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.

We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E ε4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.Isolated speech and language difficulties are often the first symptoms of focal forms of neurodegenerative diseases, particularly frontotemporal lobar degeneration (FTLD) and corticobasal degeneration (CBD). 1,2 Alzheimer's disease (AD) patients also have been shown to present with atypical focal cognitive manifestations, including fluent and nonfluent progressive aphasia. 3-7 When speech and language deficits remain the only complaint for at least 2 years, the term primary progressive aphasia (PPA) has been applied. 8Pathologically, the most frequent finding in PPA is an FTLD-type of damage such as dementia lacking distinctive pathology (DLDH) 9-11 or Pick's disease. 12,13 Cases with AD, 3 Creutzfeldt-Jakob disease, 1,4 and FTLD with motor neuron disease (FTLD-MND) pathology also have been reported 15 (for review, see Mesulam, 16 Grossman, 17 and Black 18 ). Kertesz first included CBD in the FTLD/Pick's spectrum of diseases and recently reported four PPA cases with pathologically proven CBD. 12,19 Address correspondence to Dr Gorno-Tempini, UCSF Memory and Aging Center, 350 Parnassus Avenue, Suite 706, Box 1207. San Francisco, CA 94143. E-mail: marilu@itsa.ucsf.edu. NIH Public Access Author ManuscriptAnn Neurol. Author manuscript; available in PMC 2008 May 1. Published in final edited form as:Ann Neurol. 2004 March ; 55(3): 335-346. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptDifferent clinical presentations of PPA have been reported, but large studies that investigate both cognitive and neuroimaging findings in the same group of patients are still lacking. Here, we consider the clinical variants that have be...

No abstract

Objective-Frontotemporal lobar degeneration (FTLD) is characterized by impairments in social, behavioral, and/or language function, but postmortem studies indicate that multiple neuropathological entities lead to FTLD. This study assessed whether specific clinical features predict the underlying pathology.Methods-A clinicopathological correlation was performed on 90 consecutive patients with a pathological diagnosis of frontotemporal dementia and was compared with an additional 24 cases accrued during the same time period with a clinical diagnosis of FTLD, but with pathology not typically associated with frontotemporal dementia.Results-Postmortem examination showed multiple pathologies including tauopathies (46%), FTLD with ubiquitin-positive inclusions (29%), and Alzheimer's disease (17%). The pathological groups manifested some distinct demographic, clinical, and neuropsychological features, although these attributes showed only a statistical association with the underlying pathology. FTLD with ubiquitin-positive inclusions was more likely to present with both social and language dysfunction, and motor neuron disease was more likely to emerge in these patients. Tauopathies were more commonly associated with an extrapyramidal disorder. Alzheimer's disease was associated with relatively greater deficits in memory and executive function.Interpretation-Clinical and neuropsychological features contribute to delineating the spectrum of pathology underlying a patient diagnosed with FTLD, but biomarkers are needed that, together with the clinical phenotype, can predict the underlying neuropathology.Frontotemporal lobar degeneration (FTLD) is characterized clinically by progressive changes in social, behavioral, and/or language function. 1-3 In the frontal or social/dysexecutive variant Address correspondence to Dr Grossman, Department of Neurology, University of Pennsylvania School of Medicine, 3600 Spruce Street, 3 West Gates, Philadelphia, PA 19104-4283. E-mail: mgrossma@mail.med.upenn NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of FTLD, there is an early change in social comportment and personality often associated with disinhibition, apathy, and lack of insight. In contrast, the aphasic variant of FTLD is further classified as either progressive nonfluent aphasia, characterized by effortful speech and phonemic errors, 4 or semantic dementia, manifested by severe problems with naming and understanding word and object meaning. 5 In both the social/dysexecutive and aphasic variants, there is relative preservation of memory, especially in early stages. In addition, some patients with FTLD manifest a motor disorder such as parkinsonism or motor neuron disease (MND). 6,7Multiple neuropathological abnormalities are associated with FTLD, 3,8 and this pathological heterogeneity is reflected in a recent classification scheme from an frontotemporal dementia (FTD) work group that was the first to incorporate both immunohistochemical and biochemical data in the diagnostic algorithm (Fig 1...