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Background: Subclinical depressive symptoms increase the risk of developing Alzheimer's disease (AD). The neurobiological mechanisms underlying this link may involve stress system dysfunction, notably related to the hippocampus which is particularly sensitive to AD. We aimed to investigate the links between blood stress markers and changes in brain regions involved in the stress response in older adults with or without subclinical depressive symptoms., Methods: This cross-sectional study was conducted using baseline data from the Age-Well trial. Cognitively unimpaired (CU) older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15-item Geriatric Depression Scale) were included in the analyses. Blood cortisol, epinephrine and norepinephrine were measured; as well as the resting-state functional connectivity (rs-FC) between, and gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields. Blood stress markers levels and neuroimaging measures were compared between groups; then regression analyses were conducted between these measures., Results: DepS participants showed higher plasma epinephrine levels, which was associated with greater rs-FC between the CA1 and Subiculum hippocampal subfields and the hypothalamus. Lower GM volume in the CA1 and DG/CA2-3-4 subfields was also found in DepS. No between-group differences were observed for blood cortisol and norepinephrine., Conclusions: Our findings show that subclinical depressive symptoms are associated with increased sympatho-adrenomedullary axis activity, together with lower GM volume in a hippocampal subfield (i.e., CA1) particularly sensitive to AD. While causation cannot be inferred, these results suggest that screening and treating subclinical depressive symptoms in CU older adults could reduce AD risk., Trial Registration: ClinicalTrials.gov Identifier: NCT02977819, Registration Date: 2016-11-25., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to the examinations, and the Age-Well randomized clinical trial was approved by the ethics committee (Comité de Protection des Personnes Nord-Ouest III, Caen, France; trial registration number: EudraCT: 2016–002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819; registration date: 2016–11-25). Consent for publication: Not applicable. Competing interests: Dr Touron reported grant from French Ministry of Higher Education and Research (PhD grant). Dr Kuhn reported grant from the French Ministry of Higher Education and Research (PhD grant), and support from INSERM (PhD). Dr Marchant, Dr Chételat and Dr Poisnel reported grants from European Union’s Horizon 2020 Research and Innovation Program under grant agreement No 667696 during the conduct of the study. Dr Marchant reported grants from a Senior Fellowship from the Alzheimer’s Society (AS-SF-15b-002). Dr Chételat reported grants, personal fees and nonfinancial support from Institut National de la Santé et de la Recherche Médicale (INSERM); personal fees from Fondation Entrepreneurs MMA, grants and personal fees from Fondation Alzheimer, grants from Région Normandie, grants from Fondation Recherche Alzheimer, grants from Association France Alzheimer, outside the submitted work. No other disclosures were reported., (© 2025. The Author(s).)

Background: Accumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer's disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly associated with AD markers or instead amplifies age-related effects, potentially increasing susceptibility of developing AD in cognitively healthy older adults., Methods: This cross-sectional study used baseline data of 129 community-dwelling cognitively healthy older adults from the Age-Well trial (NCT02977819), aged 65 years and older enrolled between 2016 and 2018, in France. Using linear regressions, we analyzed the relationship between an innovative marker of telomere shortening, the percentage of CST (%CST), structural, functional and molecular neuroimaging outcomes, and multiple blood-based biomarkers related to AD pathophysiology. The effect of apolipoprotein E ε4 genotype (APOE4) was assessed on these relationships using interaction analysis., Results: A higher %CST was associated with lower global kurtosis fractional anisotropy (β = -.230; P = .010), particularly in frontal and temporal regions. A higher %CST was also related to higher plasma levels of Neurofilament light chain (β = .195; P = .020) and a lower subiculum volume (β = -.206; P = .020), although these associations did not meet the threshold for multiple comparisons. %CST was not associated with AD-related neuroimaging markers, including the AD-sensitive gray matter pattern (β = -.060; P = .441), glucose metabolism pattern (β = -.099; P = .372), brain perfusion pattern (β = -.106; P = .694) or hippocampus volume (β = -.106; P = .194). In APOE4 carriers, higher %CST was associated with lower subiculum (β = -.423; P = 0.003), DG (β = -.410; P = 0.018) and CA1 volumes (β = -.373; P = 0.024), even though associations with DG and CA1 volumes did not survive multiple