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Background: White matter hyperintensities (WMH) are frequent in the older adults and are associated to worse cognitive performances and to dementia. Alzheimer's disease is associated with greater brain WMH volume, particularly in posterior regions, compared to cognitively unimpaired older adults. The aim of this study was to assess in details the topography of brain WMH and their links with cognition in amyloid‐positive cognitively impaired older adults, i.e. patients in the Alzheimer's continuum (ALZ), compared to amyloid‐negative cognitively unimpaired adults (controls). Method: Fifty‐four ALZ and forty controls matched for age and cardiovascular risk factors were included in the IMAP cohort (Caen, France). Amyloid status was based on Florbetapir PET scans. In addition, each participant underwent 1) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of WMH in the frontal, parietal, temporal, occipital lobes and in the corpus callosum (CC) region and subregions; 2) a comprehensive neuropsychological assessment of global cognition, episodic memory, working memory and executive functions. The regional volumes of WMH were compared between groups and the relationship of regional WMH to cognition was assessed within the ALZ patients. Result: WMH volumes were significantly higher in ALZ patients than in controls in all brain regions, with highest differences in the splenium of the CC (p= 0.00005, size effect r = 0.42) and lowest effects in the frontal lobe (p = 0.025, size effect r = 0.23) (Figure 1). Within the ALZ patient group, WMH volumes of the CC, particularly in the splenium, were negatively associated with global cognition, working memory and executive functions (Figure 2). Total and frontal WMH volumes were also negatively associated with working memory, but this relationship did not survive correction for multiple comparisons. Conclusion: WMH in the splenium of the CC most specifically characterize amyloid‐positive patients in the Alzheimer's continuum and correlate to worse cognition especially in frontal cognitive functions. These specific ALZ‐related WMH are probably not only due to small vessel disease and could be secondary to neurodegenerescence. [ABSTRACT FROM AUTHOR]

Background: Self‐reflection is conceptualised as an introspective process that involves active evaluation of one's thoughts, feelings and behaviours. Engagement in self‐reflection is thought to yield more adaptive stress responses, that in turn result in better short‐term (e.g., reduced inflammatory responses to stressors) and long‐term (e.g., recovery from major depression) outcomes. Despite self‐reflection's known protective effect against adverse health outcomes, the association between self‐reflection and Alzheimer's disease (AD) risk is unknown. Method: Baseline data from 134 healthy older adults (mean age=69.3) enrolled in the Age‐Well clinical trial and 125 older adults with subjective cognitive decline (mean age=72.5) from the SCD‐Well clinical trial were included. All participants completed an assessment of self‐reflection. Modified versions of the Preclinical Alzheimer's Cognitive Composite 5 were used to measure global cognition in both cohorts. Additionally, in Age‐Well, glucose metabolism and amyloid deposition were assessed with PET scans, and the Lifestyle‐for‐Brain‐Health (LIBRA) AD‐risk index computed to assess health and lifestyle behaviours. Separate linear regressions were run to determine associations between self‐reflection levels and AD markers (i.e., global cognition, glucose metabolism, and amyloid deposition). Analyses adjusted for available prognostic characteristics associated with AD (e.g., age, sex, education and APOE4 status) and levels of psychological distress (i.e., depression and rumination). Furthermore, to explore the potential mechanism linking self‐reflection with AD markers, the relationship between self‐reflection and LIBRA scores was investigated. Result: Self‐reflection was positively associated with global cognition in both cohorts (Age‐Well: β=0.18, p=0.023; SCD‐Well: β=0.20, p=0.024) and glucose metabolism (Age‐Well: β=0.29, p=0.027; see Figure). No relationship, however, was found with amyloid deposition (Age‐Well: β=0.13, p=0.198). Self‐reflection was associated with LIBRA scores (Age‐Well: β=‐0.31, p=0.002), with lower self‐reflection levels associated with poorer health and lifestyle behaviours. Conclusion: Self‐reflection was associated with higher glucose metabolism, and with better global cognition in two independent older adult cohorts. For the first time, we introduce preliminary support for self‐reflection as a potential protective factor against AD‐related decline. Furthermore, the results suggest that self‐reflection may affect AD risk by influencing health and lifestyle behaviours. Both Age‐Well and SCD‐Well are clinical trials. Future work will investigate whether modifying self‐reflection via interventions affects AD markers. