tests; Psychiatric Status Rating Scales
PubMed: 27042904
DOI: 10.1212/CON.0000000000000300 -
Neurotherapeutics : the Journal of the... Jul 2023Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive changes in behavior, personality, executive...
Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive changes in behavior, personality, executive function, language, and motor function. Approximately 20% of FTD cases have a known genetic cause. The three most common genetic mutations causing FTD are discussed. Frontotemporal lobar degeneration refers to the heterogeneous group of neuropathology underlying FTD clinical syndromes. While there are no current disease-modifying treatments for FTD, management includes off-label pharmacotherapy and non-pharmacological approaches to target symptoms. The utility of several different drug classes is discussed. Medications used in the treatment of Alzheimer's disease have no benefit in FTD and can worsen neuropsychiatric symptoms. Non-pharmacological approaches to management include lifestyle modifications, speech-, occupational-, and physical therapy, peer and caregiver support, and safety considerations. Recent developments in the understanding of the genetics, pathophysiology, neuropathology, and neuroimmunology underlying FTD clinical syndromes have expanded possibilities for disease-modifying and symptom-targeted treatments. Different pathogenetic mechanisms are targeted in several active clinical trials, opening up exciting possibilities for breakthrough advances in treatment and management of FTD spectrum disorders.
Topics: Humans; Frontotemporal Dementia; Syndrome; Frontotemporal Lobar Degeneration; Alzheimer Disease
PubMed: 37157041
DOI: 10.1007/s13311-023-01380-6 -
Journal of Nuclear Medicine : Official... Jun 2022Since the invention of F-FDG as a neurochemical tracer in the 1970s, F-FDG PET has been used extensively for dementia research and clinical applications. FDG, a glucose...
Since the invention of F-FDG as a neurochemical tracer in the 1970s, F-FDG PET has been used extensively for dementia research and clinical applications. FDG, a glucose analog, is transported into the brain via glucose transporters and metabolized in a concerted process involving astrocytes and neurons. Although the exact cellular mechanisms of glucose consumption are still under investigation, F-FDG PET can sensitively detect altered neuronal activity due to neurodegeneration. Various neurodegenerative disorders affect different areas of the brain, which can be depicted as altered F-FDG uptake by PET. The spatial patterns and severity of such changes can be reproducibly visualized by statistical mapping technology, which has become widely available in the clinic. The differentiation of 3 major neurodegenerative disorders by F-FDG PET, Alzheimer disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB), has become standard practice. As the nosology of FTD evolves, frontotemporal lobar degeneration, the umbrella term for pathology affecting the frontal and temporal lobes, has been subclassified clinically into behavioral variant FTD; primary progressive aphasia with 3 subtypes, semantic, nonfluent, and logopenic variants; and movement disorders including progressive supranuclear palsy and corticobasal degeneration. Each of these subtypes is associated with differential F-FDG PET findings. The discovery of new pathologic markers and clinicopathologic correlations via larger autopsy series have led to newly recognized or redefined disease categories, such as limbic-predominant age-related TDP-43 encephalopathy, hippocampus sclerosis, primary age-related tauopathy, and argyrophilic grain disease, which have become a focus of investigations by molecular imaging. These findings need to be integrated into the modern interpretation of F-FDG PET. Recent pathologic investigations also have revealed a high prevalence, particularly in the elderly, of mixed dementia with overlapping and coexisting pathologies. The interpretation of F-FDG PET is evolving from a traditional dichotomous diagnosis of AD versus FTD (or DLB) to a determination of the most predominant underlying pathology that would best explain the patient's symptoms, for the purpose of care guidance. F-FDG PET is a relatively low cost and widely available imaging modality that can help assess various neurodegenerative disorders in a single test and remains the workhorse in clinical dementia evaluation.
Topics: Aged; Alzheimer Disease; Fluorodeoxyglucose F18; Frontotemporal Dementia; Glucose; Humans; Neurodegenerative Diseases; Positron-Emission Tomography
PubMed: 35649653
DOI: 10.2967/jnumed.121.263194 -
Journal of Translational Medicine Jun 2023Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN)....
BACKGROUND
Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN.
METHODS
In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans.
RESULTS
In a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers.