comparison., Conclusions: Although an increase in %CST does not appear to be directly linked to the pathophysiology of AD in cognitively healthy older adults, it could heighten the susceptibility of APOE4 carriers to develop AD plausibly due to greater vulnerability to age-related effects. However, longitudinal studies would be necessary to determine whether %CST influences the development and progression of AD later in life., Competing Interests: Declarations. Ethics approval and consent to participate: All participants gave their written informed consent to participate in the study. The Age-Well RCT, sponsored by Institut National de la Santé et de la Recherche Médicale (INSERM), was approved by the ethics committee (CPP Nord-Ouest III, Caen). Competing interests: Dr Chételat reported receiving grants, personal fees, and nonfinancial support from the Institut National de la Santé et de la Recherche Médicale (INSERM), as well as grants from the European Union's Horizon 2020 Research and Innovation Program (grant 667696) during the conduct of the study and grants and personal fees from Fondation Entrepreneurs MMA and Fondation Alzheimer and grants from MMA and Région Normandie outside the submitted work. Dr Poisnel reported grants and nonfinancial support from INSERM grants from European Union's Horizon 2020 Research and Innovation Program [grant 667696] during the conduct of the study and grants from Région Normandie, Ministry of Higher Education and Research and INSERM outside the submitted work; and has participated in the data safety monitoring board of the Age-Well trial and to the executive committee of Medit-Ageing. No other disclosures were reported., (© 2024. The Author(s).)

Background and Objectives: Studies are sparse regarding the association between the informant-reported subjective memory decline (informant report) and Alzheimer disease (AD) biomarkers. This study thus aimed at determining the clinical relevance of the informant report throughout the AD clinical continuum, by assessing its specific relationships with amyloid deposition, cognition, and neurodegeneration., Methods: Participants from the Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce (IMAP+) primary cohort and the Alzheimer Disease Neuroimaging Initiative (ADNI) replication cohort were included; all underwent multimodal neuroimaging and neuropsychological assessments. Follow-up data of IMAP+ participants over up to 36 months were also used for longitudinal analyses. The informant report was measured with the Cognitive Difficulties Scale (IMAP+) and Everyday Cognition (ADNI). General linear models were used to assess the cross-sectional associations between the informant report and amyloid-PET, cognitive performances, and neurodegeneration (atrophy and hypometabolism) in Alzheimer signature areas; while longitudinal links were assessed in IMAP+ with linear mixed-effects models., Results: A total of 110 IMAP+ participants were included, including 32 cognitively unimpaired older individuals (controls, age: 70.91 ± 6.57 years, female: 50%), 25 patients with subjective cognitive decline (SCD, 65.88 ± 6.64, 40%), 35 with mild cognitive impairment (MCI, 72.49 ± 7.5, 34%), and 18 with Alzheimer-type dementia (AD dementia, 68.17 ± 8.59, 28%). Seven hundred thirty-one ADNI participants were included, including 157 controls (74.21 ± 5.95, 55%), 84 with SCD (72.00 ± 5.41, 63%), 369 with MCI (71.84 ± 7.4, 44%), and 121 with AD dementia (74.29 ± 7.75, 40%). In IMAP+, a higher informant report strongly correlated to greater amyloid-PET, specifically in patients with MCI (β = 0.48, p = 0.003), and to lower cognitive performance in patients with SCD (global cognition, β = -0.41, p = 0.04) and MCI (memory, β = -0.37, p = 0.03). Findings in patients with MCI were replicated in the ADNI (amyloid-PET, β = 0.25, p < 0.001; memory, β = -0.22, p < 0.001) and extended to neurodegeneration in AD signature areas (β = -0.2, p < 0.001). Longitudinal analyses in IMAP+ showed links with global cognitive decline over time in patients with MCI (estimate -0.74, SE 0.26, p = 0.005) and SCD (estimate -0.36, SE 0.26, p = 0.02) where a higher baseline informant report also predicted an increased amyloid-PET over time (estimate 0.008, SE 0.003, p = 0.02)., Discussion: Altogether, our findings suggest that the informant report is particularly relevant in patients with MCI where it strongly relates to higher amyloid-PET, indicative of impairment due to AD., Trial Registration Information: ClinicalTrials.gov Identifier: NCT01638949., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Rapid eye movement (REM) sleep is markedly altered in Alzheimer's disease (AD), and its reduction in older populations is associated with AD risk. However, little is known about the underlying brain mechanisms. Our objective was to investigate the relationships between REM sleep integrity and amyloid deposition, gray matter volume, and perfusion in aging., Methods: We included 121 cognitively unimpaired older adults (76 women, mean age 68.96 ± 3.82 years), who underwent