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Information that is processed with reference to oneself, i.e. Self-Referential Processing (SRP), is generally associated with better remembering compared to information processed in a condition not related to oneself. This positive effect of the self on subsequent memory performance is called as Self-Reference Effect (SRE). The neural basis of SRE is still poorly understood. The main goal of the present work was thus to highlight brain changes associated with SRE in terms of activity and functional coupling and during both encoding and retrieval so as to assess the relative contribution of both processes to SRE. For this purpose, we used an fMRI event-related self-referential paradigm in 30 healthy young subjects and measured brain activity during both encoding and retrieval of self-relevant information compared to a semantic control condition. We found that SRE was associated with brain changes during the encoding phase only, including both greater activity in the medial prefrontal cortex and hippocampus, and greater functional coupling between these brain regions and the posterior cingulate cortex. These findings highlight the contribution of brain regions involved in both SRP and episodic memory and the relevance of the communication between these regions during the encoding process as the neural substrates of SRE. This is consistent with the idea that SRE reflects a positive effect of the reactivation of self-related memories on the encoding of new information in episodic memory.

Background: Chronic alcohol consumption results in brain damage potentially reversible with abstinence. It is however difficult to gauge the degree of recovery of brain tissues with abstinence since changes are subtle and a significant portion of patients relapse. State-of-the-art morphometric methods are increasingly used in neuroimaging studies to detect subtle brain changes at a voxel level. Our aim was to use the most refined morphometric methods to observe in alcohol dependence the relationship between volumetric changes and interim drinking over a 6-month follow-up., Methods: Overall, 19 patients with alcohol dependence received volumetric T1-weighted magnetic resonance imaging (MRI) after detoxification. A 6-month follow-up study was then conducted, during which 11 of them received a second MRI scan. First, correlations were conducted between gray matter (GM) and white matter (WM) volumes of patients at alcohol treatment entry and the amount of alcohol consumed between treatment entry and follow-up. Second, longitudinal analyses were performed from pairs of MRI scans using tensor-based morphometry in the 11 patients, and correlations were computed between the resultant Jacobian maps of GM and WM and interim drinking., Results: Our preliminary results showed that, among others, alcoholics with smaller thalamus at alcohol treatment entry tended to resume with heavy alcohol consumption (p < 0.005 uncorrected [unc.]). Our longitudinal study revealed an overall inverse relationship between recovery of brain structures like the cerebellum, striatum, and cingulate gyrus, and the amount of alcohol consumed over the 6-month follow-up (p < 0.005 unc.). The recovery could be observed not only with strict abstinence but also in cases of moderate resumption of alcohol consumption, when there had been no drastic relapse into alcohol dependence., Conclusions: Those preliminary findings indicate that the volume of the thalamus at treatment entry may have an influence on subsequent interim drinking. There is recovery of certain brain regions even when patients resume with moderate, but not drastic, alcohol consumption., (Copyright © 2014 by the Research Society on Alcoholism.)

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Studies of functional connectivity suggest that the default mode network (DMN) might be relevant for cognitive functions. Here, we examined metabolic and structural connectivity between major DMN nodes, the posterior cingulate (PCC) and medial prefrontal cortex (MPFC), in relation to normal working memory (WM). DMN was captured using independent component analysis of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data from 35 young healthy adults (27.1 ± 5.1 years). Metabolic connectivity, a correlation between FDG uptake in PCC and MPFC, was examined in groups of subjects with (relative to median) low (n=18) and high (n=17) performance on digit span backward test as an index of verbal WM. In addition, fiber tractography based on PCC and MPFC nodes as way points was performed in a subset of subjects. FDG uptake in the DMN nodes did not differ between high and low performers. However, significantly (p=0.01) lower metabolic connectivity was found in the group of low performers. Furthermore, as compared to high performers, low performers showed lower density of the left superior cingulate bundle. Verbal WM performance is related to metabolic and structural connectivity within the DMN in young healthy adults. Metabolic connectivity as quantified with FDG-PET might be a sensitive marker of the normal variability in some cognitive functions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Episodic memory refers to the capacity to bind multimodal memories to constitute a unique personal event. Most developmental studies on episodic memory focused on one specific component, i.e., the core factual information. The present study examines the relevance of a novel episodic paradigm to assess its developmental trajectories in a more comprehensive way according to the type of association (item-feature, item-location, and item-sequence associations) with measures of both objective and subjective recollection. We conducted a behavioral study aimed at testing the effects of age in a large sample of 160 children, adolescents, and young adults (6-23 years old). We confronted the behavioral data to the neural correlates in a subgroup of 30 children using voxel-based morphometry. Behavioral data outlined differential developmental trajectories according to the type of association, with a continuous increase of factual associative memory efficiency until 10 years, a linear increase of performance in spatial associative memory that pursues until early adulthood and an abrupt increase in temporal associative memory efficiency between 9 and 10. Regarding recollection, measures showed a more pronounced enhancement from 9 to 10 years. Hence, behavioral data highlight a peculiar period in late childhood (8-10 years old) crucial for the developmental time course of episodic memory. Regarding structural data, we found that the improvement of associative memory efficiency was related to a decrease in gray matter volume in a large cerebral network including the dorsolateral and ventrolateral prefrontal cortex (and superior and anterior temporal regions), and the hippocampus bilaterally. These data suggest that multimodal integration would probably be related to the maturation of temporal regions and modulated by a fronto-parietal network. Besides, our findings emphasize the relevance of the present paradigm to assess episodic memory especially in the clinical setting.