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH) are very frequent in ageing and related to worse cognition. Recent studies suggest that WMH in the corpus callosum (CC) are particularly relevant in neurocognitive disorders, as they are strongly associated with lower cognitive performance, as well as amyloid and neurodegeneration biomarkers. This study examined whether WMH in subregions of the CC (genu, body, splenium) affect cross‐sectional and long‐term longitudinal (up to 5 years) cognitive performance in patients recruited from a memory clinic. Method: This study included memory clinic outpatients from the MEMORA cohort who had a brain MRI (T1 and FLAIR scans) within 6 months of the baseline visit. QyScore® software was used for the automatic segmentation of WMH in the CC and hippocampal volumes (HP). The cross‐sectional and longitudinal relationships between regional WMH in the CC and cognitive performance, as measured with the mini‐mental state examination (MMSE), were assessed using multivariable linear regressions and mixed models. Result: Among 236 patients included (mean age 76.2±8.8 years old; mean MMSE 23.6±4.9), 111 were diagnosed with probable Alzheimer’s disease (AD), 20 with vascular cognitive impairment (VCI), 22 with mixed AD‐VCI, 18 with another neurological disease and 65 with a subjective cognitive complaint. Cross‐sectional analyses disclosed that higher WMH in the splenium of the CC were associated with reduced MMSE (p=0.03, n=199) after adjustment for diagnosis and education. The relationship did not remain significant after adjustment for HP and total WMH. Longitudinal analyses with a follow‐up up to 5 years showed that the MMSE declined faster in patients with higher WMH in the splenium of the CC (p<0.001, n=143) after adjustment for education, diagnosis, HP and total WMH (Figure). WMH in the genu and in the body of the CC were not associated with MMSE decline (respectively p=0.92 and p=0.23, n=124, Figure). Conclusion: WMH in the splenium of the CC were associated with cognitive decline, whereas WMH in the genu and the body were not. This study highlights the clinical relevance of posterior CC WMH in a memory clinic population. [ABSTRACT FROM AUTHOR]

Background: Little is known about the prodromal phase of Dementia with Lewy bodies (DLB). In a large prospective cohort of patients attending memory clinics presenting either subjective cognitive impairment (SCI) and mild neurocognitive impairment (MCI) patients, we undertook an ancillary study aiming at detecting early DLB in a longitudinal framework. Method: We conducted a french nationwide prospective cohort of patients with cognitive complaints and a minimum follow‐up of 4 years. Participants in the Memento cohort study were recruited for either isolated subjective cognitive impairment (SCI) or mild neurocognitive impairment (MCI). Among them, patients from 12 memory resource and research centers, representing eight hundred ninety‐two patients were included in the Lewy sub‐study. Probable Pro‐DLB diagnosis was done using a two‐criteria cut‐off score among the four core clinical features of Dementia with Lewy bodies. This Pro‐DLB group was compared to two other groups: one without any core symptoms (NS group), and the one with one core symptom (1S group). A comprehensive cognitive battery, brain 3D volumetric MRI, CSF, FDG PET and amyloid PET were done. Result: The pro‐DLB group comprised 148 patients (16.6%). Compared to the other two groups, the neuropsychological profile of the pro‐DLB group showed, regarding cognition, more multidomain (59.8%) MCI with slower processing speed, semantic and neurovisual impairment, and regarding behavior, a higher proportion of patients with depression, anxiety, and apathy. Pro‐DLB patients also presented more autonomic symptoms, including lower libido, constipation, rhinorrhea, sicca syndrome, and photophobia. The Pro‐DLB group had isolated lower P‐Tau and no difference in terms of amyloid PET and FDG PET. Brain MRI analysis showed widening of sulci including fronto‐insular, occipital and olfactory sulci (FDR corrected). Evolution to dementia was not different between the three groups after 4 years of follow‐up. Conclusion: Patients with pro‐DLB represented 16.6% of SCI and MCI patients, a finding consistent with the proportion observed at the stage of dementia. In addition to the core symptoms, pro‐DLB patients presented cognitive, behavioral and autonomic symptoms. Biomarkers confirmed the non‐Alzheimer profile. The occipital, fronto‐insular, and olfactory bulb involvement on brain MRI was consistent with the symptoms and known neuropathology. [ABSTRACT FROM AUTHOR]

