Béatrice Desgranges

Discrimination between Alzheimer Dementia and Controls by Automated Analysis of Multicenter FDG PET

A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimers disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.

Autobiographical memory, autonoetic consciousness, and self-perspective in aging.

In this study, the authors examined the effects of aging on autobiographical memory in 180 participants by means of a new method designed to assess across 5 lifetime periods the nature of memories-that is, specificity and spontaneity--and the phenomenal experience of remembering--that is, self-perspective and autonoetic consciousness--via the field/observer and remember/know paradigms respectively. Age-related differences were found for the specificity and spontaneity of memories and the phenomenal experience of remembering. There was an increase in observer and know responses with age, but a decrease in field and remember responses and in the ability to justify them by recalling sensory-perceptive, affective, or spatiotemporal specific details. This pattern confirms the existence of a semantic-episodic dissociation in autobiographical memory in aging. Moreover, the data support the view that older participants can subjectively travel back in time to relive personal events in the most distant past better than those in the recent past.

Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia.

Background Hippocampal atrophy is a well-known feature of Alzheimers disease (AD), but sensitivity and specificity of hippocampal volumetry are limited. Neuropathological studies have shown that hippocampal subfields are differentially vulnerable to AD; hippocampal subfield volumetry may thus prove to be more accurate than global hippocampal volumetry to detect AD. Methods CA1, subiculum and other subfields were manually delineated from 40 healthy controls, 18 AD, 17 amnestic Mild Cognitive Impairment (aMCI), and 8 semantic dementia (SD) patients using a previously developed high resolution MRI procedure. Non-parametric group comparisons and receiver operating characteristic (ROC) analyses were conducted. Complementary analyses were conducted to evaluate differences of hemispheric asymmetry and anterior-predominance between AD and SD patients and to distinguish aMCI patients with or without β-amyloid deposition as assessed by Florbetapir-TEP. Results Global hippocampi were atrophied in all three patient groups and volume decreases were maximal in the CA1 subfield (22% loss in aMCI, 27% in both AD and SD; all p < 0.001). In aMCI, CA1 volumetry was more accurate than global hippocampal measurement to distinguish patients from controls (areas under the ROC curve = 0.88 and 0.76, respectively; p = 0.05) and preliminary analyses suggest that it was independent from the presence of β-amyloid deposition. In patients with SD, whereas the degree of CA1 and subiculum atrophy was similar to that found in AD patients, hemispheric and anterior–posterior asymmetry were significantly more marked than in AD with greater involvement of the left and anterior hippocampal subfields. Conclusions The findings suggest that CA1 measurement is more sensitive than global hippocampal volumetry to detect structural changes at the pre-dementia stage, although the predominance of CA1 atrophy does not appear to be specific to AD pathophysiological processes.

Relationships between years of education and gray matter volume, metabolism and functional connectivity in healthy elders.

More educated elders are less susceptible to age-related or pathological cognitive changes. We aimed at providing a comprehensive contribution to the neural mechanism underlying this effect thanks to a multimodal approach. Thirty-six healthy elders were selected based on neuropsychological assessments and cerebral amyloid imaging, i.e. as presenting normal cognition and a negative florbetapir-PET scan. All subjects underwent structural MRI, FDG-PET and resting-state functional MRI scans. We assessed the relationships between years of education and i) gray matter volume, ii) gray matter metabolism and iii) functional connectivity in the brain areas showing associations with both volume and metabolism. Higher years of education were related to greater volume in the superior temporal gyrus, insula and anterior cingulate cortex and to greater metabolism in the anterior cingulate cortex. The latter thus showed both volume and metabolism increases with education. Seed connectivity analyses based on this region showed that education was positively related to the functional connectivity between the anterior cingulate cortex and the hippocampus as well as the inferior frontal lobe, posterior cingulate cortex and angular gyrus. Increased connectivity was in turn related with improved cognitive performances. Reinforcement of the connectivity of the anterior cingulate cortex with distant cortical areas of the frontal, temporal and parietal lobes appears as one of the mechanisms underlying education-related reserve in healthy elders.

Memory Disorders in Alzheimer's Disease and the Organization of Human Memory

The Squire and Zola-Morgan parallel organization model of the memory and the Tulving hierarchical model were developed mainly through the study of amnesic patients. The predictions of these two models are different, the first being more open to double dissociations and less restrictive than the second. Alzheimers Disease is characterized by a differential impairment of the memory systems and by an interindividual variability which may take the form of dissociations between preserved and disturbed abilities in some patients. The objective of this study was to use the memory dysfunctions of patients with AD to test the validity of the two models. Analysis of the group data provided an average profile of memory disturbance consistent both with much of the data given in AD literature and with the two models. Using a multiple single-case strategy, we demonstrated several simple dissociations which are for the greater part compatible with the two models. Two of the dissociations underline the limits of the Tulving model, which otherwise accounts for a lot of results. The study supports the relevance of AD for the understanding of the cognitive architecture of the human memory.