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 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.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

Amyloid imaging is currently introduced to the market for clinical use. We will review the evidence demonstrating that the different amyloid PET ligands that are currently available are valid biomarkers for Alzheimer-related β amyloidosis. Based on recent findings from cross-sectional and longitudinal imaging studies using different modalities, we will incorporate amyloid imaging into a multidimensional model of Alzheimer's disease. Aside from the critical role in improving clinical trial design for amyloid-lowering drugs, we will also propose a tentative algorithm for when it may be useful in a memory clinic environment. Gaps in our evidence-based knowledge of the added value of amyloid imaging in a clinical context will be identified and will need to be addressed by dedicated studies of clinical utility.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

The amyloid cascade hypothesis, which posits that amyloid-β accumulation is the key event in Alzheimer disease neurodegeneration, has dominated the field for 20 years. Recent findings, however, show that neuronal-injury biomarkers are independent of amyloid-β, calling for reconsideration of the pathological cascade and assessment of alternative therapeutic strategies.

Introduction: (18)F-florbetaben and positron emission tomography were used to examine the relationships between β-amyloid (Aβ) deposition, cognition, hippocampal volume, and white matter hyperintensities in mild cognitive impairment (MCI)., Methods: Forty-five MCI participants were evaluated. A neocortical standardized uptake value ratio threshold ≥ 1.45 was used to discriminate high from low Aβ burden. Correlations were adjusted for age, gender and years of education., Results: High Aβ burden was found in 53% of MCI. Regression analyses showed standardized uptake value ratio (r = -0.51, P = 0.0015) and hippocampal volume (r = 0.60, P = 0.024) both contributing to episodic memory impairment in independent fashion. White matter hyperintensities correlated with nonmemory cognition, and this correlation was particularly associated with Aβ burden., Conclusion: Higher Aβ deposition in MCI is associated with more severe memory impairment and is contributing to early amnestic symptoms independent of hippocampal atrophy.

Gray matter atrophy, glucose hypometabolism, and β-amyloid Aβ deposition are well-described hallmarks of Alzheimer's disease, but their relationships are poorly understood. The present study aims to compare the local levels of these three alterations in humans with Alzheimer's disease. Structural magnetic resonance imaging, (18)F-fluorodeoxyglucose positron emission tomography (PET), and (18)F-florbetapir PET 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 recommended) were analyzed. For each patient and imaging modality, age-adjusted Z-score maps were computed, and direct between-modality voxelwise comparison and correlation analyses were performed. Significant differences in the levels of atrophy, hypometabolism, and Aβ deposition were found in most brain areas, but the hierarchy differed across regions. A cluster analysis revealed distinct subsets of regions: (1) in the hippocampus, atrophy exceeded hypometabolism, whereas Aβ load was minimal; (2) in posterior association areas, Aβ deposition was predominant, together with high hypometabolism and lower but still significant atrophy; and (3) in frontal regions, Aβ deposition was maximal, whereas structural and metabolic alterations were low. Atrophy and hypometabolism significantly correlated in the hippocampus and temporo-parietal cortex, whereas Aβ load was not significantly related to either atrophy or hypometabolism. These findings provide direct evidence for regional variations in the hierarchy and relationships between Aβ 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.

There is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elderly is the cognitive reserve, which designates the partial protection from the deleterious effects of aging that lifetime experience provides. Neuroimaging studies examining task-related activation in elderly people suggested that cognitive reserve takes the form of more efficient use of brain networks and/or greater ability to recruit alternative networks to compensate for age-related cerebral changes. In this exploratory multi-center study, we examined the relationships between cognitive reserve, as measured by education and verbal intelligence, and cerebral metabolism at rest (FDG-PET) in a sample of 74 healthy older participants. Higher degree of education and verbal intelligence was associated with less metabolic activity in the right posterior temporoparietal cortex and the left anterior intraparietal sulcus. Functional connectivity analyses of resting-state fMRI images in a subset of 41 participants indicated that these regions belong to the default mode network and the dorsal attention network respectively. Lower metabolism in the temporoparietal cortex was also associated with better memory abilities. The findings provide evidence for an inverse relationship between cognitive reserve and resting-state activity in key regions of two functional networks respectively involved in internal mentation and goal-directed attention., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The current study investigated the cerebral basis of word perceptual repetition priming with fMRI during a letter detection task that manipulated the familiarity of perceptual word form and the number of repetitions. Some neuroimaging studies have reported increases, instead of decreases, in brain activations (called "repetition enhancement") associated with repetition priming of unfamiliar stimuli which have been interpreted as the creation of new perceptual representations for unfamiliar items. According to this interpretation, several repetitions of unfamiliar items would then be necessary for the repetition priming to occur, a hypothesis not explicitly tested in prior studies. In the present study, using a letter detection task on briefly flashed words, we explored the effect of familiarity on brain response for word visual perceptual priming using both words with usual (i.e., familiar) and unusual (i.e., unfamiliar) font, presented up to four times for stimuli with unusual font. This allows potential changes in the brain responses for unfamiliar items to be assessed over several repetitions, i.e., repetition enhancement to suppression. Our results reveal significant increases of activity in the bilateral occipital areas related to repetition of words in both familiar and unfamiliar conditions. Our findings support the sharpening hypothesis, showing a lack of cerebral economy with repetition when the task requires the processing of all word features, whatever the familiarity of the material, and emphasize the influence of the nature of stimuli processing on its neuronal manifestation.

