Renaud La Joie

7. Ossenkoppele R, Pijnenburg YAL, Perry DC, Cohn-Sheehy BI, Scheltens NME, Vogel JW, Kramer JH, van der Vlies AE, La Joie R, Rosen HJ, van der Flier WM, Grinberg LT, Rozemuller AJ, Huang EJ, van Berckel BNM, Miller BL, Barkhof F, Jagust WJ, Scheltens P, Seeley WW, Rabinovici GD
Brain (2015)
A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer's disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer's disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer's disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer's disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer's disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer's disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer's disease/dysexecutive Alzheimer's disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer's disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer's disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer's disease and dysexecutive Alzheimer's disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as 'the behavioural/dysexecutive variant of Alzheimer's disease' rather than frontal variant Alzheimer's disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer's disease represent distinct phenotypes or a single continuum.

Jörn-Henrik Jacobsen , Johannes Stelzer , Thomas Hans Fritz , Gael Chételat , Renaud La Joie , Robert Turner

Musical memory is considered to be partly independent from other memory systems. In Alzheimer's disease and different types of dementia, musical memory is surprisingly robust, and likewise for brain lesions affecting other kinds of memory. However, the mechanisms and neural substrates of musical memory remain poorly understood. In a group of 32 normal young human subjects (16 male and 16 female, mean age of 28.0 ± 2.2 years), we performed a 7 T functional magnetic resonance imaging study of brain responses to music excerpts that were unknown, recently known (heard an hour before scanning), and long-known. We used multivariate pattern classification to identify brain regions that encode long-term musical memory. The results showed a crucial role for the caudal anterior cingulate and the ventral pre-supplementary motor area in the neural encoding of long-known as compared with recently known and unknown music. In the second part of the study, we analysed data of three essential Alzheimer's disease biomarkers in a region of interest derived from our musical memory findings (caudal anterior cingulate cortex and ventral pre-supplementary motor area) in 20 patients with Alzheimer's disease (10 male and 10 female, mean age of 68.9 ± 9.0 years) and 34 healthy control subjects (14 male and 20 female, mean age of 68.1 ± 7.2 years). Interestingly, the regions identified to encode musical memory corresponded to areas that showed substantially minimal cortical atrophy (as measured with magnetic resonance imaging), and minimal disruption of glucose-metabolism (as measured with 18F-fluorodeoxyglucose positron emission tomography), as compared to the rest of the brain. However, amyloid-β deposition (as measured with 18F-flobetapir positron emission tomography) within the currently observed regions of interest was not substantially less than in the rest of the brain, which suggests that the regions of interest were still in a very early stage of the expected course of biomarker development in these regions (amyloid accumulation → hypometabolism → cortical atrophy) and therefore relatively well preserved. Given the observed overlap of musical memory regions with areas that are relatively spared in Alzheimer's disease, the current findings may thus explain the surprising preservation of musical memory in this neurodegenerative disease.

Sylvia Villeneuve , Gil D. Rabinovici , Brendan I. Cohn-Sheehy , Cindee Madison , Nagehan Ayakta , Pia M. Ghosh , Renaud La Joie , Samia Kate Arthur-Bentil , Jacob W. Vogel , Shawn M. Marks , Manja Lehmann , Howard J. Rosen , Bruce Reed , John Olichney , Adam L. Boxer , Bruce L. Miller , Ewa Borys , Lee-Way Jin , Eric J. Huang , Lea T. Grinberg , Charles DeCarli , William W. Seeley , William Jagust

Amyloid-β, a hallmark of Alzheimer’s disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-β positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.

Objective

An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1 − 3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.
Method

MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.
Results

The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.
Conclusions

The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

The ε4 allele of the apolipoprotein E (APOE4) is associated with an increased risk of developing Alzheimer’s disease (AD). Hence, several studies have compared the brain characteristics of APOE4 carriers versus non-carriers in presymptomatic stages to determine early AD biomarkers. The present review provides an overview on APOE4-related brain changes in cognitively normal individuals, focusing on the main neuroimaging biomarkers for AD, i.e. cortical beta-amyloid (Aβ) deposition, hypometabolism and atrophy. The most consistent findings are observed with Aβ deposition as most studies report significantly higher cortical Aβ load in APOE4 carriers compared with non-carriers. Fluorodeoxyglucose-positron emission tomography studies are rare and tend to show hypometabolism in brain regions typically impaired in AD. Structural magnetic resonance imaging findings are the most numerous and also the most discrepant, showing atrophy in AD-sensitive regions in some studies but contradicting results as well. Altogether, this suggests a graded effect of APOE4, with a predominant effect on Aβ over brain structure and metabolism. Multimodal studies confirm this view and also suggest that APOE4 effects on brain structure and function are mediated by both Aβ-dependent and Aβ-independent pathological processes. Neuroimaging studies on asymptomatic APOE4 carriers offer relevant information to the understanding of early pathological mechanisms of the disease, although caution is needed as to whether APOE4 effects reflect AD pathological processes, and are representative of these effects in non-carriers.

Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.

Alzheimer’s disease (AD) and semantic dementia (SD) are both characterized by severe atrophy in the hippocampus, a brain region underlying episodic memory; paradoxically, episodic memory is relatively preserved in SD. Here, we used intrinsic connectivity analyses and showed that the brain networks differentially vulnerable to each disease converge to the hippocampus in the healthy brain. As neurodegeneration is thought to spread within preexisting networks, the common hippocampal atrophy in both diseases is likely due to its location at the crossroad between both vulnerable networks. Yet, we showed that in the normal brain, these networks harbor different functions, with episodic memory relying on the AD-vulnerable network only. Overall, disease-associated cognitive deficits seem to reflect the disruption of targeted networks more than atrophy in specific brain regions: in AD, over hippocampal atrophy, episodic memory deficits are likely due to disconnection within a memory-related network.

Gray matter atrophy, glucose hypometabolism and β-amyloid deposition are well-described hallmarks of Alzheimer’s disease but their relationships are poorly understood. The present study aims at comparing the local levels of these three alterations in humans with Alzheimer’s disease. Structural magnetic resonance imaging, 18F-fluorodeoxyglucose positron emission tomography and 18F-Florbetapir positron emission tomography data from 34 amyloid-negative healthy controls and 20 demented patients with a high probability of Alzheimer’s disease etiology (attested using neuroimaging biomarkers as recently recommanded) were analyzed. For each patient and imaging modality, age-adjusted z-score maps were computed and direct between-modality voxel-wise comparison and correlation analyses were performed. Significant differences in the levels of atrophy, hypometabolism and β-amyloid deposition were found in most brain areas but the hierarchy differed across regions. A cluster analysis revealed distinct subsets of regions: i) in the hippocampus, atrophy exceeded hypometabolism while β-amyloid load was minimal; ii) in posterior association areas, Aβ deposition was predominant, together with high hypometabolism and lower but still significant atrophy; iii) in frontal regions, β-amyloid deposition was maximal while structural and metabolic alterations were low. Atrophy and hypometabolism significantly correlated in the hippocampus and temporo-parietal cortex while β-amyloid load was not significantly related to either atrophy or hypometabolism. These findings provide direct evidence for regional variations in the hierarchy and relationships between β-amyloid load, hypometabolism and atrophy. Altogether, these variations probably reflect the differential involvement of region-specific pathological or protective mechanisms such as the presence of neurofibrillary tangles, disconnection as well as compensation processes.

Background. Hippocampal atrophy is a well-known feature of Alzheimer’s 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 is 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 was 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.

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.

Recent developments of PET amyloid ligands have made it possible to visualize the presence of Aβ deposition in the brain of living participants and to assess the consequences especially in individuals with no objective sign of cognitive deficits. The present review will focus on amyloid imaging in cognitively normal elderly, asymptomatic at-risk populations, and individuals with subjective cognitive decline. It will cover the prevalence of amyloid-positive cases amongst cognitively normal elderly, the influence of risk factors for AD, the relationships to cognition, atrophy and prognosis, longitudinal amyloid imaging and ethical aspects related to amyloid imaging in cognitively normal individuals. Almost ten years of research have led to a few consensual and relatively consistent findings: some cognitively normal elderly have Aβ deposition in their brain, the prevalence of amyloid-positive cases increases in at-risk populations, the prognosis for these individuals is worse than for those with no Aβ deposition, and significant increase in Aβ deposition over time is detectable in cognitively normal elderly. More inconsistent findings are still under debate; these include the relationship between Aβ deposition and cognition and brain volume, the sequence and cause-to-effect relations between the different AD biomarkers, and the individual outcome associated with an amyloid positive versus negative scan. Preclinical amyloid imaging also raises important ethical issues. While amyloid imaging is definitely useful to understand the role of Aβ in early stages, to define at-risk populations for research or for clinical trial, and to assess the effects of anti-amyloid treatments, we are not ready yet to translate research results into clinical practice and policy. More researches are needed to determine which information to disclose from an individual amyloid imaging scan, the way of disclosing such information and the impact on individuals and on society.

