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With age, the brain undergoes both structural and functional alterations, probably resulting in reported cognitive declines. Relatively few investigations have sought to identify those areas that remain intact with aging, or undergo the least deterioration, which might underlie cognitive preservations. Our aim here was to establish a comprehensive profile of both structural and functional changes in the aging brain, using up-to-date voxel-based methodology (i.e. optimized voxel-based morphometry (VBM) procedure; resting-state (18)FDG-PET with correction for partial volume effects (PVE)) in 45 optimally healthy subjects aged 20-83 years. Negative and positive correlations between age and both gray matter (GM) volume and (18)FDG uptake were assessed. The frontal cortex manifested the greatest deterioration, both structurally and functionally, whereas the anterior hippocampus, the thalamus and (functionally) the posterior cingulate cortex were the least affected. Our results support the developmental theory which postulates that the first regions to emerge phylogenetically and ontogenetically are the most resistant to age effects, and the last ones the most vulnerable. Furthermore, the lesser affected anterior hippocampal region, together with the lesser functional alteration of the posterior cingulate cortex, appear to mark the parting of the ways between normal aging and Alzheimer's disease, which is characterized by early and prominent deterioration of both structures.

Alzheimer's disease (AD) is characterised by macroscopic cerebral damages which can be studied in vivo with neuroimaging techniques, even at the earliest stage. Studies were conducted in patients with amnestic Mild Cognitive Impairment (MCI) who best represent incipient AD. Right temporo-parietal hypometabolism, assessed by resting-state (18)FDG-PET, distinguishes patients who further develop AD from those who remain stable. From the pre-dementia stage of MCI, atrophy of the hippocampal region detected with structural MRI contrasts with functional alteration of the posterior cingulate gyrus measured with (18)FDG-PET and SPECT. Results from resting-state fMRI confirm this pattern of functional abnormalities and highlight changes in the hippocampal region functional connectivity, decreased with the posterior cingulate region, and increased with some frontal areas. Altogether with a structural connectivity impairment highlighted by DTI, those results support the hypothesis of a dysconnexion between the hippocampal and the posterior cingulate regions. Finally, activation fMRI data support the hypothesis of a functional compensation involving not only the frontal cortex but also, at the pre-dementia stage, the hippocampal region. Thus, this synthesis focuses on the hypotheses of dysconnexion and functional compensation, suggested to explain the discrepancies between the structural and functional alteration patterns, as well as on relevant results from resting-state fMRI, DTI and activation fMRI studies. Furthermore, this synthesis emphasizes the relevance of neuroimaging for the early detection of AD.

We used functional magnetic resonance imaging to determine the cerebral structures required during the recollection of episodic autobiographical memories according to 5 time periods covering the whole lifespan to test the 2 concurring models of memory consolidation, which propose either a temporary (standard model) or a permanent (multiple-trace model) role of the hippocampus in episodic memory retrieval. The experimental paradigm was specially designed to engage subjects (67.17 +/- 5.22 years old) in the retrieval of episodic autobiographical memories, whatever the time period, from personally relevant cues selected by questioning a family member. Moreover, the nature of the memories was checked at debriefing by means of behavioral measures to control the degree of episodicity. Behavioral data showed that recollected memories were characterized by specificity and details whatever their remoteness. Main neuroimaging data (Statistical Parametric Mapping 99) revealed the activation of a network including the left superior frontal gyri, bilateral precuneus/posterior cingulate and lingual gyri, left angular gyrus, and left hippocampus, although the subtraction analyses detected subtle differences between certain time periods. Small volume correction centered on the hippocampus detected left hippocampal activation for all time periods and additional right hippocampal activation for the intermediate periods. Further confirmation was provided by using a 3-way analysis of variance on blood oxygen level-dependent values, which revealed hippocampal activation whatever the time interval. The present data challenge the standard model of memory consolidation and support the multiple-trace model, instead. The comparison with previous literature stresses the idea that a bilateral involvement of the hippocampus characterizes rich episodic autobiographical memory recollection.

Patients suffering from frontal variant of frontotemporal dementia (fv-FTD) undergo autobiographical amnesia encompassing all time periods. We previously demonstrated in a group of 20 fv-FTD patients that this impairment involved deficits in executive function and semantic memory for all periods as well as new episodic learning and behavioural changes for the most recent period covering the last 12 months [Matuszewski, V., Piolino, P., de la Sayette, V., Lalevée, C., Pélerin, A., Dupuy, B., et al. (2006). Retrieval mechanisms for autobiographical memories: Insights from the frontal variant of frontotemporal dementia, Neuropsychologia, 44, 2386-2397]. The aim of the present study was to unravel the neural bases of this impairment by mapping in a subgroup of patients correlations between resting-state brain glucose utilization measured by FDG-PET and measures of autobiographical memory (AM) using the TEMPau task which is designed to gauge personal event recollection across five life time periods. Like in our previous report, the group of patients was impaired regardless of time periods compared to healthy subjects providing generic memories instead of event specific sensory-perceptual-affective details, i.e., episodic memories. New data showed that the patients were also impaired in sense of reliving and self-perspective during retrieval. The cognitivo-metabolic correlations between the AM score and resting normalized FDG-Uptake were computed using statistical parametric mapping (SPM2) and controlling for age and dementia severity. They revealed that AM deficits were mainly subserved by the dysfunction of left-sided orbitofrontal and also temporal neocortical areas whatever the period. Additional analysis showed that specific memories were associated with left orbitofrontal areas whereas generic memories were mainly associated with the left temporal pole. This study supports the view that fv-FTD patients undergo a breakdown of generative processes which relies regardless of the remoteness on the left orbitofrontal cortex and temporal neocortex to gain access to AM.

The aims of this study were to determine the influence of the onset of Alzheimer's disease (AD) on 1) memory and cerebral glucose metabolism, 2) the relationships between cognitive performance and cerebral glucose metabolism. Brain metabolism was measured by 18FDG-PET in 12 early onset AD patients (age < 65 years) and 26 late onset ones (> 65), with comparable mean MMSE scores. Working memory, semantic memory and episodic memory were assessed. Cognitivo-metabolic correlations (CMC) and complementary interregional correlations were performed in order to identify specific neurocognitive processes within each group. Both AD groups performed poorly on all tasks, except digit span in the late onset group. The early onset group performed more poorly than the late onset one on both the digit span and Brown-Peterson Paradigm (BPP) tasks. Temporo-parietal hypometabolism was found in both groups, the left hemisphere being more affected than the right, especially in the early onset patients, who also showed specific left frontal hypometabolism. For the BPP task, the CMC principally involved left frontal areas in the early onset group, and the cerebellum in the late onset one. For the digit span task, they involved cerebellar and occipital regions in the latter. Regarding the digit span, the occipital and cerebellar involvement may have reflected an effective compensatory mechanism in the late onset patients, while high left supramarginal gyrus hypometabolism in the early onset patients may have explained their failure in this task. In the BPP task, the lower performance of the early onset group may have been due to a frontal lobe dysfunction, as suggested by 1) the hypometabolism of this region, 2) the CMC results, 3) the interregional correlations, which indicated greater disruption of the antero- posterior loop.