Morphological brain plasticity induced by musical expertise is accompanied by modulation of functional connectivity at rest

The aim of this study was to explore whether musical practice-related gray matter increases in brain regions are accompanied by modifications in their resting-state functional connectivity. 16 young musically experienced adults and 17 matched nonmusicians underwent an anatomical magnetic resonance imaging (MRI) and a resting-state functional MRI (rsfMRI). A whole-brain two-sample t test run on the T1-weighted structural images revealed four clusters exhibiting significant increases in gray matter (GM) volume in the musician group, located within the right posterior and middle cingulate gyrus, left superior temporal gyrus and right inferior orbitofrontal gyrus. Each cluster was used as a seed region to generate and compare whole-brain resting-state functional connectivity maps. The two clusters within the cingulate gyrus exhibited greater connectivity for musicians with the right prefrontal cortex and left temporal pole, which play a role in autobiographical and semantic memory, respectively. The cluster in the left superior temporal gyrus displayed enhanced connectivity with several language-related areas (e.g., left premotor cortex, bilateral supramarginal gyri). Finally, the cluster in the right inferior frontal gyrus displayed more synchronous activity at rest with claustrum, areas thought to play a role in binding sensory and motor information. We interpreted these findings as the consequence of repeated collaborative use in general networks supporting some of the memory, perceptual-motor and emotional features of musical practice.

Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity.

Normal aging is characterized by brain glucose metabolism decline predominantly in the prefrontal cortex. The goal of the present study was to assess whether this change was associated with age-related alteration of white matter (WM) structural integrity and/or functional connectivity. FDG-PET data from 40 young and 57 elderly healthy participants from two research centers (n=49/48 in Center 1/2) were analyzed. WM volume from T1-weighted MRI (Center 1), fractional anisotropy from diffusion-tensor imaging (Center 2), and resting-state fMRI data (Center 1) were also obtained. Group comparisons were performed within each imaging modality. Then, positive correlations were assessed, within the elderly, between metabolism in the most affected region and the other neuroimaging modalities. Metabolism decline in the elderly predominated in the left inferior frontal junction (LIFJ). LIFJ hypometabolism was significantly associated with macrostructural and microstructural WM disturbances in long association fronto-temporo-occipital fibers, while no relationship was found with functional connectivity. The findings offer new perspectives to understand normal aging processes and open avenues for future studies to explore causality between age-related metabolism and connectivity changes.

New questions on the hemispheric encoding/retrieval asymmetry (HERA) model assessed by divided visual-field tachistoscopy in normal subjects.

According to the hemispheric encoding/retrieval asymmetry (HERA) model, based on data obtained through functional neuroimaging, the left and right prefrontal cortices are preferentially, and, respectively, involved in long-term episodic memory encoding and retrieval. In this study, the HERA model was tested from a behavioral perspective using divided visual-field tachistoscopy. A recognition paradigm with both verbal and visuospatial materials was devised to differentiate memory-related effects (encoding vs. retrieval) from effects linked to the materials. The paradigm used lists of 12 and four items to assess long-term episodic memory and short-term memory, respectively. The aim of the latter condition was to test whether the HERA model is applicable in short-term memory. For long-term episodic memory, the data obtained validated the HERA model; the direction of the hemispheric asymmetry was found to depend on the type of materials used, whereas its magnitude was determined by the type of memory process. For verbal short-term memory, the HERA model seems to be confirmed. The pre-existing representations of the material could take into account the similarity of the hemispheric asymmetry pattern between short-term memory and long-term memory. In contrast, for visuospatial short-term memory, Baddeleys working memory model seems to better explain our results insofar as the asymmetries were essentially linked to the material in encoding but not in retrieval. This latter difference between short-term memory and long-term indicates that processes involved in LTM depend on episodic processes per se, hence, lending more support for the HERA model. Accordingly, these two memory systems seem to bring into play two different modes of hemisphere specialization.

The hyperpriming phenomenon in normal aging: a consequence of cognitive slowing?

Increased semantic priming effects (hyperpriming) are sometimes observed in Alzheimers disease (AD) and in normal aging. Whereas the processes underlying this phenomenon are now well understood in AD, the interpretation is much more woolly in normal aging. To explore semantic priming, the authors used a lexical decision task in which the influence of attention and cognitive slowing was controlled. To explore the semantic organization, the words had coordinate (tiger-lion) or attribute relations (zebra-stripes). Priming scores of 21 older and 20 young participants were equivalent in the 2 conditions. These results reflect the integrity of semantic memory with normal aging and call into question some investigations showing hyperpriming for older participants; this may instead be an artifact of a general slowing effect.

The Semantic and Episodic Subcomponents of Famous Person Knowledge: Dissociation in Healthy Subjects

Fifty-two subjects between ages 40 and 79 years were administered a questionnaire assessing their ability to recall semantic information about famous people from 4 different decades and to recollect its episodic source of acquisition together with autonoetic consciousness via the remember-know paradigm. In addition, they underwent a battery of standardized neuropsychological tests to assess episodic and semantic memory and executive functions. The analyses of age reveal differences for the episodic source score but no differences between age groups for the semantic scores within each decade. Regardless of the age of people, the analyses also show that semantic memory subcomponents of the famous person test are highly associated with each other as well as with the source component. The recall of semantic information on the famous person test relies on participants semantic abilities, whereas the recall of its episodic source depends on their executive functions. The present findings confirm the existence of an episodic-semantic distinction in knowledge about famous people. They provide further evidence that personal source and semantic information are at once distinct and highly interactive within the framework of remote memory.