Age-related effects on the default mode network (DMN) connectivity as measured at rest using functional magnetic resonance imaging (fMRI) are now well described. Little is known however about the relationships between these changes and age-related effects on cognition or on the unconstrained thoughts which occur during the resting-state scan, called inner experience. Brain resting-state activity, inner experience, and cognitive ability measurements were obtained in 70 participants aged 19-80 years. The anterior-posterior disruption of DMN activity with age reported in previous studies was recovered here. A significant effect of age was also found on cognitive abilities but not on inner experience. Finally, age-related changes in DMN connectivity were found to correlate with cognitive abilities, and more specifically with autobiographical memory performance. These findings provide new information to fuel the debate on the role of the brain default mode and more specifically on the effect of age-related changes in resting-state activity as measured with fMRI.

""PURPOSE:
Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer's disease (AD). The aim of this study was to test the feasibility of using PET imaging with (18)F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC).
METHODS:
In this study, 46 subjects (20 men and 26 women, mean age of 69.0 ± 7.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean ± SD of radioactivity injected, 259 ± 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region.
RESULTS:
The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p = 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55-0.98) and a specificity of 38.1% (95% CI 0.18-0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894).
CONCLUSION:
These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools.""

Identifying the specific substrates of memory deficits in early Alzheimer's disease would help to develop clinically-relevant therapies. The present study assesses the relationships between encoding versus retrieval deficits in patients with amnestic Mild Cognitive Impairment (aMCI) and atrophy specifically within the hippocampus and throughout the white matter. Twenty-two aMCI patients underwent T1-weighted MRI scans and neuropsychological testing. Grey matter and white matter segments obtained from the MRI images were each entered in correlation analyses, assessed only in the hippocampus for grey matter segments, with encoding and retrieval memory performances. For the grey matter segments, the resulting spmT correlation maps were then superimposed onto a 3D surface view of the hippocampus to identify the relative involvement of the different subfields, a method already used and validated elsewhere. Memory encoding deficits specifically correlated with CA1 subfield atrophy, while no relationship was found with white matter atrophy. In contrast, retrieval deficits were weakly related to hippocampal atrophy and did not involve a particular subfield, while they strongly correlated with loss of white matter, specifically in medial parietal and frontal areas. In aMCI patients, encoding impairment appears specifically related to atrophy of the CA1 hippocampal subfield, consistent with the predominance of encoding deficits and CA1 atrophy in aMCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network.

High motivation to change is a crucial triggering factor to patients' engagement in clinical treatment. This study investigates whether the low readiness to change observed in some alcoholic inpatients at treatment entry could, at least partially, be linked with macrostructural gray matter abnormalities in critical brain regions. Participants comprised 31 alcoholic patients and 27 controls, who underwent 1.5-T magnetic resonance imaging. The Readiness to Change Questionnaire, designed to assess three stages of motivation to change (precontemplation, contemplation and action stages), was completed by all patients, who were then divided into "Action" (i.e. patients in action stage) and "PreAction" (i.e. patients in precontemplation or in contemplation stage) subgroups. The PreAction subgroup, but not the Action subgroup, had gray matter volume deficits compared with controls. Unlike the patients in the Action subgroup, the PreAction patients had gray matter abnormalities in the cerebellum (Crus I), fusiform gyri and frontal cortex. The low level of motivation to modify drinking behavior observed in some alcoholic patients at treatment entry may be related to macrostructural brain abnormalities in regions subtending cognitive, emotional and social abilities. These brain volume deficits may result in impairment of critical abilities such as decision making, executive functions and social cognition skills. Those abilities may be needed to resolve ambivalence toward alcohol addiction and to apply "processes of change", which are essential for activating the desire to change problematic behavior.

