Structural MRI studies in FTD

Regional atrophy detected with magnetic resonance imaging (MRI) can be considered as a biological marker of degenerative diseases. In AD, accurate volumetric measurements have indicated that atrophy in the medial temporal lobe can be detected early in the disease course and this has been proposed as being a diagnostic indicator (Jack et al., 1992). On the contrary, atrophy in the frontal and temporal lobes in FTD is a more controversial diagnostic marker for many reasons. First, different studies have

provided contrasting results. Some have found frontal and asymmetrical atrophy in FTD patients (Miller et al., 1999; Duara et al., 1999) while others could not find any evidence for frontal and temporal atrophy in small series of typical and very early FTD patients (Hokoishi et al., 1999; Gregory et al., 1999). Second, most studies either did not compare atrophy in FTD patients to that of controls or other types of dementia (Miller et al., 1999; Gregory et al., 1999), or else gave only visual subjective ratings of the extent of atrophy (Miller et al., 1999; Gregory et al., 1999; Larsson et al., 2000). Unexpected results derived from the comparison of very typical ROIs that might separate different conditions such as AD and FTD: the volumes of hippocampus and entorhinal cortex in AD and FTD were measured, but these volumes had good discriminative power only for AD versus controls (Frisoni et al., 1999). The failure of this strategy, that was aimed at measuring structures considered to be severely involved in AD and not crucially damaged in FTD, suggested that a pattern of atrophy in different regions, rather than the amount of atrophy in a single region, could be more informative in the differential diagnostic process. The first authors who used the “pattern” approach to characterize different diseases successfully separated dementia with Lewy body (DLB), AD, and vascular dementia (Barber et al., 2000), and postmortem volumes of progressive supranuclear palsy (PSP), Parkinson's disease (PD) and DLB (Cordato et al., 2000). In the first study, MRI scans were quantitatively compared indicating a different distribution of atrophy through the ventricles, frontal and temporal lobes, hippocampus and amygdala. The relative preservation of frontal lobes was constant in the three diagnostic conditions, which were separated mainly by the medial temporal volumes, that showed severe atrophy in AD, a tendency towards atrophy in vascular disease and very mild involvement in dementia with Lewy Bodies. In the second study, postmortem measures were taken from whole gray and white matter, lobar cortices, medial temporal structures, basal ganglia and thalamus, and indicated very severe involvement of globus pallidus and amygdala in PSP, and, to a lesser degree, of frontal and parietal cortices.

Together with the finding of relative preservation of hippocampus, the whole pattern helped distinguish PSP from DLB, where this structure was involved, while the globus pallidus was not affected. The whole pattern was, again, distinct in PD, where only the medial temporal structures, and particularly the amygdala, revealed significant atrophy (Table 1).

Table 1. Brain volumes in different kinds of dementia.

Volumes at MRI

DLB AD VaD Volumes at autopsy PSP PD DLB Whole brain n.s ↓ ↓ Whole gray matter ↓ n.s. n.s.

Ventricles ↑ ↑ ↑ Internal globus

pallidus ↓↓ n.s. n.s.

Frontal cortex

n.s n.s n.s Frontal cortex ↓↓ n.s. ↓↓

Temporal cortex

↓ ↓ ↓ Parietal cortex ↓ n.s. n.s.

Hippocampus ↓ ↓↓ ↓ Hippocampus ↓ n.s. ↓↓

Amygdala n.s ↓↓ ↓ Amygdala ↓↓ ↓↓ ↓

Modified from Barber et al., 2000 and from Cordato et al., 2000

These works suggested that the pattern of atrophy might be more informative and discriminative between the different diseases and be superior to the single region approach, since atrophy of single regions may overlap in the different diagnostic groups.

Some authors have studied the pattern of atrophy in FTD patients but have not investigated its discriminative power from other types of dementia (Fukui and Kertesz, 2000; Kitagaki et al., 1998) and others claimed that they could not obtain a good discriminative power (Frisoni et al., 1999). MRI-based measures of lobar volumes of FTD, primary progressive aphasia and AD patients were compared, and the right and left frontal volumes provided a correct classification of 93% of FTD and primary progressive aphasia patients, but specificity versus AD patients was not reported (Fukui and Kertesz, 2000).

Table 2: MR Imaging morphometric studies on FTD.

Author Year of

publication

Structure of interest Method of analysis Atrophic structures Other studied characteristics

Williams et al. 2005 whole GM VBM anterior temporal lobes

ROI tracing (correlation study) Agreeableness

McMillan et al. 2004 Whole GM VBM Left temporal lobe Confrontation naming

Simons et al. 2002 hippocampus ROI tracing hippocampus Recollection based memory

Rosen et al. 2002b PFC, OFC, ATC, amygdala ROI tracing ATC, amygdala, OFC Emotion comprehension

Rosen et al. 2002a Whole GM VBM Anterior Cingulate, OFC, anterior

insula

-

Chan et al. 2001 Whole GM BBSI PFC Rate of atrophy

Fukui et al. 2000 Lobes and basal ganglia Semiautomated ROI

segmentation Frontal lobe Neuropsychological functions Laakso et al. 2000 Hippocampus, entorhinal

cortex Manual ROI tacing Anterior hippocampus, entorhinal

cortex Topographic distribution of

atrophy within the atrophic structure

Frisoni et al. 1999 Hippocampus and entorhinal cortex

Manual ROI tracing Hippocampus, entorhinal cortex - Kitagaki et al. 1998 Whole cortical surface Automated ROI

segmentation PFC, AT, and whole cortex Asymmetry of atrophy Kaufer et al. 1997 Corpus callosum and

pericallosum regions Semiautomated ROI

tracing Anterior corpus callosum MMSE

Overall, imaging studies on FTD have the main gap of focusing attention on single regions of interest that turn out to be of little help in discriminative diagnosis and pathogenesis comprehension, with few exceptions. These exceptions, on the other hand, did not investigate the discriminative power of such findings in the differential diagnosis with other kinds of dementias, mainly AD. As well, the comprehension of the pathogenesis of FTD and the origin of its symptoms is far from exhaustive. Finalized researches seeking the origins of individual symptoms, or of the whole syndrome, are lacking in the literature.

As well, other minor aspects were disregarded or corresponded to contrasting results.

For example, the distribution of atrophy among the right and left hemispheres was variably described in different studies, that analyzed different samples or used different techniques (i.e. volumes or perfusion). Another aspect is the representation of the ε4 allele of APOE: among the contrasting results about the allelic frequency, studies investigating its role in the clinical or morphological expression of the disease are lacking.