CONCLUSIONS
These findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204 .
Topics: Humans; Mice; Animals; Progranulins; Frontotemporal Dementia; Intercellular Signaling Peptides and Proteins; Mutation
PubMed: 37322482
DOI: 10.1186/s12967-023-04251-y -
International Review of Psychiatry... Apr 2013
Topics: Frontotemporal Dementia; Humans; Psychiatry
PubMed: 23611342
DOI: 10.3109/09540261.2013.785169 -
Neurotherapeutics : the Journal of the... Jan 2011Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia,... (Review)
Review
Dementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington's disease, progressive supranuclear palsy, multiple system atrophy, Parkinson's disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias.
Topics: Alzheimer Disease; Dementia; Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography
PubMed: 21274688
DOI: 10.1007/s13311-010-0012-2 -
Alzheimer's Research & Therapy Dec 2016Progressive and relatively circumscribed loss of semantic knowledge, referred to as semantic dementia (SD) which falls under the broader umbrella of frontotemporal... (Review)
Review
Progressive and relatively circumscribed loss of semantic knowledge, referred to as semantic dementia (SD) which falls under the broader umbrella of frontotemporal dementia, was officially identified as a clinical syndrome less than 50 years ago. Here, we review recent neuroimaging, pathological, and genetic research in SD. From a neuroimaging perspective, SD is characterised by hallmark asymmetrical atrophy of the anterior temporal pole and anterior fusiform gyrus, which is usually left lateralised. Functional magnetic resonance imaging (fMRI) studies have revealed widespread changes in connectivity, implicating the anterior temporal regions in semantic deficits in SD. Task-related fMRI have also demonstrated the relative preservation of frontal and parietal regions alongside preserved memory performance. In addition, recent longitudinal studies have demonstrated that, with disease progression, atrophy encroaches into the contralateral temporal pole and medial prefrontal cortices, which reflects emerging changes in behaviour and social cognition. Notably, unlike other frontotemporal dementia subtypes, recent research has demonstrated strong clinicopathological concordance in SD, with TDP43 type C as the most common pathological subtype. Moreover, an underlying genetic cause appears to be relatively rare in SD, with the majority of cases having a sporadic form of the disease. The relatively clear diagnosis, clinical course, and pathological homogeneity of SD make this syndrome a promising target for novel disease-modifying interventions. The development of neuroimaging markers of disease progression at the individual level is an important area of research for future studies to address, in order to assist with this endeavour.
Topics: Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Neuropsychological Tests
PubMed: 27915998
DOI: 10.1186/s13195-016-0219-5 -
Psychiatry and Clinical Neurosciences Aug 2022Frontotemporal dementia is a neurodegenerative disease characterized by focal degeneration of the frontal and temporal lobes, clinically presenting with disinhibited... (Review)
Review
Frontotemporal dementia is a neurodegenerative disease characterized by focal degeneration of the frontal and temporal lobes, clinically presenting with disinhibited behavior, personality changes, progressive non-fluent aphasia and/or impaired semantic memory. Research progress has been made in re-organizing the clinical concept of frontotemporal dementia and neuropathological classification based on multiple accumulating proteins. Alongside this progress a list of genetic mutations or variants that are causative or increase the risk of frontotemporal dementia have been identified and some of these gene products are extensively studied. However, there are still a lot of points that need to be overcome, including lack of specific diagnostic biomarker which enable antemortem diagnosis of underlying neurodegenerative process, and lack of disease modifying therapy which could prevent disease progression. Early and precise diagnosis of frontotemporal dementia is urgently required. In this context, how to define prodromal frontotemporal dementia and early differential diagnosis from primary psychiatric disorders are also important issues. In this review we will summarize and discuss current understanding of biological basis and psychiatric symptoms in frontotemporal dementia.
Topics: Diagnosis, Differential; Frontotemporal Dementia; Humans; Memory Disorders; Neurodegenerative Diseases; Temporal Lobe
PubMed: 35557018
DOI: 10.1111/pcn.13375 -
CMAJ : Canadian Medical Association... Dec 2023
Topics: Humans; Frontotemporal Dementia; Diagnosis, Differential
PubMed: 38081627
DOI: 10.1503/cmaj.230407