a polysomnography, T1-weighted magnetic resonance imaging, early and late Florbetapir positron emission tomography scans to evaluate gray matter volume, perfusion, and amyloid deposition. We computed indices reflecting REM sleep macro- and microstructural integrity (ie, normalized electroencephalographic spectral power values). Voxel-wise multiple regression analyses were conducted between REM sleep indices and neuroimaging data, controlling for age, sex, education, the apnea-hypopnea index, and the apolipoprotein E ε4 status., Results: Lower perfusion in frontal, anterior and posterior cingulate, and precuneus areas was associated with decreased delta power and electroencephalographic slowing (slow/fast frequencies ratio), and increased alpha and beta power. To a lower extent, similar results were obtained between gray matter volume and delta, alpha, and beta power. In addition, lower REM sleep theta power was more marginally associated with greater diffuse amyloid deposition and lower gray matter volume in fronto-temporal and parieto-occipital areas., Interpretation: These results suggest that alterations of REM sleep microstructure are associated with greater neurodegeneration and neocortical amyloid deposition in older adults. Further studies are warranted to replicate these findings, and determine whether older adults exhibiting REM sleep alterations are more at risk of cognitive decline and belonging to the Alzheimer's continuum. ANN NEUROL 2023;93:979-990., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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., (© 2022. The Author(s).)

Importance: No 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., Objective: To investigate the effects of meditation training on brain integrity in older adults., Design, Setting, and Participants: Age-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., Interventions: Meditation 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 Measures: Primary 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., Results: Among 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 Relevance: The 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 Registration: ClinicalTrials.gov Identifier: NCT02977819.

Background and Objectives: Self-reflection (the active evaluation of ones thoughts, feelings, and behaviors) can confer protection against adverse health outcomes. Its effect on markers sensitive to Alzheimer disease (AD), however, is unknown. The primary objective of this cross-sectional study was to examine the association between self-reflection and AD-sensitive markers., Methods: This study used baseline data from cognitively unimpaired older adults enrolled in the Age-Well clinical trial and older adults with subjective cognitive decline from the SCD-Well clinical trial. In both cohorts, self-reflection was measured via the reflective pondering subscale of the Rumination Response Scale, global cognition assessed via the Preclinical Alzheimer's Cognitive Composite 5, and a modified late-life Lifestyle-for-Brain-Health (LIBRA) index computed to assess health and lifestyle factors. In Age-Well, glucose metabolism and amyloid deposition were quantified in AD-sensitive gray matter regions via fluorodeoxyglucose- and AV45-PET scans, respectively. Associations between self-reflection and AD-sensitive markers (global cognition, glucose metabolism, and amyloid deposition) were assessed via unadjusted and adjusted regressions. Furthermore, we explored whether associations were independent of health and lifestyle factors. To control for multiple comparisons in Age-Well, false discovery rate-corrected p values ( p FDR ) are reported., Results: A total of 134 (mean age 69.3 ± 3.8 years, 61.9% women) Age-Well and 125 (mean age 72.6 ± 6.9 years, 65.6% women) SCD-Well participants were included. Across unadjusted and adjusted analyses, self-reflection was associated with better global cognition in both cohorts (Age-Well: adjusted-β = 0.22, 95% CI 0.05-0.40, p FDR = 0.041; SCD-Well: adjusted-β = 0.18, 95% CI 0.03-0.33, p = 0.023) and with higher glucose metabolism in Age-Well after adjustment for all covariates (adjusted-β = 0.29, 95% CI 0.03-0.55, p FDR = 0.041). Associations remained following additional adjustment for LIBRA but did not survive false discovery rate (FDR) correction. Self-reflection was not associated with amyloid deposition (adjusted-β = 0.13, 95% CI -0.07 to 0.34, p FDR = 0.189)., Discussion: Self-reflection was associated with better global cognition in 2 independent cohorts and with higher glucose metabolism after adjustment for covariates. There was weak evidence that relationships were independent from health and lifestyle behaviors. Longitudinal and experimental studies are warranted to elucidate whether self-reflection helps preserve cognition and glucose metabolism or whether reduced capacity to self-reflect is a harbinger of cognitive decline and glucose hypometabolism., Trial Registration Information: Age-Well: NCT02977819; SCD-Well: NCT03005652., (© 2022 American Academy of Neurology.)

