Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD) in the FTD spectrum

Abstract

Purpose: 'Phenocopy' frontotemporal dementia (phFTD) patients may clinically mimic the behavioral variant of FTD (bvFTD), but do not show functional decline or abnormalities upon visual inspection of routine neuroimaging. We aimed to identify abnormalities in gray matter (GM) volume and perfusion in phFTD and to assess whether phFTD belongs to the FTD spectrum. We compared phFTD patients with both healthy controls and bvFTD patients.

Materials & methods: Seven phFTD and 11 bvFTD patients, and 20 age-matched controls underwent structural T1-weighted magnetic resonance imaging (MRI) and 3D pseudo-continuous arterial spin labeling (pCASL) at 3T. Normalized GM (nGM) volumes and perfusion, corrected for partial volume effects, were quantified regionally as well as in the entire supratentorial cortex, and compared between groups taking into account potential confounding effects of gender and scanner.

Results: PhFTD patients showed cortical atrophy, most prominently in the right temporal lobe. Apart from this regional atrophy, GM volume was generally not different from either controls or from bvFTD. BvFTD however showed extensive frontotemporal atrophy. Perfusion was increased in the left prefrontal cortex compared to bvFTD and to a lesser extent to controls.

Conclusion: PhFTD and bvFTD show overlapping cortical structural abnormalities indicating a continuum of changes especially in the frontotemporal regions. Together with functional changes suggestive of a compensatory response to incipient pathology in the left prefrontal regions, these findings are the first to support a possible neuropathological etiology of phFTD and suggest that phFTD may be a neurodegenerative disease on the FTD spectrum.

Keywords: Arterial spin labeling-MRI; Behavioral variant frontotemporal dementia; Cerebral blood flow; Gray matter volume; Phenocopy frontotemporal dementia.

Fig. 1

Schematic overview of cortical regions showing (A) normalized GM volume and (B) perfusion abnormalities. Panel 1A shows in red regional nGM atrophy present in both phFTD and bvFTD; in blue regional nGM volume loss in bvFTD compared to both phFTD and controls; and in yellow regional nGM volume loss in in bvFTD when compared to controls, but not compared to phFTD. Panel 1B shows in cyan hyperperfusion in phFTD compared to bvFTD in regions that show hypoperfusion in bvFTD compared to controls; in green regional hyperperfusion in phFTD compared to both bvFTD and controls; and in violet regional hyperperfusion in phFTD compared to bvFTD. HC = healthy controls; phFTD = phenocopy frontotemporal dementia; bvFTD = behavioral variant frontotemporal dementia; nGM = normalized gray matter. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

A) normalized GM (% ICV) and B) CBF (ml/100 g GM/min) in the different lobes for healthy controls (HC), phFTD (PH) and bvFTD (BV) patients. The central box represents values from lower to upper quartile (25-75th percentile), the middle line represents the median, and vertical bars extend from minimum to maximum value. Spheres outside the bars indicate extreme values (value ≥ 1.5 × interquartile range). Note that GM volumes in phFTD are generally in-between those of HC and bvFTD, and that perfusion in phFTD is generally higher than in bvFTD and controls. HC = healthy controls; phFTD = phenocopy frontotemporal dementia; bvFTD = behavioral variant frontotemporal dementia; nGM = normalized gray matter; ICV = intracranial volume; CBF = cerebral blood flow.