Functional compensation in incipient Alzheimer's disease

Abstract

Aim of this study was to investigate the functional compensation mechanism in incipient Alzheimer's disease (AD). Seventeen elderly healthy subjects and nine amnestic MCI patients with incipient AD underwent brain MR scan and 99mTc ECD SPECT. We processed all images with SPM2, we created t maps, showing the wholebrain GM atrophy and functional changes, and we properly masked them with each other in order to assess relatively preserved perfusion or depression. Incipient AD showed GM atrophy in the medial temporal and temporoparietal lobes, in the insula and in the retrosplenial cortex, and GM hypoperfusion in the medial temporal and temporoparietal lobes. Relatively preserved perfusion, we could hypothesize to be compensatory in the setting of neuronal loss, was found in the posterior cingulate, in the head of the hippocampus, in the amigdala, and in the insula bilaterally, while functional depression occurred in bilateral parahippocampal gyri. In AD, a perfusional compensatory mechanism takes place in the neocortex, while perfusional depression occurs in the medial temporal lobe. These results help understand the reactive phenomena induced by the brain to try and counteract the pathological changes of AD.

Introduction

Mild cognitive impairment (MCI) is a clinical syndrome characterized by cognitive deficits without functional impact on daily living, and thus not severe enough to allow a diagnosis of dementia (Petersen et al., 1999). MCI has often been considered a preclinical stage of Alzheimer Dementia (AD), converting to dementia in the frequency of 10–15% per year (Petersen et al., 2001) vs. 2% per year of cognitively intact persons (Petersen et al., 1999, Flicker et al., 1991). The relevant clinical issue is to identify MCI patients who will progress to AD from those who will not. An accurate study of MCI patients with preclinical AD could help in better understanding AD pathology, and would make it possible to implement strategies to prevent or delay dementia, given that early therapeutical interventions are more likely to be effective.

Alzheimer's disease is associated with widespread structural and functional brain alterations. Both profiles of alterations have been well documented, with consistent regional distribution of atrophy (Baron et al., 2001, Frisoni et al., 2002, Good et al., 2002, Matsuda et al., 2002a, Karas et al., 2003) and hypoperfusion/hypometabolism (Minoshima et al., 1997, Anchisi et al., 2005, Drzezga et al., 2003, Drzezga et al., 2005, Chételat et al., 2003) across studies.

As in AD, already at the early stage, the atrophy and functional alteration patterns partially overlap and partially do not (Matsuda et al., 2002a), it would be interesting to investigate the existing relationship between the two processes with a special focus on the regions affected by AD neuropathology, in order to see whether the GM tissue loss is the only responsible for functional reduction, and whether the partial divergence between the two patterns either is due to co-registration and partial volume effect problems of SPECT/PET techniques or rather it reflects an existing difference between the two processes. Several SPECT/PET studies have already investigated atrophy and hypoperfusion or hypometabolism. Some PET or SPECT studies, after applying partial volume effect (PVE) correction, concluded that gray matter loss did not entirely explain the observed hypometabolism (Ibanez et al., 1998, De Santi et al., 2001, Nestor et al., 2003, Mosconi et al., 2005, Matsuda et al., 2002b), and few studies assessed both the structural and functional wholebrain alteration profiles in the same patients (De Santi et al., 2001, Matsuda et al., 2002a, Ishii et al., 2005, Mosconi et al., 2006, Kawachi et al., 2006, Caroli et al., 2007b). However, none of the previous studies assessed the relative degree of wholebrain GM atrophy and functional changes.

Aim of this study was thus to compare on a voxel-by-voxel basis GM atrophy and functional reduction (assessed in terms of cerebral perfusion deficits) in incipient AD, using a method specifically designed for this purpose, in order to investigate the functional compensation mechanism in the regions affected by AD neuropathology.