Frontotemporal lobar degeneration—a coming of age

Abstract

Frontotemporal lobar degeneration (FTLD) Wrst made its mark in 1892 with initial descriptions by Arnold Pick on the clinical features of six patients with behavioural disorder and language problems, a syndrome which he called amnestic aphasia [20]. Pick also emphasised the focal nature of the macroscopic atrophy, which involved particularly the temporal lobes. Post-mortem brain examination of such patients did not occur until 1911, when Alzheimer noted the absence of senile plaques and neuroWbrillary tangles but revealed the curious presence of swollen or ballooned neurones and rounded, argyrophilic, intraneuronal inclusion bodies within the cerebral cortex and hippocampus [1]—a histopathological picture quite distinct from that of Alzheimer’s disease, for which the Wrst pathological description had itself been given only 4 years earlier. Just as Pick had entitled Alzheimer’s descriptions of plaques and tangles, ‘Alzheimer’s disease’, Onari and Spatz [19] later designated Pick’s cases as ‘Picks disease’, and the swollen cells became known as Pick cells, and the inclusion bodies, Pick bodies. However, what in pathological terms constituted Pick’s disease became increasingly unclear in following years, and all cases of frontotemporal atrophy were to become designated in such a manner, even when the pathognomonic Pick bodies and Pick cells were absent. This broader view of ‘Pick’s disease’ was strengthened by Constantinidis et al. [6], in which the disorder was grouped into three categories, depending on the appearance of the neuropathological changes. Group A cases were ‘classic’ with Pick bodies and Pick cells. Group B cases were associated with cortical atrophy and swollen cells, and probably today diagnosed as corticobasal degeneration. Group C cases had neither of these features, and might now be viewed as progressive subcortical gliosis. DiYculties in distinguishing and classifying histologic subtypes of FTLD paradoxically led to an increasing focus on the deWnition of the clinical symptoms. In 1994, the Manchester–Lund criteria for frontotemporal dementia [4] provided descriptions of the characteristic clinical features, which led to improved recognition of cases, and the realization that FTLD was a relatively common disorder among younger persons with dementia. The Lund–Manchester criteria were further reWned in 1998 by Neary et al. [16], which provided clinical descriptions of the three common presentations of FTLD: frontotemporal dementia (FTD) a social conduct disorder with disinhibition, progressive nonXuent aphasia (PNFA), and semantic dementia (SD) a Xuent aphasia with impairment of semantic verbal memory. Nonetheless, while our understanding of the clinical syndromes underlying FTLD was advancing, in pathogenetic terms, FTLD largely remained on the shelf of pathological curiosities, compared to its more illustrious ‘cousin’, Alzheimer’s disease where major advances in the biology for the major pathological proteins, -amyloid and tau, were being made. This remained so until geneticists, buoyed up by the successful identiWcation of mutations in the amyloid precursor protein (APP) [10] and presenilin (PSEN) [5] genes responsible for early onset familial Alzheimer’s disease, turned their attentions to certain other families with early onset of dementia. Some of these families had in fact been thought to have suVered from Alzheimer’s disease, and had caused some degree of consternation when D. Mann (&) Greater Manchester Neuroscience Center, University of Manchester, Stott Lane, Salford, M6 8HD, UK e-mail: david.mann@man.ac.uk