The aim of the present study was to explore the cerebral substrates of episodic memory disorders in Alzheimer's disease (AD) and investigate patients' hyperactivations frequently reported in the functional imaging literature. It remains unclear whether some of these hyperactivations reflect real increased activity or deactivation disturbances in the default mode network (DMN). Using positron emission tomography ((15)O-H(2)O), cerebral blood flow was measured in 11 AD patients and 12 healthy elderly controls at rest and during encoding and stem-cued recall of verbal items. Subtractions analyses between the target and control conditions were performed and compared between groups. The average signal was extracted in regions showing hyperactivation in AD patients versus controls in both contrasts. To determine whether hyperactivations occurred in regions that were activated or deactivated during the memory tasks, we compared signal intensities between the target conditions versus rest. Our results showed reduced activation in AD patients compared to controls in several core episodic memory regions, including the medial temporal structures, during both encoding and retrieval. Patients also showed hyperactivations compared to controls in a set of brain areas. Further analyses conducted on the signal extracted in these areas indicated that most of these hyperactivations actually reflected a failure of deactivation. Indeed, whereas almost all of these regions were significantly more activated at rest than during the target conditions in controls, only one region presented a similar pattern of deactivation in patients. Altogether, our findings suggest that hyperactivations in AD must be interpreted with caution and may not systematically reflect increased activity. Although there has been evidence supporting the existence of genuine compensatory mechanisms, dysfunction within the DMN may be responsible for part of the apparent hyperactivations reported in the literature on AD.

Magnetic resonance (MR) provides a non-invasive way to investigate changes in the brain resulting from aging or neurodegenerative disorders such as Alzheimer's disease (AD). Performing accurate analysis for population studies is challenging because of the interindividual anatomical variability. A large set of tools is found to perform studies of brain anatomy and population analysis (FreeSurfer, SPM, FSL). In this paper we present a newly developed surface-based processing pipeline (MILXCTE) that allows accurate vertex-wise statistical comparisons of brain modifications, such as cortical thickness (CTE). The brain is first segmented into the three main tissues: white matter, gray matter and cerebrospinal fluid, after CTE is computed, a topology corrected mesh is generated. Partial inflation and non-rigid registration of cortical surfaces to a common space using shape context are then performed. Each of the steps was firstly validated using MR images from the OASIS database. We then applied the pipeline to a sample of individuals randomly selected from the AIBL study on AD and compared with FreeSurfer. For a population of 50 individuals we found correlation of cortical thickness in all the regions of the brain (average r=0.62 left and r=0.64 right hemispheres). We finally computed changes in atrophy in 32 AD patients and 81 healthy elderly individuals. Significant differences were found in regions known to be affected in AD. We demonstrated the validity of the method for use in clinical studies which provides an alternative to well established techniques to compare different imaging biomarkers for the study of neurodegenerative diseases., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The hippocampus is affected at an early stage in the development of Alzheimer's disease (AD). With the use of structural magnetic resonance (MR) imaging, we can investigate the effect of AD on the morphology of the hippocampus. The hippocampal shape variations among a population can be usually described using statistical shape models (SSMs). Conventional SSMs model the modes of variations among the population via principal component analysis (PCA). Although these modes are representative of variations within the training data, they are not necessarily discriminative on labeled data or relevant to the differences between the subpopulations. We use the shape descriptors from SSM as features to classify AD from normal control (NC) cases. In this study, a Hotelling's T2 test is performed to select a subset of landmarks which are used in PCA. The resulting variation modes are used as predictors of AD from NC. The discrimination ability of these predictors is evaluated in terms of their classification performances with bagged support vector machines (SVMs). Restricting the model to landmarks with better separation between AD and NC increases the discrimination power of SSM. The predictors extracted on the subregions also showed stronger correlation with the memory-related measurements such as Logical Memory, Auditory Verbal Learning Test (AVLT) and the memory subscores of Alzheimer Disease Assessment Scale (ADAS)., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Background: Postmortem studies have suggested that β-amyloid (Aβ) deposition was only weakly related to the degree of cognitive impairment in Alzheimer's disease (AD). The development of Aβ ligands for in vivo PET imaging has greatly facilitated the assessment of this question., Objective: The objective of the present study was to provide an overview of our current knowledge regarding the relationship between Aβ deposition and episodic memory deficits in nondemented elderly and in patients with mild cognitive impairment or AD., Methods: Information was obtained both from studies comparing memory performance in individuals with high Pittsburgh compound B (PiB) and those with low PiB and from studies performing correlation analyses between memory performance and PiB retention considered as a continuous variable., Results: Previous studies assessing the relationship between memory and global neocortical PiB reported conflicting findings, and overall suggest that this link is weak, probably indirect, and detectable only in early stages. Assessing the relationship with regional instead of global neocortical PiB, we found a specific relationship between episodic memory deficits and neocortical temporal PiB, independent from hippocampal atrophy, in the predementia stage of the disease., Conclusion: There is a relationship between regional Aβ deposition and episodic memory deficits in the presymptomatic stage of AD., (Copyright © 2012 S. Karger AG, Basel.)

Background: The noninvasive evaluation of nigrostriatal dopaminergic integrity by PET can provide useful information for the differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD)., Objectives: To evaluate the diagnostic potential of imaging striatal monoaminergic terminal integrity with the novel vesicular monoamine transporter type 2 (VMAT2) radioligand [(18)F]AV-133 and PET to distinguish DLB from AD., Methods: Fifty participants [9 DLB, 11 AD, 20 Parkinson's disease (PD) and 10 healthy age-matched control subjects (HC)] underwent [(18)F]AV-133 PET studies. Additionally, 20 participants underwent amyloid imaging PET scans with either [(11)C]PiB or (18)F-florbetaben. VMAT2 density was calculated through normalized tissue uptake value ratios (R(T)) at 120-140 min after injection using the primary visual or the cerebellar cortex as reference region. Comparison of the R(T) for [(18)F]AV-133 was done between the different clinical diagnostic groups., Results: Significantly lower striatal VMAT2 densities were observed in DLB and PD when compared to AD and HC, especially in the posterior putamen. In contrast to PD and DLB, no reductions were observed in AD patients when compared to HC., Conclusions: [(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. In contrast to amyloid imaging, VMAT2 imaging with [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in DLB patients, assisting in the differential diagnosis from AD., (Copyright © 2012 S. Karger AG, Basel.)