Background: Given the burden related to dementia, identifying prevention targets against cognitive aging and Alzheimer's disease (AD) and related disorders is of high interest. While factors of resilience, i.e. education, physical or cognitive activity, or social network, are thought to mitigate the effect of cerebral damage on cognition, mechanisms involved are not well understood. This work thus aims to investigate the pathways involved in the association between resilience and cognition. Method: Data were collected as part of the Memento study, a French nationwide cohort including patients from 28 memory clinics with either isolated cognitive complaints or mild cognitive impairment. Factors contributing to resilience, such as education level, salary, physical activity, leisure activities, or social network, as well as MRI markers of brain health were collected at baseline. AD cerebrospinal fluid (CSF) biomarkers were assessed in a subsample (n=410). Based on resilience factors, we established a global resilience score using a latent variable from a structural equation model. Structural equation models were also used to evaluate cross‐sectional pathways between resilience, brain ageing biomarkers in relation to cognition, taking into account potential confounders (Figure). Estimates from latent variables were standardized and results reported are for one SD of resilience. Result: Participants' mean age was 70.9 years old, 62% were women, 28% were APOE‐ε4 carriers, and 59% had a CDR score of 0.5. Resilience score obtained for each participants, ranged from ‐2.28 to 2.73. AD CSF biomarkers were all significantly associated with worse cognition. Higher resilience was significantly associated with higher cognitive performances (total βres_cog=0.569, p<.0001). In addition to a direct effect on cognition (direct βres_cog=0.519, p<.0001), this association was partly mediated by an indirect effect of resilience on cognition (indirect βres_cog=0.050, p<.0001) through lower neurodegeneration (direct βres_nd=‐0.128, p<.0001). White matter hyperintensities volume, CSF Aβ42/Aβ40 ratio, and CSF phosphorylated tau were not involved in the association between resilience and cognition. Conclusion: Resilience preserves cognitive functions both directly and indirectly through an apparent protection against neurodegeneration. Beside, AD and small vessel disease markers are not associated with resilience and they do not mediate the protective effect of resilience on cognition. [ABSTRACT FROM AUTHOR]

Background: Brain white matter hyperintensities (WMH) are frequent in older adults, including cognitively unimpaired individuals and are associated to decreased cognitive performances. The prevalence of WMH and their links with cognitive performance and with cortical β‐amyloid (Aβ) burden have been rarely assessed in younger adults. The aim of this study was to assess the impact of WMH in younger and older cognitively unimpaired adults on cognitive performances and the possible interaction with cortical β‐amyloid (Aβ) burden. Method: Two hundred and seventy‐two cognitively unimpaired adults from the community (from the IMAP study and the Age‐Well trial) were enrolled and age‐stratified in 86 younger adults (YA; ≤60 years old) and 187 older adults (OA; >60 years old). All participants underwent i) a comprehensive neuropsychological assessment allowing to obtain composite scores of episodic memory, processing speed, working memory, executive functions, and global cognition; ii) brain structural T1 and FLAIR MRI scans used for automatic segmentation of WMH volumes; and iii) a Florbetapir‐PET scan to measure cortical Aβ. Within each group, the relationships of total and regional WMH to age and cognition were assessed, as well as the impact of cortical Aβ on these relationships. Result: WMH increased with age in both groups but more sharply in OA than YA, particularly in the parietal lobe. Higher WMH volume was associated to worse cognitive performances in both groups. Particularly, working memory, processing speed and global cognition were negatively associated with global and regional WMH in YA and executive functions were negatively associated to occipital WMH in OA. Cortical Aβ differentially impacts the links between WMH and cognition in YA versus OA. Conclusion: WMH volume increases with age and is negatively associated to cognitive performances including in YA. This study argues for the clinical relevance of WMH even in middle age. [ABSTRACT FROM AUTHOR]