Towards a nosology for frontotemporal lobar degenerations—A meta-analysis involving 267 subjects

Abstract

Frontotemporal lobar degeneration is the second most common diagnosis of dementia in individuals younger than 65 years. We conducted a systematic and quantitative meta-analysis to examine neural correlates of frontotemporal lobar degeneration and its subtypes and to place the disease in a framework of cognitive neuropsychiatry. MedLine and Current Contents search engines were used to identify functional and anatomical imaging studies investigating frontotemporal lobar degeneration between 1980 and 2005. Studies were included, if they were peer-reviewed, applied internationally recognized diagnostic criteria, were original studies, and had results normalized to a stereotactic space. 19 studies were identified reporting either atrophy or decreases in glucose utilization. Finally, the analysis involved 267 subjects suffering from frontotemporal lobar degeneration and 351 control subjects. A quantitative meta-analysis was performed. Maxima of the studies resulted in activation likelihood estimates. The meta-analysis revealed specific neural networks for each of the three clinically defined subtypes of frontotemporal lobar degeneration, namely frontotemporal dementia, semantic dementia, and progressive non-fluent aphasia. Networks did not overlap as shown by a conjunction analysis, and they corresponded to clinical characteristics. The study relates the clinical features of each subtype of frontotemporal lobar degeneration specifically to its neural substrate. By ‘triple dissociating’ frontotemporal lobar degenerations into three clinicoanatomical prototypes, the study contributes to placing these disorders in cognitive neuropsychiatry and suggests a respective nosology.

Introduction

Recent studies suggest that frontotemporal lobar degeneration (FTLD) is the second most common diagnosis of dementia in individuals younger than 65 years (Johnson et al., 2005). Although the size of FTLD cohorts is modest at any one center, the recent establishment of consensus criteria for FTLD (Clinical and Neuropathological Criteria for Frontotemporal Dementia by the Lund and Manchester groups, 1994, Neary et al., 1998) represents an opportunity to begin large-scale studies. These criteria (Neary et al., 1998) divide FTLD into three major subgroups: frontotemporal dementia (FTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). FTD is characterized by alterations in behavior and personality, namely by decline in social interpersonal conduct, impairment in regulation of personal conduct, emotional blunting, and loss of insight. Patients meet the criteria for SD if they exhibit a language disorder characterized by the following: empty fluent speech, loss of word meaning, or semantic paraphasias, a perceptual disorder characterized by impaired recognition of familiar faces or object identity, preserved perceptual matching and drawing reproduction, preserved single-word repetition, and preserved ability to read aloud and write to dictation orthographically regular words. Finally, patients meet the criteria for PNFA if they have non-fluent spontaneous speech with at least one of the following: agrammatism, phonemic paraphasias, or anomia. Behavioral changes are almost absent. Besides the clinical criteria, neuropsychological and brain imaging criteria have been proposed by Neary et al. (1998). According to these criteria, FTD is characterized by bilateral impairment in the (pre-) frontal and anterior temporal brain regions, PNFA by mainly left-sided alterations in the same areas, and SD by changes in the anterior temporal lobe greater on the left than on the right side.

The clinical criteria for FTLD represent a first step toward understanding neurodegenerative disorders that affect the frontal and temporal lobes. However, neural deficits seem to overlap in the different subtypes of FTLD (Neary et al., 1998). Accordingly, one aim of our study was to analyze neural substrates of FTLD and its subtypes and to investigate their specificity in particular. Because FTLD subtypes can be clinically dissociated (Neary et al., 1998), we also hypothesized a dissociation of the neural networks involved. Moreover, we wanted to contribute to a cognitive neuropsychiatry of FTLD by relating clinical deficits to their neural substrates (Halligan and David, 2001) as previously shown for one subtype, namely FTD (Schroeter et al., 2007). Because recently introduced diagnostic criteria enable comparisons of cohorts from different centers (Clinical and Neuropathological Criteria for Frontotemporal Dementia by the Lund and Manchester groups, 1994, Neary et al., 1998), we applied a systematic meta-analytic approach. The meta-analysis included morphometric studies investigating brain atrophy with magnetic resonance imaging (MRI) and functional imaging studies measuring reduction in glucose utilization by (¹⁸F) fluorodeoxyglucose positron emission tomography (FDG-PET). We chose the method developed by Turkeltaub et al. (2002), since it enables a quantitative meta-analytic approach, is considered as the most sophisticated and well-validated of coordinate-based voxel-wise meta-analyses (Fox et al., 2005), and has been recently introduced to studies on morphometry and glucose utilization (Schroeter et al., 2007).