Background and Purpose: To provide guidance regarding the most appropriate voxel-based morphometry (VBM)-derived method for assessing hippocampal atrophy in early Alzheimer's disease (AD)., Methods: T1-MRI volume data were collected in 23 patients with amnestic mild cognitive impairment (aMCI) and 18 controls. Three types of data (unmodulated and 2 types of modulated MRI) and 2 extraction methods (with reference to the hippocampal peak of atrophy identified from a preliminary whole-brain analysis, or using a template region of interest-ROI-approach) were compared to the gold-standard individual ROI (ROI-i) method through 2 statistical approaches (ANOVA and Pearson's R)., Results: First, whole-brain analyses performed on modulated data are as sensitive as the ROI-i approach in detecting aMCI patients' hippocampal atrophy. Second, values extracted from the ROI-template applied to modulated data provide measures of hippocampal volume comparable to those obtained using the ROI-i approach., Conclusions: This study provides guidance on how to extract accurate hippocampal measures from VBM-derived data in early AD, as a time-saving and easy alternative to the reference ROI-i method., (© 2010 by the American Society of Neuroimaging.)

The 'preclinical' phase of Alzheimer's disease is a future target for treatment, but additional research is essential to understand the relationship between β-amyloid burden and cognition during this time. We investigated this relationship using a large sample of apparently healthy older adults (N=177), which also enabled examination of whether the relationship differed according to age, gender, years of education, apolipoprotein E status, and the presence of subjective memory complaints. In addition to episodic memory, a range of cognitive measures (global cognition, semantic memory, visuospatial performance, and executive function) were examined. Participants were aged over 60 years with no objective cognitive impairment and came from the imaging arm of the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study of ageing. (11)C-PiB PET was used to measure β-amyloid burden and a PiB 'cut-off' level of 1.5 was used to separate participants with low PiB retention from those with high PiB retention. Thirty-three percent of participants had a PiB positive scan. PiB positive participants were 5 years older, twice as likely to carry an apolipoprotein E ɛ4 allele, and their composite episodic memory was 0.26 SD worse than PiB negative volunteers. Linear regressions with β-amyloid burden as a dichotomous predictor, revealed an interaction between β-amyloid burden and gender, as well as age and education effects, in predicting episodic memory and visuospatial performance. In females, but not in males, increased β-amyloid was related to worse episodic memory and visuospatial performance. Furthermore, an interaction between β-amyloid burden and APOE status was found in predicting visuospatial performance, whereby there was a trend for increased β-amyloid to relate to worse visuospatial performance for those without an APOE ɛ4 allele. There were no other main or interaction effects of β-amyloid on any of the other composite cognitive measures. These cross-sectional findings suggest that β-amyloid burden does not have a large effect on cognition in this subset of apparently healthy older people. The finding of gender differences deserves further research to answer definitively the important question of gender susceptibility to adverse cognitive effects from β-amyloid., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To assess the diagnostic potential of imaging striatal monoaminergic terminal integrity with the vesicular monoamine transporter type 2 (VMAT2) radioligand (18)F 9-fluropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) and positron emission tomography to distinguish dementia with Lewy bodies (DLB) from Alzheimer disease (AD)., Design, Setting, and Participants: Nine patients with DLB, 10 patients with AD, 20 patients with Parkinson disease (PD), and 10 healthy age-matched control subjects underwent [(18)F]AV-133 positron emission tomography studies. VMAT2 density was calculated through normalized tissue uptake value ratios at 120 to 140 minutes postinjection using the primary visual cortex as the reference region., Main Outcome Measure: Comparison of the tissue ratio for [(18)F]AV-133 between the different clinical diagnostic groups., Results: Lower VMAT2 densities were observed in patients with DLB when compared with patients with AD especially in the posterior putamen (caudate: mean [SD], 1.24 [0.6] vs 2.83 [0.9]; P < .001; effect size = 2.1; anterior putamen: mean [SD], 0.90 [0.5] vs 3.01 [0.9]; P < .001; effect size = 2.9; posterior putamen: mean [SD], 0.62 [0.5] vs 2.87 [0.8]; P < .001; effect size = 3.4). Compared with healthy controls, [(18)F]AV-133 tissue ratios were significantly lower by 88% and 74% in the posterior putamen, 74% and 65% in the anterior putamen, and 53% and 51% in the caudate nucleus of patients with PD and DLB, respectively. In contrast to patients with PD and DLB, no reductions were observed in patients with AD., Conclusions: [(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in patients with DLB and assist in the differential diagnosis from AD.

Neuroimaging offers a promising tool for the priority goals of current researches in Alzheimer's disease (AD) including early diagnosis, monitoring the progression of the disease and understanding the underlying mechanisms. The brain profiles of atrophy and hypometabolism associated with AD are well known and they can be used as support for early diagnosis, although the accuracy of each of these biomarkers on its own is not sufficient. An increasing number of studies highlights the relevance of disconnection processes in the development and progression of AD. The recent development of PET tracers such as the Pittsburg compound (PiB) allowing to visualize in vivo one of the neuropathological lesions characterizing AD (i.e. beta-amyloid depositions) offers a unique opportunity to better understand the mechanisms underlying this multifaceted disease., (© 2011 médecine/sciences - Inserm / SRMS.)

