Decline of cerebral glucose metabolism in frontotemporal dementia: a longitudinal 18F-FDG-PET-study

Abstract

Objective

To identify the pattern of progression of decline of cerebral glucose metabolism in frontotemporal dementia (FTD, frontal variant).

Methods

22 patients with mild FTD underwent 18F-FDG-positron emission tomography at baseline and at follow-up in average 19.5 months later. Patient scans were compared with scans from 15 healthy age-matched control subjects on a voxel-by-voxel basis using SPM-99.

Results

As compared with healthy control subjects at baseline patients with FTD showed a significant symmetrical hypometabolism of the frontal lobes sparing the motor cortex, of the caudate nuclei, insula and thalamus bilaterally. At follow-up further significant reductions in glucose metabolism were observed in the parietal and temporal cortices.

Conclusions

In early stages of FTD the neurodegenerative process is limited to the frontal lobes. During the progression of the disease, the pathological changes pass over the lobar borders and spread into the parietal and temporal cortices.

Introduction

Frontotemporal lobar degenerations (FTLD) are relatively common causes of dementia, accounting for at least 20% of presenile cases [32]. FTLD is characterized by the progressive loss of cerebral tissue primarily in the frontal and anterior temporal lobes. The clinical presentation is determined by the localization of the neurodegenerative process. Diagnostic criteria for FTLD [27] differentiate three clinical syndromes: (1) Frontotemporal dementia (FTD), which is caused by cerebral atrophy that particularly involves the frontal lobe. Due to the focus of brain atrophy in the frontal lobes, some authors call FTD “frontal variant of FTD” [18]. (2) Semantic dementia (SD), also termed “temporal variant of FTD”, is associated with brain atrophy predominantly in the anterior temporal lobes. (3) The syndrome of primary progressive aphasia (PPA) is characterized by an accentuated asymmetric involvement of frontotemporal, perisylvian cortical areas on the dominant, language-relevant hemisphere.

FTD is the most frequent of the three clinical syndromes of FTLD [23]. The clinical picture is dominated by early and progressive changes in personality and social conduct, characterized by apathy and loss of volition. Patients may become socially disinhibited and easily distracted [27]. They typically develop emotional blunting with a reduced ability to display and recognize social emotions. Loss of insight in their own condition is a universal symptom. Overeating, altered food preference, wandering, and involuntary utilization of objects behavior as well as stereotyped motor and verbal behavior may also occur [33]. Although changes in personality and social conduct are paramount symptoms of FTD, deterioration of cognitive ability must not be overlooked. In particular, memory impairment and language problems invariably occur [18]. With progression of the disease, there is a reduction of verbal output, most patients show deficits in word finding and verbal fluency. Gradually, spontaneous speech converts into repetitious, echolalic and stereotyped utterances, until finally most patients become entirely mute [8], [27], [34]. FTD is a progressive and highly malignant disorder. The median survival from symptom onset is 6 ± 1.1 years [17].

Brain imaging has become an increasingly useful tool in the study of FTLD. Several studies using magnetic resonance imaging (MRI) have demonstrated frontal lobe atrophy in FTD [4], [12], [26], [30]. In addition, studies have been conducted with PET to examine changes of cerebral glucose metabolism in FTLD [7], [13], [20], [22], [31].

Serial imaging of patients allows to demonstrate the progression of a neurodegenerative process, as has been shown in various studies in Alzheimer's disease (AD) [11], [21]. Longitudinal studies using MRI have been carried out to detect and quantify the pattern and rates of change of structural alterations in FTD [4], [24], [35]. However, with the exception of one case report [25] and work of our group [14], there are no follow-up studies in FTD that take advantage of PET. Using abnormalities of metabolic activity as a marker [15] this technique can identify neurodegenerative processes before atrophy becomes apparent on structural imaging. There is broad consensus on the potential of PET for accurate and early diagnosis, for monitoring disease progression, and for an enhanced understanding of the pathophysiological basis of neurodegenerative diseases.

The aim of this study was to determine the progression of changes in cerebral glucose metabolism in FTD in a follow-up study using 18F-fluoro-2-desoxy-d-glucose positron emission tomography scanning (18F-FDG-PET) and to examine the sequential involvement of cortical and subcortical structures. We investigated cross-sectional and longitudinal reductions in regional cerebral glucose metabolism of 22 patients with mild FTD and sought to identify specific brain regions showing maximal decline. We applied a voxel-based approach using Statistical Parametric Mapping, SPM 99 (Wellcome Department of Cognitive Neurology, London, UK), which allows automated measurement of reduction of cerebral glucose metabolism.