Mindfulness-based programs (MBPs) are increasingly utilized to improve mental health. Interest in the putative effects of MBPs on cognitive function is also growing. This is the first meta-analysis of objective cognitive outcomes across multiple domains from randomized MBP studies of adults. Seven databases were systematically searched to January 2020. Fifty-six unique studies (n = 2,931) were included, of which 45 (n = 2,238) were synthesized using robust variance estimation meta-analysis. Meta-regression and subgroup analyses evaluated moderators. Pooling data across cognitive domains, the summary effect size for all studies favored MBPs over comparators and was small in magnitude (g = 0.15; [0.05, 0.24]). Across subgroup analyses of individual cognitive domains/subdomains, MBPs outperformed comparators for executive function (g = 0.15; [0.02, 0.27]) and working memory outcomes (g = 0.23; [0.11, 0.36]) only. Subgroup analyses identified significant effects for studies of non-clinical samples, as well as for adults aged over 60. Across all studies, MBPs outperformed inactive, but not active comparators. Limitations include the primarily unclear within-study risk of bias (only a minority of studies were considered low risk), and that statistical constraints rendered some p-values unreliable. Together, results partially corroborate the hypothesized link between mindfulness practices and cognitive performance. This review was registered with PROSPERO [CRD42018100904]., (© 2021. The Author(s).)

Background: Depressive and anxiety symptoms are frequent in Alzheimer's disease and associated with increased risk of developing Alzheimer's disease in older adults. We sought to examine their relationships to Alzheimer's disease biomarkers across the preclinical and clinical stages of the disease., Method: Fifty-six healthy controls, 35 patients with subjective cognitive decline and 56 amyloid-positive cognitively impaired patients on the Alzheimer's continuum completed depression and anxiety questionnaires, neuropsychological tests and neuroimaging assessments. We performed multiple regressions in each group separately to assess within group associations of depressive and anxiety symptoms with either cognition (global cognition and episodic memory) or neuroimaging data (gray matter volume, glucose metabolism and amyloid load)., Results: Depressive symptoms, but not anxiety, were higher in patients with subjective cognitive decline and cognitively impaired patients on the Alzheimer's continuum compared to healthy controls. Greater depressive symptoms were associated with higher amyloid load in subjective cognitive decline patients, while they were related to higher cognition and glucose metabolism, and to better awareness of cognitive difficulties, in cognitively impaired patients on the Alzheimer's continuum. In contrast, anxiety symptoms were not associated with brain integrity in any group., Conclusion: These data show that more depressive symptoms are associated with greater Alzheimer's disease biomarkers in subjective cognitive decline patients, while they reflect better cognitive deficit awareness in cognitively impaired patients on the Alzheimer's continuum. Our findings highlight the relevance of assessing and treating depressive symptoms in the preclinical stages of Alzheimer's disease., Competing Interests: GP was a member of the DSMB of the Age-well trial for the Inserm Partner (not paid). GC was Member of the External Advisory Board (EAB) of the Lifebrain H2020 European project and of the Operational Committee of the Foundation Plan Alzheimer (personal fees) and of the Imaging Scientific Advisory Groups of European Prediction of Alzheimer’s Disease (EPAD) Consortium, EU (not paid). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moulinet, Touron, Mézenge, Dautricourt, De La Sayette, Vivien, Marchant, Poisnel and Chételat.)