Remembering the past and envisioning the future rely on episodic memory which enables mental time travel. Studies in young adults indicate that past and future thinking share common cognitive and neural underpinnings. No imaging data is yet available in healthy aged subjects. Using fMRI, we scanned older subjects while they remembered personal events (PP: last 12 months) or envisioned future plans (FP: next 12 months). Behaviorally, both time-periods were comparable in terms of visual search strategy, emotion, frequency of rehearsal and recency of the last evocation. However, PP were more episodic, engaged a higher state of autonoetic consciousness and mental visual images were clearer and more numerous than FP. Neuroimaging results revealed a common network of activation (posterior cingulate cortex, precuneus, prefrontal cortex, hippocampus) reflecting the use of similar cognitive processes. Furthermore, the episodic nature of PP depended on hippocampal and visuo-spatial activations (occipital and angular gyri), while, for FP, it depended on the inferior frontal and lateral temporal gyri, involved in semantic memory retrieval. The common neural network and behavior suggests that healthy aged subjects thought about their future prospects in the past. The contribution of retrospective thinking into the future that engages the same network as the one recruited when remembering the past is discussed. Within this network, differential recruitment of specific areas highlights the episodic distinction between past and future mental time travel., (Copyright © 2010 Elsevier Inc. All rights reserved.)

During memory encoding, increased hippocampal activity-thought to reflect the binding of different types of information into unique episodes-has been shown to correlate with subsequent recollection of those episodes. Repetition priming-thought to induce more efficient perceptual processing of stimuli-is normally associated with decreased neocortical activity and is often assumed to reduce encoding into episodic memory. Here, we used fMRI to compare activity to primed and unprimed auditory words in the presence of distracting sounds as a function of whether participants subsequently recollected the word-sound associations or only had a feeling of familiarity with the word in a subsequent surprise recognition task. At the behavioral level, priming increased the incidence of subsequent recollection. At the neuronal level, priming reduced activity in the superior temporal gyrus (STG) but also reversed the traditional increase in encoding-related hippocampal activity associated with subsequent recollection relative to subsequent familiarity. To explain this interaction pattern, further analyses using dynamic causal modeling showed an increase in connectivity from left STG to left hippocampus specific to words that were later recollected. These findings show that successful episodic encoding is not determined solely by local hippocampal activity and emphasize instead the importance of increased functional neocortical-hippocampal coupling. Such coupling might be a better predictor of subsequent recollection than the direction of local hippocampal changes per se. We propose that one consequence of priming is to "free up" attentional resources from processing an item in a noisy context, thereby allowing greater attention to encoding of that context.

In the past decade, a "default mode network" (DMN) has been highlighted in neuroimaging studies as a set of brain regions showing increased activity in task-free state compared to cognitively demanding task, and synchronized activity at rest. Changes within this network have been described in healthy aging as well as in Alzheimer's disease (AD) and populations at risk for AD, that is, amnestic Mild Cognitive Impairment (aMCI) patients and APOE-ε4 carriers. This is of particular interest in the context of early diagnosis and more generally for our understanding of the physiopathological mechanisms of AD. This paper gives an overview of the anatomical and physiological characteristics of this network as well as its relationships with cognition, before focusing on changes in the DMN over normal aging and Alzheimer's disease. While perturbations of the DMN have been consistently reported, especially within the posterior cingulate, further studies are needed to understand their clinical implication.

β-Amyloid deposition is one of the main hallmarks of Alzheimer's disease thought to eventually cause neuronal death. Post-mortem and neuroimaging studies have consistently reported cases with documented normal cognition despite high β-amyloid burden. It is of great interest to understand what differentiates these particular subjects from those without β-amyloid deposition or with both β-amyloid deposition and cognitive deficits, i.e. what allows these subjects to resist the damage of the pathological lesions. [¹¹C]Pittsburgh compound B positron emission tomography and magnetic resonance brain scans were obtained in 149 participants including healthy controls and patients with subjective cognitive impairment, mild cognitive impairment and Alzheimer's disease. Magnetic resonance data were compared between high versus low-[11C]Pittsburgh compound B cases, and between high-[¹¹C]Pittsburgh compound B cases with versus those without cognitive deficits. Larger temporal (including hippocampal) grey matter volume, associated with better episodic memory performance, was found in high- versus low-[¹¹C]Pittsburgh compound B healthy controls. The same finding was obtained using different [¹¹C]Pittsburgh compound B thresholds, correcting [¹¹C]Pittsburgh compound B data for partial averaging, using age, education, Mini-Mental State Examination, apolipoprotein E4 and sex-matched subsamples, and using manual hippocampal delineation instead of voxel-based analysis. By contrast, in participants with subjective cognitive impairment, significant grey matter atrophy was found in high-[¹¹C]Pittsburgh compound B cases compared to low-[¹¹C]Pittsburgh compound B cases, as well as in high-[¹¹C]Pittsburgh compound B cases with subjective cognitive impairment, mild cognitive impairment and Alzheimer's disease compared to high-[¹¹C]Pittsburgh compound B healthy controls. Larger grey matter volume in high-[¹¹C]Pittsburgh compound B healthy controls may reflect either a tissue reactive response to β-amyloid or a combination of higher 'brain reserve' and under-representation of subjects with standard/low temporal volume in the high-[¹¹C]Pittsburgh compound B healthy controls. Our complementary analyses tend to support the latter hypotheses. Overall, our findings suggest that the deleterious effects of β-amyloid on cognition may be delayed in those subjects with larger brain (temporal) volume.