Recent advances in neuroimaging have highlighted the interest to differentiate hippocampal subfields for cognitive neurosciences and more notably in assessing the effects of normal and pathological aging. The main goal of the present study is to investigate the effects of normal aging onto the volume of the different hippocampal subfields. For this purpose, we developed a new magnetic resonance sequence together with reliable tracing guidelines to assess the volume of different subfields of the hippocampus using a 3 Tesla scanner, and estimated the validity of a simpler and less time-consuming method based on the widely-used automatic Voxel-Based Morphometry (VBM) technique. Three hippocampal regions of interest were delineated on the right and left hippocampi of 50 healthy subjects between 18 and 68 years old corresponding to the CA1, subiculum and other (including CA2-3-4 and Dentate Gyrus) subfields. A strong effect of age was found on the volume of the subiculum only, with a decrease paralleling that of the global gray matter volume, while CA1 and other subfields seemed relatively spared. Although less precise than the ROI-tracing technique, the VBM-based method appeared as a reliable alternative especially to distinguish CA1 and subiculum subfields. Our findings of a specific effect of age on the subiculum are consistent with the developmental hypothesis ("last-in first-out" theory). This contrasts with the predominant vulnerability of the CA1 subfield to Alzheimer's disease reported in several previous studies, suggesting that the assessment of hippocampal subfields may improve the discrimination between normal and pathological aging.

Alcohol-dependent individuals usually favor instant gratification of alcohol use and ignore its long-term negative consequences, reflecting impaired decision-making. According to the somatic marker hypothesis, decision-making abilities are subtended by an extended brain network. As chronic alcohol consumption is known to be associated with brain shrinkage in this network, the present study investigated relationships between brain shrinkage and decision-making impairments in alcohol-dependent individuals early in abstinence using voxel-based morphometry. Thirty patients performed the Iowa Gambling Task and underwent a magnetic resonance imaging investigation (1.5T). Decision-making performances and brain data were compared with those of age-matched healthy controls. In the alcoholic group, a multiple regression analysis was conducted with two predictors (gray matter [GM] volume and decision-making measure) and two covariates (number of withdrawals and duration of alcoholism). Compared with controls, alcoholics had impaired decision-making and widespread reduced gray matter volume, especially in regions involved in decision-making. The regression analysis revealed links between high GM volume in the ventromedial prefrontal cortex, dorsal anterior cingulate cortex and right hippocampal formation, and high decision-making scores (P<0.001, uncorrected). Decision-making deficits in alcoholism may result from impairment of both emotional and cognitive networks.

The role of the hippocampus in declarative memory consolidation is a matter of intense debate. We investigated the neural substrates of memory retrieval for recent and remote information using functional magnetic resonance imaging (fMRI). 18 young, healthy participants learned a series of pictures. Then, during two fMRI recognition sessions, 3 days and 3 months later, they had to determine whether they recognized or not each picture using the “Remember/Know” procedure. Presentation of the same learned images at both delays allowed us to track the evolution of memories and distinguish consistently episodic memories from those that were initially episodic and then became familiar or semantic over time and were retrieved without any contextual detail. Hippocampal activation decreased over time for initially episodic, later semantic memories, but remained stable for consistently episodic ones, at least in its posterior part. For both types of memories, neocortical activations were observed at both delays, notably in the ventromedial prefrontal and anterior cingulate cortices. These activations may reflect a gradual reorganization of memory traces within neural networks. Our data indicate maintenance and strengthening of hippocampal and cortico-cortical connections in the consolidation and retrieval of episodic memories over time, in line with the Multiple Trace theory (Nadel and Moscovitch, 1997). At variance, memories becoming semantic over time consolidate through strengthening of cortico-cortical connections and progressive disengagement of the hippocampus.

The development of musical skills by musicians results in specific structural and functional modifications in the brain. Surprisingly, no functional magnetic resonance imaging (fMRI) study has investigated the impact of musical training on brain function during long-term memory retrieval, a faculty particularly important in music. Thus, using fMRI, we examined for the first time this process during a musical familiarity task (i.e., semantic memory for music). Musical expertise induced supplementary activations in the hippocampus, medial frontal gyrus, and superior temporal areas on both sides, suggesting a constant interaction between episodic and semantic memory during this task in musicians. In addition, a voxel-based morphometry (VBM) investigation was performed within these areas and revealed that gray matter density of the hippocampus was higher in musicians than in nonmusicians. Our data indicate that musical expertise critically modifies long-term memory processes and induces structural and functional plasticity in the hippocampus.