Marine Fouquet

Sequential relationships between grey matter and white matter atrophy and brain metabolic abnormalities in early Alzheimer's disease

Hippocampal atrophy, posterior cingulate and frontal glucose hypometabolism, and white-matter tract disruption are well described early macroscopic events in Alzheimers 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.

Age effect on the default mode network, inner thoughts, and cognitive abilities

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.

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

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

Imaging Brain Effects of APOE4 in Cognitively Normal Individuals Across the Lifespan

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.

A simple way to improve anatomical mapping of functional brain imaging.

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.

Role of hippocampal CA1 atrophy in memory encoding deficits in amnestic Mild Cognitive Impairment

Identifying the specific substrates of memory deficits in early Alzheimers 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.

Interaction between years of education and APOE ε4 status on frontal and temporal metabolism

Objective: To examine interactions between years of education and APOE ε4 status on gray matter volume and metabolism in cognitively healthy participants. Methods: Seventy-two healthy participants (28 APOE ε4 carriers and 44 noncarriers; from 23 to 84 years of age) with FDG-PET and structural MRI were included. A subgroup also underwent florbetapir-PET. We tested the interaction effect between years of education and APOE ε4 status (carrier vs noncarrier) on FDG-PET and structural MRI within the whole brain (voxel-wise) adjusting for age and sex. Computed florbetapir standardized uptake value ratios were used for complementary analyses. Results: We found an interaction between years of education and APOE ε4 status on frontotemporal FDG-PET metabolism, such that higher education was positively related to frontotemporal metabolism only in APOE ε4 carriers. Complementary analyses revealed that (1) this interaction was independent from amyloid load; (2) increased metabolism in APOE ε4 carriers in this region correlated with episodic memory performances; (3) lower educated APOE ε4 carriers showed decreased metabolism relative to noncarriers in medial temporal and prefrontal areas, while higher educated carriers were comparable to noncarriers in these areas and showed increased metabolism in the middle temporal lobe. Conclusions: Our results showed that education may counteract the effects of APOE ε4 on metabolism independently of amyloid deposition. Higher metabolism in higher (compared to lower) educated APOE ε4 carriers was found in regions that sustain episodic memory. Overall, our results point to education as a protective factor that may help to postpone cognitive changes in APOE ε4 carriers.

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

INTRODUCTION The E4 allele of the apolipoprotein E (APOE4) is the major known genetic risk factor for Alzheimers disease (AD), with a dramatic increase in the risk of developing AD as the number of APOE4 alleles increases from 0 to 2. For this reason, asymptomatic APOE4 carriers as a group offer a great opportunity to search for the presence of early biomarkers for AD. The present article reviews neuroimaging studies on APOE4 carriers, focusing on cognitively normal individuals and on the main neuroimaging biomarkers for AD, i.e. atrophy with structural MRI, hypometabolism with FDG-PET, and amyloid deposition with amyloid-PET imaging. STATE OF THE ART There are a great number of studies on the effect of APOE4 on brain structures, and they tend to show significant atrophy in APOE4 carriers compared to non-carriers especially in regions susceptible to AD pathology such as the hippocampus. However, results are rather discrepant which suggests that the effect of APOE4 on brain structure is subtle. As for FDG-PET metabolism, the few available studies show decreased metabolism, again especially in AD-sensitive regions such as posterior associative parietal areas, with a dose-dependent effect (i.e. worsening as the number of APOE4 alleles increases). Finally, there is a unanimous and major effect of APOE4 on amyloid deposition with an increase in Aβ load as the number of APOE4 alleles increases and a decrease in the age of predicted amyloid-positivity in APOE4 carriers. This graded effect of APOE4 on atrophy, hypometabolism, and amyloid deposition is consistent with multimodal neuroimaging studies suggestive of a predominant effect of APOE4 on amyloid rather than tau-related injury and on brain metabolism rather than brain structure. Neuroimaging studies also suggest that APOE4 effects may be mediated by both Aβ-dependent and Aβ-independent pathological processes. This contradicts the view that Aβ pathology is a necessary upstream event to neuronal injury in AD. PERSPECTIVES AND CONCLUSION Future studies should tell whether the mechanisms and sequences evidenced in carriers are comparable to those found in non-carriers, but it is likely that APOE4 not only influences the risk for AD, but also modulates the pathophysiological cascade. Altogether, APOE4 carriers offer a great opportunity to investigate brain changes in the asymptomatic stages of AD and to further our understanding of the pathophysiology of the disease, although precaution is needed for interpretation in AD at large.

Relative effect of APOE ε4 on neuroimaging biomarker changes across the lifespan.

Objective: To provide a comprehensive understanding of APOE ε4 effects across the lifespan on the 3 main neuroimaging biomarkers. Methods: Two hundred seven community-dwelling, cognitively normal APOE ε4 carriers and noncarriers aged 20–87 years were involved in this study. They underwent structural MRI, fluorodeoxyglucose-PET, and florbetapir-PET scans. The effects of APOE, age, and APOE × age interaction were assessed voxel-wise for each modality. Results: There was no significant effect of APOE or APOE × age interaction on gray matter volume and glucose metabolism, although decreases with age tended to be stronger in noncarriers than in carriers. In contrast, β-amyloid (Aβ) deposition was significantly higher in carriers compared with noncarriers in a largely distributed network, and there was a significant APOE × age interaction such that Aβ deposition increased nonlinearly with age in APOE ε4 carriers only. Conclusions: Our findings highlight a differential effect of APOE ε4 on amyloid vs neurodegeneration biomarkers. APOE ε4 mainly influences Aβ deposition, while the effects on gray matter volume and glucose metabolism are at best subtle. ClinicalTrials.gov identifier: NCT01638949.

A specific relationship between hippocampal CA1 subfield atrophy and episodic memory encoding in amnestic mild cognitive impairment

uptake ratios were calculated within a ROI including frontal, temporoparietal, and retrosplenial cortices (FLR-ROI), using the cerebellum as reference region. Based on a FLR-threshold of 1.15, subjects were divided into PIBpositive (+) and -negative (-). Three age-matched groups were studied: A) 12 PIB(-) cognitively normal elderly controls, B) 12 PIB(+) cognitively normal elderly controls and C) 13 PIB(+) MCI-patients. Voxel-based and ROI-based statistical analyses were performed. The overlap between hypometabolism andWBC-abnormalities inMCI was used to define a ROI to extract values for correlation analysis between different modalities. Results: Group comparison between MCI and PIB(-) controls revealed significant hypometabolism and regionally overlapping WBC-reductions in MCI in posterior cingulate cortex/precuneus (typical cortical hubs, see figure 1). PIB-FLR values were negatively correlated with FDG-values (r 1⁄4 -0.67) and WBC-values (r 1⁄4 -0.42) and a linear positive correlation was found between FDG and WBC-values (r 1⁄4 0.51) across the entire population (groups A, B and C). These results survived correction for age and grey matter density.Conclusions: These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer-pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.