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., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: A "resting state" or "default mode network" has been highlighted in functional neuroimaging studies as a set of brain regions showing synchronized activity at rest or in task-independent cognitive state., State of the Art: A considerable and increasing number of studies have been conducted over the last few years so as to unravel the cognitive function(s) of this brain network., Perspectives: This review gives an overview of anatomical, physiological and phenomenological data regarding the default mode network. Different hypotheses have been proposed regarding the role of this network. Several studies have highlighted its involvement in autobiographical memory, prospection, self, attention, and theory of mind. The influence of the attention level and consciousness onto resting state brain network activity has also been discussed. Specific changes have been described in normal aging, Alzheimer's disease (AD) and multiple sclerosis (MS)., Conclusions: These studies altogether contribute to a better definition of the default mode network, in terms of implicated brain structures, subtending mechanisms, and potential cognitive roles. For instance, similarities and relationships were found between self-related brain activity and resting-state activity in regions belonging to this network, namely posterior cingulate and prefrontal areas that may reflect introspective activity experienced, more or less consciously, when the brain is not specifically engaged in a cognitive task. As a whole, the default mode network appears as a non human-specific intrinsic functional network, active all over the life from birth until aging where it is progressively modified, and sensitive to different pathologies including AD and MS. On the other hand, many points remain to be clarified concerning this network, such as the exact part of its activity dedicated to self-related cognitive processes (introspection, imaginary mental scenario based on past autobiographical experiences) and that involved in a sentinel-like attentional process designated to react to possible environmental events. Indeed, it seems that this network is functional even in case of low level of consciousness, i.e., during light sleep. Conversely, a loss of self and environment perception as in coma, deep sleep or anesthesia might modulate its connectivity along the anteroposterior axis, i.e., frontal activity disappearance associated with a parietal reinforcement of connectivity. Since studies aiming at highlighting these points are still uncommon to date, exhaustive and objective explorations are needed to better understand all these resting state processes., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Hippocampal atrophy, posterior cingulate and frontal glucose hypometabolism, and white-matter tract disruption are well described early macroscopic events in Alzheimer's disease. The relationships between these three types of alterations have been documented in previous studies, but their chronology still remains to be established. The present study used multi-modal fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging longitudinal data to address this question in patients with amnestic mild cognitive impairment. We found unidirectional, specific sequential relationships between: (i) baseline hippocampal atrophy and both cingulum bundle (r = 0.70; P = 3 × 10⁻³) and uncinate fasciculus (r = 0.75; P = 7 × 10⁻⁴) rate of atrophy; (ii) baseline cingulum bundle atrophy and rate of decline of posterior (r = 0.72; P = 2 × 10⁻³); and anterior (r = 0.74; P = 1 × 10⁻³) cingulate metabolism; and (iii) baseline uncinate white matter atrophy and subgenual metabolism rate of change (r = 0.65; P = 6 × 10⁻³). Baseline local grey matter atrophy was not found to contribute to hypometabolism progression within the posterior and anterior cingulate as well as subgenual cortices. These findings suggest that hippocampal atrophy progressively leads to disruption of the cingulum bundle and uncinate fasciculus, which in turn leads to glucose hypometabolism of the cingulate and subgenual cortices, respectively. This study reinforces the relevance of remote mechanisms above local interactions to account for the pattern of metabolic brain alteration observed in amnestic mild cognitive impairment, and provides new avenues to assess the sequence of events in complex diseases characterized by multiple manifestations.

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.

Background and Purpose: Advances in functional neuroimaging studies have led to the need for improved anatomical precision to face with more and more specific challenges. Nevertheless, functional magnetic resonance imaging (MRI) (fMRI) suffers from geometrical distortions, which limit the matching between functional and anatomical data necessary to interpret fMRI results. The "FieldMap" method is the most widely used technique to correct for geometrical distortions but in some cases cannot be applied or provides unsatisfactory results. The objective of this study is thus to provide a very simple alternative method for distortion correction and to demonstrate its efficiency., Methods: This correction relies on the nonlinear registration of echo-planar imaging (EPI) acquisitions onto their corresponding undistorted non-EPI T2 Star volume, and was tested on two independent groups of subjects undertaking the same paradigm but scanned with distinct EPI sequences., Results: This procedure was found to considerably decrease the mismatch between functional and anatomical data in both groups, as revealed through several quantitative and qualitative measures on both EPI volumes and activation maps., Conclusion: This study describes a simple, rapid, and easily implementable method to significantly improve neuroanatomical accuracy of fMRI results localization, which may be relevant for future neuroimaging studies., (Copyright © 2010 by the American Society of Neuroimaging.)

We previously demonstrated that episodic autobiographical memories (EAMs) rely on a network of brain regions comprising the medial temporal lobe (MTL) and distributed neocortical regions regardless of their remoteness. The findings supported the model of memory consolidation, which proposes a permanent role of MTL during EAM retrieval (multiple-trace theory or MTT) rather than a temporary role (standard model). Our present aim was to expand the results by examining the interactions between the MTL and neocortical regions (or MTL-neocortical links) during EAM retrieval with varying retention intervals. We used an experimental paradigm specially designed to engage aged participants in the recollection of EAMs, extracted from five different time-periods, covering their whole life-span, in order to examine correlations between activation in the MTL and neocortical regions. The nature of the memories was checked at debriefing by means of behavioral measures to control the degree of episodicity and properties of memories. Targeted correlational analyses carried out on the MTL, frontal, lateral temporal, and posterior regions revealed strong links between the MTL and neocortex during the retrieval of both recent and remote EAMs, challenging the standard model of memory consolidation and supporting MTT instead. Further confirmation was given by results showing that activation in the left and right hippocampi significantly correlated during the retrieval of both recent and remote memories. Correlations among extra-MTL neocortical regions also emerged for all time-periods, confirming the critical role of the prefrontal, temporal (lateral temporal cortex and temporal pole), precuneus, and posterior cingulate regions in EAM retrieval. Overall, this paper emphasizes the role of a bilateral network of MTL and neocortical areas whose activation correlate during the recollection of rich phenomenological recent and remote EAMs., (Copyright 2009 Wiley-Liss, Inc.)

