Frontotemporal Dementias: A Clinicopathologic Approach To a Heterogeneous Syndrome
Abstract & Commentary
By Claire Henchcliffe, MD, DPhil Dr. Henchcliffe is Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.
Synopsis: Although the tau negative and positive histologies are predicted to some extent by the clinical onset, the extent of the overlap and the convergence of the syndromes in the course of the disease argue in favor of maintaining the clinical and pathological varieties under a single umbrella.
Source: Kertesz A, et al. The Evolution and Pathology of Frontotemporal Dementia. Brain. 2005;128:1996-2005.
This clinicopathologic study prospectively characterized 60 patients referred to a cognitive neurology clinic between 1990 and 2004, for frontotemporal dementia (FTD)/Pick complex. All 60 were followed to autopsy. Upon initial referral, detailed clinical, neuropsychological, and neuroimaging (MRI or CT and SPECT) evaluation were performed. Individuals were then divided into 4 clinical syndromes based on initial presentation by history. Subgroups comprised: behavioral variant of FTD (FTD-bv) (n = 32), primary progressive aphasia (PPA) (n = 22), corticobasal degeneration syndrome (CBD) (n = 4), and progressive supranuclear palsy (PSP) (n = 2). To establish progression patterns, subjects were clinically reevaluated at approximately yearly intervals. Kertesz and colleagues demonstrate differences in progression between subject groups. For example, those presenting with FTD-bv commonly progressed to progressive aphasia (PA) (20/32), whereas very few developed other syndromes, such as motor neuron disease (MND) (2/32). Twelve of this same group then developed a third syndrome (CBD in 7, MND in 3, PA in 2). In contrast, of 22 presenting with PPA, only 12 developed a second syndrome (FTD-bv in 7; CBD/PSP in 5), and only 7 of those progressed to a third syndrome (CBD/PSP in 4; FTD-bv in 3) prior to death. All 4 patients presenting initially with CBD went on to develop PA, and 2 had features of FTD-bv.
Autopsy findings in brain were heterogeneous, including motor neuron disease type inclusions (MNDI) (n = 18), corticobasal degeneration (CBD) (n = 12), Alzheimer pathology (n = 10), Pick's disease (n = 6), dementia lacking distinctive histology (DLDH) (n = 6), PSP (n = 3), or 5 other (of which 1 had Binswanger's disease, and 1 had Gerstmann-Straussler-Scheinker pathology). Of 18 subjects with MNDI pathology, FTD-bv was the most common presentation (n = 14). PPA was the most common presenting syndrome (n = 5) in the 12 with CBD histological changes, followed by FTD-bv (n = 4). Among those with Alzheimer or other pathologies, the most common presenting syndrome was PPA. The cohort was further divided into those with pathological tau deposition (CBD, PSP, Pick body) termed tau positive (n = 21), and those without (MNDI, DLDH) termed tau negative (n = 24). FTD-bv as the presenting syndrome was common among those with tau-negative pathology, while PPA was highly associated with tau-positive pathology.
Commentary
Pick's disease, or frontotemporal lobar degeneration, was first described in 1892, by Arnold Pick, who focused on clinical features of progressive aphasia, behavior change and apraxia, along with frontotemporal atrophy. FTD is a common cause for dementia before the age of 65, and constitutes about 5% of all irreversible dementias. It is associated with a variety of pathologic processes, which may be interrelated, and abnormal tau deposition has been implicated in many. Kertesz et al have consistently argued that FTD, PPA, and CBD exist on a clinical and pathologic spectrum. Interpretation of the present study is subject to referral bias to a highly specialized clinic, but there are several major findings that extend previous descriptions. First, differences in progression are predicted to some extent by the clinical onset. Second, despite the existence of clinically distinguishable syndromes at presentation, as the disease evolves, there is significant phenotypic overlap. Third, associated pathology is heterogeneous, but there appears to be a major divide between those with tau negative vs tau positive pathology, suggesting that certain clinical features correlate with abnormally phosphorylated tau protein within neuronal cytoplasmic inclusions or glia. Such apparent pathologic heterogeneity may reflect limitations of the traditional means of disease classification, and, as Kertesz et al suggest, it is appropriate at present to consider these syndromes "under a single umbrella." However, with the advent of more sophisticated technologies allowing biochemical studies, structural, functional, and molecular imaging using novel tracers, it may be possible to more accurately classify patients at an early disease stage. This is important if we are to address how to study these heterogeneous diseases in clinical trials, and how to treat and advise patients with such potentially devastating disease.
References
1. Okamura N, et al. A Novel Imaging Probe for In Vivo Detection of Neuritic and Diffuse Amyloid Plaques in the Brain. J Mol Neurosci. 2004;24:247-255.
Although the tau negative and positive histologies are predicted to some extent by the clinical onset, the extent of the overlap and the convergence of the syndromes in the course of the disease argue in favor of maintaining the clinical and pathological varieties under a single umbrella.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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