 Question: Which brain changes are associated with sleep-disordered breathing (SDB) in aging?  Findings: In this cross-sectional study of 127 cognitively unimpaired communitydwelling older individuals, the presence of SDB was associated with greater amyloid burden, gray matter volume, metabolism, and perfusion in the posterior cingulate cortex and precuneus. There was no association with cognitive performance, selfreported cognitive or sleep difficulties, nor excessive daytime sleepiness.  Meaning: SDB-related changes include amyloid deposition in brain regions typically involved in Alzheimer's disease (AD), which might explain why SDB is associated with an increased risk for developing Alzheimer's clinical syndrome at a younger age.

Background White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults. Methods One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aβ. The relationships of total and regional WMH to age, vascular risk factors, cortical Aβ, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old). Results WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aβ, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aβ load in the models did not alter the results, and there was no interaction between WMH and Aβ on cognition. Conclusion WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aβ load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.

Background Subjective cognitive decline (SCD) defines a heterogeneous population, part of which having Alzheimer’s disease (AD). We aimed at characterizing SCD populations according to whether or not they referred to a memory clinic, by assessing the factors associated with increased AD risk. Methods Seventy-eight cognitively unimpaired older adults from the IMAP+ study (Caen) were included, amongst which 28 healthy controls (HC) and 50 SCD recruited from the community (SCD-community; n = 23) or from a memory clinic (SCD-clinic; n = 27). Participants underwent cognitive, psychoaffective, structural MRI, FDG-PET, and amyloid-PET assessments. They were followed up over a mean period of 2.4 ± 0.8 years. The groups were compared in terms of baseline and follow-up levels of SCD (self- and informant-reported), cognition, subclinical anxiety and depression, and atrophy progression over time. We also investigated SCD substrates within each SCD group through the correlations between self-reported SCD and other psychometric and brain measures. Results Compared to HC, both SCD groups showed similar cognitive performances but higher informant-reported SCD and anxiety. Compared to SCD-community, SCD-clinic showed higher informant-reported SCD, depression score, and atrophy progression over time but similar brain amyloid load. A significant increase over time was found for depression in the SCD-community and for self-reported praxis-domestic activities SCD factor in the SCD-clinic. Higher self-reported SCD correlated with (i) lower grey matter volume and higher anxiety in SCD-community, (ii) greater informant-reported SCD in SCD-clinic, and (iii) lower glucose metabolism in both SCD groups. Conclusions Higher subclinical depression and informant-reported SCD specifically characterize the SCD group that refers to a memory clinic. The same group appears as a frailer population than SCD-community as they show greater atrophy progression over time. Yet, both the SCD groups were quite similar otherwise including for brain amyloid load and the SCD-community showed increased depression score over time. Altogether, our findings highlight the relevance of assessing psychoaffective factors and informant-reported SCD in SCD populations and point to both differences and similarities in SCD populations referring or not to a memory clinic. Electronic supplementary material The online version of this article (10.1186/s13195-019-0514-z) contains supplementary material, which is available to authorized users.

Subclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD), but the brain mechanisms underlying this relationship are still unclear. We aimed to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data. We included cognitively unimpaired older adults from the baseline data of the primary cohort Age-Well (n = 135), and from the replication cohort ADNI (n = 252). In both cohorts, subclinical depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale; based on this scale, participants were classified as having depressive symptoms (>0) or not (0). Voxel-wise between-group comparisons were performed to highlight differences in gray matter volume, glucose metabolism and amyloid deposition; as well as white matter integrity (only available in Age-Well). Age-Well participants with subclinical depressive symptoms had lower gray matter volume in the hippocampus and lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum, compared to participants without symptoms. Hippocampal atrophy was recovered in ADNI, where participants with subclinical depressive symptoms also showed glucose hypometabolism in the hippocampus, amygdala, precuneus/posterior cingulate cortex, medial and dorsolateral prefrontal cortex, insula, and temporoparietal cortex. Subclinical depressive symptoms were not associated with brain amyloid deposition in either cohort. Subclinical depressive symptoms in ageing are linked with neurodegeneration biomarkers in the frontolimbic network including brain areas particularly sensitive to AD. The relationship between depressive symptoms and AD may be partly underpinned by neurodegeneration in common brain regions.

Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.

The determination of the safety of a patient with dementia who continues to drive is a difficult taskfor the physician who cares for geriatric patients. This study used the Traffic Sign Recognition Test (TSRT) discrimination between dementia patients who continue to drive and normal elderly volunteers. Thirty-seven subjects with dementia who continue to drive and 47 normal elderly volunteers were recruited to participate in the study. Each group was tested with the TSRT similar to that usedfor licensing in the state ofIndiana. The difference in total number of signs correctly identified between the two groups was determined using the Wilcoxon Rank Sum Test. The difference between groups of each individual sign recognition was determined using a Chi Square test. The affected group was also tested with a neuropsychological battery (NB) designed to

ImportanceNo lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk.ObjectiveTo investigate the effects of meditation training on brain integrity in older adults.Design, Setting, and ParticipantsAge-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021.InterventionsMeditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices.Main Outcomes and MeasuresPrimary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores.ResultsAmong 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, −0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, −0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, −0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, −0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002).Conclusions and RelevanceThe study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas.Trial RegistrationClinicalTrials.gov Identifier: NCT02977819

Subjective memory decline is associated with neurodegeneration and increased risk of cognitive decline in participants with no or subjective cognitive impairment, while in patients with mild cognitive impairment or Alzheimer’s-type dementia findings are inconsistent. Our aim was to provide a comprehensive overview of subjective memory decline changes, relative to objective memory performances, and its relationships with neurodegeneration across the clinical continuum of Alzheimer’s disease. Two hundred participants from the Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce (IMAP+) primary cohort and 731 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) replication cohort were included. They were divided into four clinical groups (IMAP+/ADNI): controls (N = 67/147, age: 60–84/60–90, female: 54/55%), patients with subjective cognitive decline (N = 30/84, age: 54–84/65–80, female: 44/63%), mild cognitive impairment (N = 50/369, age: 58–86/55–88, female: 45/44%) or Alzheimer’s-type dementia (N = 36/121, age: 51–86/61–90, female: 41/41%). Subjective and objective memory scores, and their difference (i.e. delta score reflecting memory awareness), were compared between groups. Then, voxelwise relationships between subjective memory decline and neuroimaging measures of neurodegeneration (atrophy (T1-MRI) and hypometabolism (FDG-PET)) were assessed across clinical groups and assessing the interactive effect of the level of cognitive impairment within the entire sample. Analyses were adjusted for age, sex and education, and repeated including only the amyloid-positive participants. In IMAP+, the level of subjective memory decline was higher in all patient groups (all p < 0.001) relative to controls, but similar between patient groups. In contrast, objective memory deficits progressively worsened from the subjective cognitive decline to the dementia group (all p < 0.001). Accordingly, the delta score showed a progressive decline in memory awareness across clinical groups (all p < 0.001). Voxelwise analyses revealed opposite relationships between the subjective memory decline score and neurodegeneration across the clinical continuum. In the earliest stages (i.e. patients with subjective cognitive decline or Mini Mental State Examination > 28), greater subjective memory decline was associated with increased neurodegeneration, while in later stages (i.e. patients with mild cognitive impairment, dementia or Mini Mental State Examination < 27) a lower score was related to more neurodegeneration. Similar findings were recovered in the ADNI replication cohort, with slight differences according to the clinical group, and in the amyloid-positive subsamples. Altogether, our findings suggest that the subjective memory decline score should be interpreted differently from normal cognition to dementia. Higher scores might reflect greater neurodegeneration in earliest stages, while in more advanced stages lower scores might reflect decreased memory awareness, i.e. more anosognosia associated with advanced neurodegeneration.