Olfactory deficits and increased amyloid-β (Aβ) burden are observed in people with amnestic mild cognitive impairment (aMCI); both factors may be predictive of Alzheimer's disease (AD). We explored whether olfactory identification is related to in vivo measures of Aβ burden using Pittsburgh Compound B (PiB) PET. Nineteen control, 24 aMCI, and 20 AD participants completed an olfactory identification task and underwent PiB PET scanning. Control participants performed better on olfactory identification and showed lower PiB binding than aMCI patients. There was a significant correlation between both factors when pooling all groups together but not when considering each group separately. In addition, the olfactory identification score did not differ between aMCI participants who were PiB-positive and those who were PiB-negative. We conclude that AD-related olfactory identification deficits are not directly related to Aβ burden.

Alzheimer's disease has become a major public health issue for occidental societies. Since animal models of Alzheimer's disease currently fail to perfectly mimic pathophysiological mechanisms or the manifestations of the disease, in vivo neuroimaging has a key role in better understanding the pathophysiology of Alzheimer's disease. The diversity of anatomical and functional neuroimaging techniques - anatomical (T1-MRI), functional (fMRI) and diffusion tensor imaging (DTI) via magnetic resonance imaging (MRI) as well as position emission tomography coupled to fluorodeoxyglucose ((18)FDG-PET) - offers a large possibility of investigation of brain alterations in Alzheimer's disease. These techniques have thus provided morphological and functional brain alterations mapping of Alzheimer's disease: on one hand grey matter atrophy first concerns the medial temporal lobe before extending to the temporal neocortex and then other neocortical areas; on the other hand, metabolic alterations are first located within the posterior cingulate cortex and then reach the temporo-parietal area as well as the prefrontal cortex, especially in its medial part. Assessments of white matter alterations with DTI have highlighted a variety of tract alterations including the cingulum bundle, a white matter tract connecting the medial temporal lobe to the posterior cingulate cortex. Finally fMRI activation studies have evidenced compensatory mechanisms through hyperactivations in Alzheimer's disease patients. Altogether these results have led to the hypothesis of two major pathophysiological mechanisms in Alzheimer's disease: on one hand compensatory mechanisms in regions where atrophy exceeds metabolic alterations, on the other disconnection between medial temporal lobe and posterior cingulate cortex through the cingulum bundle, accounting for higher metabolic than structural alterations in the posterior cingulate cortex. Our work has extensively contributed to this disconnection hypothesis thanks to the use of cross-sectional and longitudinal multi-modal neuroimaging approaches. It has underlined the relevance of distant over local mechanisms in the pathophysiology of Alzheimer's disease and offers new perspectives to the exploration of the neural bases of cognitive impairments in this disorder., (© Société de Biologie, 2010.)

Background: Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS). Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies., Methodology/principal Findings: Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and (18)F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients., Conclusions/significance: These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker.

We describe a new method to automatically discriminate between patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) and elderly controls, based on multidimensional classification of hippocampal shape features. This approach uses spherical harmonics (SPHARM) coefficients to model the shape of the hippocampi, which are segmented from magnetic resonance images (MRI) using a fully automatic method that we previously developed. SPHARM coefficients are used as features in a classification procedure based on support vector machines (SVM). The most relevant features for classification are selected using a bagging strategy. We evaluate the accuracy of our method in a group of 23 patients with AD (10 males, 13 females, age+/-standard-deviation (SD)=73+/-6 years, mini-mental score (MMS)=24.4+/-2.8), 23 patients with amnestic MCI (10 males, 13 females, age+/-SD=74+/-8 years, MMS=27.3+/-1.4) and 25 elderly healthy controls (13 males, 12 females, age+/-SD=64+/-8 years), using leave-one-out cross-validation. For AD vs controls, we obtain a correct classification rate of 94%, a sensitivity of 96%, and a specificity of 92%. For MCI vs controls, we obtain a classification rate of 83%, a sensitivity of 83%, and a specificity of 84%. This accuracy is superior to that of hippocampal volumetry and is comparable to recently published SVM-based whole-brain classification methods, which relied on a different strategy. This new method may become a useful tool to assist in the diagnosis of Alzheimer's disease.

Cognitive procedural learning occurs in three qualitatively different phases (cognitive, associative, and autonomous). At the beginning of this process, numerous cognitive functions are involved, subtended by distinct brain structures such as the prefrontal and parietal cortex and the cerebellum. As the learning progresses, these cognitive components are gradually replaced by psychomotor abilities, reflected by the increasing involvement of the cerebellum, thalamus, and occipital regions. In elderly subjects, although cognitive studies have revealed a learning effect, performance levels differ during the acquisition of a procedure. The effects of age on the learning of a cognitive procedure have not yet been examined using functional imaging. The aim of this study was therefore to characterize the cerebral substrates involved in the learning of a cognitive procedure, comparing a group of older subjects with young controls. For this purpose, we performed a positron emission tomography activation study using the Tower of Toronto task. A direct comparison of the two groups revealed the involvement of a similar network of brain regions at the beginning of learning (cognitive phase). However, the engagement of frontal and cingulate regions persisted in the older group as learning continued, whereas it ceased in the younger controls. We assume that this additional activation in the older group during the associative and autonomous phases reflected compensatory processes and the fact that some older subjects failed to fully automate the procedure., (2008 Wiley-Liss, Inc.)

This study set out to establish the relationship between changes in episodic memory retrieval in normal aging on the one hand and gray matter volume and (18)FDG uptake on the other. Structural MRI, resting-state (18)FDG-PET, and an episodic memory task manipulating the depth of encoding and the retention interval were administered to 46 healthy subjects divided into three groups according to their age (young, middle-aged, and elderly adults). Memory decline was found not to be linear in the course of normal aging: Whatever the retention interval, the retrieval of shallowly encoded words was impaired in both the middle-aged and the elderly, whereas the retrieval of deeply encoded words only declined in the elderly. In middle-aged and elderly subjects, the reduced performance in the shallow encoding condition was mainly related to posterior mediotemporal volume and metabolism. By contrast, the impaired retrieval of deeply encoded words in the elderly group was mainly related to frontal and parietal regions, suggesting the adoption of inefficient strategic processes.

