Accuracy of clinical diagnosis of
dementia is increasingly important for therapeutic and scientific investigations. In this study, we examine diagnostic accuracy in a consecutive series of 228 patients referred to a specialist early-onset
dementia clinic, whose brains were subsequently examined at post-mortem. Diagnosis was based on structured history, neurological examination and neuropsychological assessment, with emphasis on qualitative as well as quantitative aspects of performance. Neuroimaging provided support for but did not alter the clinical diagnosis. We set out the principles that guided diagnosis: (i) time course of illness; (ii) weighting of physical, behavioural and
cognitive symptoms and signs; (iii) 'anterior' versus 'posterior' hemisphere character of cognitive change; and (iv) specificity of deficit, paying attention to the differentiation between syndromes of
frontotemporal lobar degeneration and focal forms of
Alzheimer's disease. Forty-two per cent of the patients had clinical diagnoses of one of the syndromes of
frontotemporal lobar degeneration, the high proportion reflecting the research interests of the group. Forty-six per cent were diagnosed with
Alzheimer's disease and the remaining patients,
dementia with Lewy bodies,
Creutzfeldt-Jakob disease, vascular or unclassified
dementia.
Frontotemporal lobar degeneration was identified with 100% sensitivity and 97% specificity and
Alzheimer's disease with 97% sensitivity and 100% specificity. Patients with other pathologies were accurately identified on clinical grounds. Examination of subsyndromes of
frontotemporal lobar degeneration showed a relatively predictable relationship between clinical diagnosis and pathological subtype. Whereas the behavioural disorder of
frontotemporal dementia was associated with tau, transactive response
DNA binding protein 43 and fused-in-
sarcoma pathology, cases of
frontotemporal dementia with motoneuron disease,
semantic dementia and, with one exception, progressive non-
fluent aphasia were associated with transactive response
DNA binding protein 43 pathology, distinguished by
ubiquitin subtyping (types B, C and A, respectively). Clinical diagnoses of progressive
apraxia,
corticobasal degeneration and
progressive supranuclear palsy were, with one exception, associated with Pick, corticobasal and
progressive supranuclear palsy subtypes of tau pathology, respectively. Unanticipated findings included Alzheimer pathology in two patients presenting with the behavioural syndrome of
frontotemporal dementia and corticobasal pathology in four others with clinical
frontotemporal dementia. Notwithstanding such anomalies, which serve as a reminder that there is not an absolute concordance between clinical phenotype and underlying pathology, the findings show that
dementias can be distinguished in life with a high level of accuracy. Moreover, careful clinical phenotyping allows prediction of histopathological subtype of
frontotemporal lobar degeneration. The principles guiding diagnosis provide the foundation for future prospective studies.