What Is Frontotemporal Lobar Degeneration? New Clues Emerge

Abstract and Commentary

By Cary S. Gunther, MD, PhD and Michael Lin, MD. Dr. Gunther is a Clinical Fellow in Behavioral Neurology, Weill Cornell Medical College; Dr. Lin is Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Lin and Dr. Gunther report no financial relationships relevant to this field of study.

Synopsis: Two studies have identified a novel inclusion found in a subset of FTLD brains and categorize the clinical entity of the behavioral variant of FTLD, based on anatomical patterns.

Sources: Neumann M, Rademakers R, Roeber S, et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 2009;132:2922-2931. Whitwell JL, Przybelski SA, Weigand SD, et al. Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: A cluster analysis study. Brain 2009;132:2932-2946.

A pair of studies published in a recent issue of Brain attempt to further elucidate definitions and underlying pathology of frontotemporal lobar degeneration (FTLD). Neumann and colleagues identified a new pathologic subtype of FTLD. They showed that the fused in sarcoma (FUS) protein, recently identified in inclusions in familial amyotrophic lateral sclerosis, is present in FTLD cases which are negative for tau- or TDP-43 but positive for ubiquitin. FUS is normally present in most cell types, and appears to be a transcriptional activator that is involved in RNA-protein binding. It is similar in this regard to TDP-43. FUS putatively acts to transport mRNA to dendrites for local translation, thus promoting plasticity and integrity of synapses. The authors identified 15 sporadic early-onset (mean age = 38) FTLD cases, and found FUS immunoreactivity in cytoplasmic inclusions and novel intranuclear inclusions. The FUS inclusions were most numerous in hippocampal dentate fascia and were also significantly present in frontal and temporal neocortex and striatum. FUS co-localized with ubiquitin in the neuronal inclusions. FUS antibodies also stained previously undescribed glial inclusions not seen with ubiquitin staining alone. No mutation in the FUS gene was found in any of the cases. Except for brains from patients with Huntington's disease, the controls, including brains with other neurodegenerative diseases, did not show FUS inclusions, strongly associating this pathological process with an FTLD phenotype.

Whitwell et al examined the neuroanatomy of patients presenting with behavioral variant FTLD (bvFTLD). They used volumetric MRI to compare patterns of grey matter loss in 66 bvFTLD subjects against a digital atlas. Clustering the results yielded four anatomical subtypes: frontal dominant, frontotemporal, temporal dominant, and temporofrontoparietal. Interestingly, although the degree of temporal lobe atrophy observed in some cases is atypical for bvFTLD, in the temporal dominant and frontotemporal subtypes the temporal atrophy was slightly right hemisphere dominant, a distribution previously associated with behavioral presentations of FTLD. Among the four subtypes, significant differences occurred in tests of delayed recall and naming, with temporal dominant patients performing worst and frontal dominant patients performing best. There was a trend towards poorer performance on tests of executive function in frontal dominant and frontotemporal subtypes. No significant differences were measured in visuospatial abilities. Little variation occurred in the severity of behavioral disturbance or type of aberrant behaviours. Autopsy data were available for 25 of the subjects, but not uniformly distributed across the four groups. Pathological and clinical evidence of motor neuron disease was present in three subjects in frontal dominant group, while Pick's disease and progressive supranuclear palsy were present in frontotemporal and frontal dominant groups. All subjects with Alzheimer's disease pathology occurred in the temporofrontoparietal or frontal dominant groups; corticobasal and FTD-TDP-43 pathology were also seen in the temporofrontoparietal group.

Commentary

Neumann and colleagues point out similarities between roles and structures of FUS and TDP-43 as supportive of a putative FUS role in disease. Co-localization with ubiquitin in pathological inclusions strengthens this hypothesis. However, this preliminary evidence falls short of demonstrating a causal role of FUS in FTLD. The authors note that future directions include looking for an FUS role in other TDP-43-negative ubiquitin inclusion diseases. If therapeutics are to be developed based on FUS, it will be important to elucidate the mechanism by which its solubility is altered and how this might affect neuronal function or survival.

Whitwell and team used neuroimaging to identify four anatomical subtypes of FTLD, then sought clinical and pathological correlates to these subdivisions. The clinical syndrome of FTLD is known to be associated with variable pathology, most commonly with abnormal accumulations of TDP-43 or tau, but sometimes with AD pathology. So it stands to reason that FTLD is heterogeneous in other ways as well. Distinctions within the FTLD syndrome begin to come to light in this study, as the authors observed differences in age of onset (with the youngest onset in temporal dominant subset) and distribution of cellular pathologies across subtypes. The sample size for this study was too small to draw statistical conclusions, and longitudinal data are needed to establish whether patients with these patterns of atrophy at presentation follow divergent clinical trajectories. But this research paves the way for further clarification of FTLD into cohorts in which internally consistent disorders may occur. Ultimately, the anatomical distribution of neuronal and synaptic destruction or dysfunction produces a given phenotype, and the patterns seem associated with underlying molecular mechanisms.