Background: This study assesses the relationships between dynamic functional network connectivity (DFNC) and dementia risk., Methods: DFNC of the default mode (DMN), salience (SN), and executive control networks was assessed in 127 cognitively unimpaired older adults. Stepwise regressions were performed with dementia risk and protective factors and biomarkers as predictors of DFNC., Results: Associations were found between times spent in (i) a "weakly connected" state and lower self-reported engagement in early- and mid-life cognitive activity and higher LDL cholesterol; (ii) a "SN-negatively connected" state and higher blood pressure, higher depression score, and lower body mass index (BMI); (iii) a "strongly connected" state and higher self-reported engagement in early-life cognitive activity, Preclinical Alzheimer's cognitive composite-5 score, and BMI; and (iv) a "DMN-negatively connected" state and higher self-reported engagement in early- and mid-life stimulating activities and lower LDL cholesterol and blood pressure. The lower number of state transitions was associated with lower brain perfusion., Conclusion: DFNC states are differentially associated with dementia risk and could underlie reserve., (© 2022. The Author(s).)

Introduction: Physical inactivity and female sex are independently associated with increased Alzheimer's disease (AD) lifetime risk. This study investigates the possible interactions between sex and physical activity on neuroimaging biomarkers., Methods: In 134 cognitively unimpaired older adults (≥65 years, 82 women) from the Age-Well randomized controlled trial (baseline data), we investigated the association between physical activity and multimodal neuroimaging (gray matter volume, glucose metabolism, perfusion, and amyloid burden), and how sex modulates these associations., Results: The anterior cingulate cortex volume was independently associated with sex and physical activity. Sex and physical activity interacted on perfusion and amyloid deposition in medial parietal regions, such that physical activity was related to perfusion only in women, and to amyloid burden only in men., Discussion: Physical activity has both sex-dependent and sex-independent associations with brain integrity. Our findings highlight partly distinct reserve mechanisms in men and women, which might in turn influence their risk of AD., Highlights: Sex and physical activity have been linked to Alzheimer's disease (AD) progression.The association of sex and physical activity with brain health is partly independent.Different reserve mechanisms exist in men and women., Competing Interests: Dr. Chételat reported grants, personal fees, and non‐financial support from Institut National de la Santé et de la Recherche Médicale (Inserm), grants from European Union's Horizon 2020 research and innovation programme under grant agreement No 667696 (PI), grants from Fondation d'entreprise MMA des Entrepreneurs du Futur, during the conduct of the study; personal fees from Fondation Entrepreneurs MMA, grants and personal fees from Fondation Alzheimer, grants from Région Normandie, grants from Fondation Recherche Alzheimer, and grants from Association France Alzheimer, outside the submitted work. No other disclosures were reported., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Anxiety and depressive symptoms are associated with impaired well-being, higher risk of developing psychoaffective disorders and are risk factors for Alzheimer's disease (AD). To further understand their relevance and the mechanisms underlying their link with AD, our aims were to assess how anxiety and depressive symptoms changed with age and related to AD neuroimaging biomarkers across the adult lifespan, while also exploring sex specificities., Methods: 210 cognitively normal participants aged 19-86 years (101 men, 109 women) completed assessments of anxiety and depressive symptoms with the STAI-A and MADRS respectively, and neuroimaging measurements including structural MRI, FDG-PET and amyloid-PET. 167 of those were followed-up over 1.5-3 years. Multiple regressions were performed to assess the links between anxiety or depressive symptoms versus age, global cognition or each imaging modality, both cross-sectionally and longitudinally; and general linear models we used to test the interactive effect of sex on these associations., Results: Depressive symptoms decreased with age, while anxiety symptoms increased only among women. Higher anxiety symptoms were associated with lower grey matter (GM) volume and glucose metabolism, with an interaction of sex, this relationship being significant only in women. Longitudinally, only low baseline GM volume predicted an increase in anxiety symptoms with time., Limitations: Only 43% of participants reported depressive symptoms. Despite additional analyses, the low variability in the measure might have prevented us from detecting subtle changes., Conclusions: This study emphasizes the need to consider anxiety symptoms in assessments for dementia risk, particularly in women., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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 of their 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 ( Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce /Alzheimer's Disease Neuroimaging Initiative): 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 ( 18 F-fluorodeoxyglucose-PET)] were assessed across clinical groups and the interactive effect of the level of cognitive impairment within the entire sample was assessed. Analyses were adjusted for age, sex and education, and repeated including only the amyloid-positive participants. In Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce , 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 Alzheimer's Disease Neuroimaging Initiative 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., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: As the population ages, maintaining mental health and well-being of older adults is a public health priority. Beyond objective measures of health, self-perceived quality of life (QoL) is a good indicator of successful aging. In older adults, it has been shown that QoL is related to structural brain changes. However, QoL is a multi-faceted concept and little is known about the specific relationship of each QoL domain to brain structure, nor about the links with other aspects of brain integrity, including white matter microstructure, brain perfusion and amyloid deposition, which are particularly relevant in aging. Therefore, we aimed to better characterize the brain biomarkers associated with each QoL domain using a comprehensive multimodal neuroimaging approach in older adults., Methods: One hundred and thirty-five cognitively unimpaired older adults (mean age ± SD: 69.4 ± 3.8 y) underwent structural and diffusion magnetic resonance imaging, together with early and late florbetapir positron emission tomography scans. QoL was assessed using the brief version of the World Health Organization's QoL instrument, which allows measuring four distinct domains of QoL: self-perceived physical health, psychological health, social relationships and environment. Multiple regression analyses were carried out to identify the independent global neuroimaging predictor(s) of each QoL domain, and voxel-wise analyses were then conducted with the significant predictor(s) to highlight the brain regions involved. Age, sex, education and the other QoL domains were entered as covariates in these analyses. Finally, forward stepwise multiple regressions were conducted to determine the specific items of the relevant QoL domain(s) that contributed the most to these brain associations., Results: Only physical health QoL was associated with global neuroimaging values, specifically gray matter volume and white matter mean kurtosis, with higher physical health QoL being associated with greater brain integrity. These relationships were still significant after correction for objective physical health and physical activity measures. No association was found with global brain perfusion or global amyloid deposition. Voxel-wise analyses revealed that the relationships with physical health QoL concerned the anterior insula and ventrolateral prefrontal cortex, and the corpus callosum, corona radiata, inferior frontal white matter and cingulum. Self-perceived daily living activities and self-perceived pain and discomfort were the items that contributed the most to these associations with gray matter volume and white matter mean kurtosis, respectively., Conclusions: Better self-perceived physical health, encompassing daily living activities and pain and discomfort, was the only QoL domain related to brain structural integrity including higher global gray matter volume and global white matter microstructural integrity in cognitively unimpaired older adults. The relationships involved brain structures belonging to the salience network, the pain pathway and the empathy network. While previous studies showed a link between objective measures of physical health, our findings specifically highlight the relevance of monitoring and promoting self-perceived physical health in the older population. Longitudinal studies are needed to assess the direction and causality of the relationships between QoL and brain integrity., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear., Objective: To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism., Design, Setting, and Participants: This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses., Main Outcomes and Measures: Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes., Results: Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms., Conclusions and Relevance: The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk., Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

268 patients with suspected lung cancer were examined over the period 1 January 1972 to 31 May 1974. On the basis of the 735 investigations performed, a 6-8 h workup program has been established including physical and functional examination, standard X-rays and hilar tomography, endoscopy and biopsy for cytologic or histologic study. Several biopsy technics are described and their indications tabulated according to their efficiency in relation to the radiologic aspect of the lesion. The number of cases and the yield for each technic are summarized in Table 2.