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.
Over the last ten years, we have conducted research in Alzheimer's disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms ...underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques. Also, we conducted several studies in cognitively intact at-risk elderly (e.g., subjective cognitive decline patients and APOE4 carriers) to better identify biomarkers associated with increased risk of developing AD. Regarding the physiopathological mechanisms, specific multimodal neuroimaging techniques allowed us to highlight the relevance of diaschisis, the mismatch between neurodegeneration and local Aβ deposition and the regional variation in the mechanisms underlying structural or functional alterations. Further works integrating other biomarkers known to play a role in the physiopathology of AD (tau, TDP-43, inflammation, etc.) in a longitudinal design would be useful to get a comprehensive understanding of their relative role, sequence, and causal relationships. Our works also highlighted the relevance of functional connectivity in further understanding the specificity of cognitive deficits in AD and how connectivity differentially influences the propagation of the different AD biomarkers. Finally, we conducted several studies on the links between lifestyle factors and neuroimaging biomarkers to unravel mechanisms of reserve. Further efforts are needed to better understand which lifestyle factor, or combination of factors, impact on AD pathology, and when, to help translating our knowledge to training programs that might prevent or delay brain and cognitive changes leading to AD dementia.
Highlights • Hippocampal subfield structure can be assessed in vivo with (high-resolution) MRI. • AD-related atrophy is initially focal (in CA1) before spreading to other subfields. • This pattern of ...atrophy could be a sensitive biomarker for early AD detection. • The effect of age and specific memory–volume correlations are less clear. • Variations in methods and segmentation protocols cause important discrepancies.
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.
Abstract 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-state18 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 and18 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.
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.
•We relate education to gray matter volume, metabolism and functional connectivity.•Volume and metabolism increases with education predominate in the anterior cingulate.•Anterior cingulate connectivity is also reinforced with education.•This increased connectivity relates to improved cognitive performances.
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.
•Musical practice shapes the brain structurally, mainly in auditory and motor areas.•Musical practice is also accompanied by functional plasticity.•We linked these two forms of brain plasticity using seed-based approach of rsfMRI.•Only musicians show more gray matter volume and enhanced functional connectivity.•Musical practice modulates brain networks implicated in high cognitive functions.
This scientific commentary refers to 'Effects of amyloid pathology and neurodegeneration on cognitive change in cognitively normal adults', by Bilgel et al.. (doi:10.1093/brain/awy150).
Objective
Impaired awareness is a common symptom in many mental disorders including Alzheimer disease (AD). This study aims at improving our understanding of the neural mechanisms underlying ...anosognosia of memory deficits in AD by combining measures of regional brain metabolism (resting state fluorodeoxyglucose positron emission tomography FDG‐PET) and intrinsic connectivity (resting state functional magnetic resonance imaging fMRI).
Methods
Twenty‐three patients diagnosed with probable AD based on clinical and biomarker data and 30 matched healthy control subjects were recruited in this study. An anosognosia index (difference between subjective and objective memory scores) was obtained in each participant. Resting state FDG‐PET for glucose metabolism measurement and resting state fMRI for intrinsic connectivity measurement were also performed. AD and control groups were compared on behavioral data, and voxelwise correlations between anosognosia and neuroimaging data were conducted within the AD group.
Results
AD patients underestimated their memory deficits. Anosognosia in AD patients correlated with hypometabolism in orbitofrontal (OFC) and posterior cingulate (PCC) cortices. Using OFC and PCC as seed regions, intrinsic connectivity analyses in AD revealed a significant association between anosognosia and reduced intrinsic connectivity between these regions as well as with the medial temporal lobe.
Interpretation
Anosognosia in AD is due not only to functional changes within cortical midline structures involved in self‐referential processes (OFC, PCC), but also to disconnection between these regions as well as with the medial temporal lobe. These findings suggest that the lack of awareness of memory deficits in AD results from a disruption of the communication within, but also between, the self‐related and the memory‐related brain networks. Ann Neurol 2015 Ann Neurol 2015;78:477–486
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