Neural correlates of controlled memory processes in questionable Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by a progressive loss of controlled cognitive processes (processes requiring mental effort and attentional resources), and functional neuroimaging at early stages of AD provides an opportunity to tease out the neural correlates of controlled processes. Controlled and automatic memory performance was assessed with the Process Dissociation Procedure in 50 patients diagnosed with questionable Alzheimer’s disease (QAD). The patients’ brain glucose metabolism was measured using FDG-PET. After a follow-up period of 36 months, 27 patients had converted to AD, while 23 remained stable. Both groups showed a similar decrease in controlled memory processes but preserved automatic processes at entry into the study, suggesting that impairment of controlled memory would not be specific for AD. Patients who subsequently converted to Alzheimer type dementia showed significantly decreased brain metabolism at baseline compared to stable QAD in associative cortices known to be involved in AD (the left precuneus, the right inferior parietal lobule and bilateral middle temporal cortex).Voxel-based cognitive and metabolic correlations showed that a decrease in controlled memory processes was preferentially correlated with lower activity in the dorsomedial prefrontal and posterior cingulate cortices in very early AD patients. The dorsomedial prefrontal cortex would play a role in controlled memory processes as they relate to reflective and monitoring processes, while the posterior cingulate cortex is involved in the controlled access to previously encoded episodes. In stable QAD patients, reduced controlled performance in verbal memory correlated with impaired activity in the left anterior hippocampal structure, which would alter the reactivation of associations created at encoding

Les corrélats métaboliques des processus contrôlés en mémoire dans la maladie d'Alzheimer très débutante

Les processus contrôlés et automatiques de récupération mnésique ont été évalués au moyen de la Procédure de Dissociation des Processus appliquée à une tâche de complètement de trigrammes chez 59 patients diagnostiqués comme « questionable Alzheimer’s disease » (QAD ou Mild Cognitive Impairment). Par ailleurs, le métabolisme cérébral du glucose des patients a été mesuré par FDG-PET. Comparativement à des volontaires âgés sains appariés, le profil mnésique des patients QAD était caractérisé par un déficit des processus contrôlés, mais une préservation des processus automatiques. Après un suivi de 30 mois, 27 des patients ont développé une maladie d’Alzheimer, tandis que 23 patients restèrent des QAD stables (9 sujets n’ont pas complété le suivi ou ont reçu un autre diagnostic au terme de celui-ci). Les deux sous-groupes présentaient le même degré de déclin des processus de mémoire contrôlés. Des corrélations cognitivo-métaboliques, ainsi qu’une analyse en composantes principales, ont permis de montrer que les corrélats métaboliques des processus contrôlés (à l’entrée dans l’étude) n’étaient les mêmes chez les patients qui allaient développer la maladie d’Alzheimer et chez les patients qui allaient rester stables. Chez les patients qui développaient ultérieurement une maladie d’Alzheimer, l’utilisation correcte des processus contrôlés était positivement corrélée à l’activité du cortex préfrontal dorsomédian, qui pourrait jouer un rôle dans les processus réflexifs de monitoring agissant sur les produits de la récupération. L’activité du cortex préfrontal dorsomédian était corrélée à l’activité métabolique des régions frontales bilatérales et du cortex cingulaire postérieur. Par contraste, chez les patients QAD stables, nous avons trouvé une corrélation avec la formation hippocampique antérieure, une région qui intervient dans la réactivation de l’épisode d’encodage des événements

On the multivariate nature of brain metabolic impairment in Alzheimer’s disease

We used principal component analysis to decompose functional images of patients with AD in orthogonal ensembles of brain regions with maximal metabolic covariance. Three principal components explained 38% of the total variance in a large sample of FDG-PET images obtained in 225 AD patients. One functional ensemble (PC2) included limbic structures from Papez's circuit (medial temporal regions, posterior and anterior cingulate cortex, thalamus); its disruption in AD patients was related to episodic memory impairment. Another principal component (PC1) illustrated major metabolic variance in posterior cerebral cortices, and patients' scores were correlated to instrumental functions (language and visuospatial abilities). PC3 comprised frontal, parietal, temporal and posteromedial (posterior cingulate and precuneus) cortices, and patients' scores were related to executive dysfunction and global cognitive impairment. The three main metabolic covariance networks converged in the posterior cingulate area that showed complex relationships with medial temporal structures within each PC. Individual AD scores were distributed as a continuum along PC axes: an individual combination of scores would determine specific clinical symptoms in each patient

Decomposition of metabolic brain clusters in the frontal variant of frontotemporal dementia

Previous studies that measured brain activity in frontotemporal dementia (FTD) used univariate analyses, examining each region of interest separately. We explored in a multicenter European research program the principal brain clusters characterized by a common variability in cerebral metabolism in FTD. Seventy patients with frontal variant (fv) FTD were selected according to international clinical recommendations; principal component analysis (PCA) was performed on FDG-PET metabolic images, looking for covariance clusters in this large population. A first metabolic cluster included most of the lateral and medial prefrontal cortex, bilaterally; PC1 scores correlated with performances on memory and executive neuropsychological tasks. Moreover, FDG-PET images in fv-FTD were further characterized by a metabolic covariance in two clusters comprising the subcallosal medial frontal region, the temporal pole, medial temporal structures and the striatum, separately in the left and in the right hemisphere. The study provides original data-driven arguments for metabolic involvement of separate brain clusters in the rostral limbic system, corresponding to pathological poles differentially affected in each FTD patient