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.

Purpose: To prospectively evaluate the accuracy of automated hippocampal volumetry to help distinguish between patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and elderly controls, by using established criteria for patients with AD and MCI as the reference standard., Materials and Methods: The regional ethics committee approved the study and written informed consent was obtained from all participants. The study included 25 patients with AD (11 men, 14 women; mean age +/- standard deviation [SD], 73 years +/- 6; Mini-Mental State Examination (MMSE) score, 24.4 +/- 2.7), 24 patients with amnestic MCI (10 men, 14 women; mean age +/- SD, 74 years +/- 8; MMSE score, 27.2 +/- 1.4) and 25 elderly healthy controls (13 men, 12 women; mean age +/- SD, 64 years +/- 8). For each participant, the hippocampi were automatically segmented on three-dimensional T1-weighted magnetic resonance (MR) images with high spatial resolution. Segmentation was performed by using recently developed software that allows fast segmentation with minimal user input. Group differences in hippocampal volume were assessed by using Student t tests. To obtain robust estimates of P values, the correct classification rate, sensitivity, and specificity, bootstrap methods were used., Results: Significant hippocampal volume reductions were detected in all groups of patients (-32% in AD patients vs controls, P < .001; -19% in MCI patients vs controls, P < .001; and -15% in AD patients vs MCI patients, P < .01). Individual classification on the basis of hippocampal volume resulted in 84% correct classification (sensitivity, 84%; specificity, 84%) between AD patients and controls and 73% correct classification (sensitivity, 75%; specificity, 70%) between MCI patients and controls., Conclusion: This automated method can serve as an alternative to manual tracing and may thus prove useful in assisting with the diagnosis of AD., ((c) RSNA, 2008.)

In early Alzheimer's disease (AD), the hippocampal region is the area most severely affected by cellular and structural alterations, yet glucose hypometabolism predominates in the posterior association cortex and posterior cingulate gyrus. One prevalent hypothesis to account for this discrepancy is that posterior cingulate hypometabolism results from disconnection from the hippocampus through disruption of the cingulum bundle. However, only partial and indirect evidence currently supports this hypothesis. Thus, using structural magnetic resonance imaging and 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography in 18 patients with early AD, we assessed the relationships between hippocampal atrophy, white matter integrity, and gray matter metabolism by means of a whole-brain voxel-based correlative approach. We found that hippocampal atrophy is specifically related to cingulum bundle disruption, which is in turn highly correlated to hypometabolism of the posterior cingulate cortex but also of the middle cingulate gyrus, thalamus, mammillary bodies, parahippocampal gyrus, and hippocampus (all part of Papez's circuit), as well as the right temporoparietal associative cortex. These results provide the first direct evidence supporting the disconnection hypothesis as a major factor contributing to the early posterior hypometabolism in AD. Disruption of the cingulum bundle also appears to relate to hypometabolism in a large connected network over and above the posterior cingulate cortex, encompassing the whole memory circuit of Papez (consistent with the key location of this white matter tract within this loop) and also, but indirectly, the right posterior association cortex.

Previous neuroimaging studies in the visual domain have shown that neurons along the perceptual processing pathway retain the physical properties of written words, faces, and objects. The aim of this study was to reveal the existence of similar neuronal properties within the human auditory cortex. Brain activity was measured using functional magnetic resonance imaging during a repetition priming paradigm, with words and pseudowords heard in an acoustically degraded format. Both the amplitude and peak latency of the hemodynamic response (HR) were assessed to determine the nature of the neuronal signature of spoken word priming. A statistically significant stimulus type by repetition interaction was found in various bilateral auditory cortical areas, demonstrating either HR suppression and enhancement for repeated spoken words and pseudowords, respectively, or word-specific repetition suppression without any significant effects for pseudowords. Repetition latency shift only occurred with word-specific repetition suppression in the right middle/posterior superior temporal sulcus. In this region, both repetition suppression and latency shift were related to behavioral priming. Our findings highlight for the first time the existence of long-term spoken word memory traces within the human auditory cortex. The timescale of auditory information integration and the neuronal mechanisms underlying priming both appear to differ according to the level of representations coded by neurons. Repetition may "sharpen" word-nonspecific representations coding short temporal variations, whereas a complex interaction between the activation strength and temporal integration of neuronal activity may occur in neuronal populations coding word-specific representations within longer temporal windows.

We aimed at identifying the cerebral structures whose synaptic function subserves the recollection of lifetime's episodic autobiographical memory (AM) via autonoetic consciousness. Twelve healthy middle-aged subjects (mean age: 59 years +/- 2.5) underwent a specially designed cognitive test to assess the ability to relive richly detailed episodic autobiographical memories from five time periods using the Remember/Know procedure. We computed an index of episodicity (number of Remember responses justified by the recall of specific events and details) and an index of retrieval spontaneity, and additionally an index of semanticized memories (number of Know responses). The regional cerebral blood flow (rCBF) was measured in the resting state, with H(2)O(15) as part of an activation PET study. The indexes were correlated with blood flow using volumes of interest in frontotemporal regions, including hippocampus and voxel-wise analyses in SPM. With both analyses, significant correlations were mainly found between the index of episodicity and rCBF in the medial temporal lobe, including hippocampus, across the five time periods (unlike the index of semanticized memories) and between the spontaneity index and rCBF in the prefrontal areas. These results highlight, in healthy subjects, the distinct role of these two structures in AM retrieval and support the view that the hippocampus is needed for reexperiencing detailed episodic memories no matter how old they are., (2008 Wiley-Liss, Inc.)