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Introduction White matter hyperintensities (WMH) are often described in Alzheimer's disease (AD), but their topography and specific relationships with cognition remain unclear. Methods Regional WMH were estimated in 54 cognitively impaired amyloid beta–positive AD (Aβpos‐AD), compared to 40 cognitively unimpaired amyloid beta–negative older controls (Aβneg‐controls) matched for vascular risk factors. The cross‐sectional association between regional WMH volume and cognition was assessed within each group, controlling for cerebral amyloid burden, global cortical atrophy, and hippocampal atrophy. Results WMH volume was larger in Aβpos‐AD compared to Aβneg‐controls in all regions, with the greatest changes in the splenium of the corpus callosum (S‐CC). In Aβpos‐AD patients, larger total and regional WMH volume, especially in the S‐CC, was strongly associated with decreased cognition. Discussion WMH specifically contribute to lower cognition in AD, independently from amyloid deposition and atrophy. This study emphasizes the clinical relevance of WMH in AD, especially posterior WMH, and most notably S‐CC WMH.

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 White matter hyperintensities (WMH) are frequently found in Alzheimer’s disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aβ) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aβ burden, glucose hypometabolism, and gray matter volume reduction. Methods In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aβ deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. Results There were no significant associations between global Aβ burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aβ deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. Conclusions This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

Objective:Physical activity has been associated with a decreased risk for dementia, but the mechanisms underlying this association remain to be determined. Our objective was to assess whether cardiovascular risk factors mediate the association between physical activity and brain integrity markers in older adults.Methods:Participants from the Age-Well study underwent, at baseline, a physical activity questionnaire, cardiovascular risk factors collection (systolic blood pressure, body mass index [BMI], current smoker status, HDL-cholesterol, total-cholesterol, insulin) and multimodal neuroimaging (structural-MRI, diffusion-MRI, FDG-PET, Florbetapir-PET). Multiple regressions were conducted to assess the association between physical activity, cardiovascular risk factors, and neuroimaging. Mediation analyses were performed to test whether cardiovascular risk factors mediated the associations between physical activity and neuroimaging.Results:134 cognitively unimpaired older adults (≥65 years) were included. Higher physical activity was associated with higher grey matter (GM) volume (ß=0.174, p=0.030) and cerebral glucose metabolism (ß=0.247, p=0.019), but not with amyloid deposition or white matter integrity. Higher physical activity was associated with lower insulin and BMI, but not with the other cardiovascular risk factors. Lower insulin and BMI were related to higher GM volume, but not to cerebral glucose metabolism. When controlling for insulin and BMI, the association between physical activity and cerebral glucose metabolism remained unchanged, while the association with GM volume was lost. When insulin and BMI were entered in the same model, only BMI remained a significant predictor of GM volume. Mediation analyses confirmed that insulin and BMI mediated the association between physical activity and GM volume. Analyses were replicated within Alzheimer’s disease-sensitive regions, and results remained overall similar.Conclusions:The association between physical activity and GM volume is mediated by changes in insulin and BMI. In contrast, the association with cerebral glucose metabolism seems to be independent from cardiovascular risk factors. Older adults practicing physical activity have cardiovascular benefits, through the maintenance of a lower BMI and insulin, resulting in greater structural brain integrity. This study has strong implications as understanding how physical activity affects brain health may help developing strategies to prevent or delay age-related decline.Trial Registration Information:EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

In a population initially presenting with memory complaints and depicting a CSF AD signature, a high proportion of medial temporal amnesia is disclosed as expected, but also a proportion of dysexecutive amnesia and normal FCSRT.

White matter hyperintensities (WMH), frequently seen in older adults, are usually considered vascular lesions, and participate in the vascular contribution to cognitive impairment and dementia. However, emerging evidence highlights the heterogeneity of WMH pathophysiology, suggesting that non‐vascular mechanisms could also be involved, notably in Alzheimer's disease (AD). This led to the alternative hypothesis that in AD, part of WMH may be secondary to AD‐related processes. The current perspective brings together the arguments from different fields of research, including neuropathology, neuroimaging and fluid biomarkers, and genetics, in favor of this alternative hypothesis. Possible underlying mechanisms leading to AD‐related WMH, such as AD‐related neurodegeneration or neuroinflammation, are discussed, as well as implications for diagnostic criteria and management of AD. We finally discuss ways to test this hypothesis and remaining challenges. Acknowledging the heterogeneity of WMH and the existence of AD‐related WMH may improve personalized diagnosis and care of patients.

Background: Alzheimer’s disease and related diseases (ADRD) are a major cause of health-related cost increase. Objectives: This study aimed to estimate the real medical direct costs of care of patients followed at a memory center, and to investigate potential associations between patients’ characteristics and costs. Design: Cross-sectional analyses conducted on matched data between clinical data of a cohort of patients and the claims database of the French Primary Health Insurance Fund. Setting: Memory center in France Participants: Patients attending a memory center with subjective cognitive complaint Measurements: Medical or nonmedical direct costs (transportation) reimbursed by the French health insurance during the one year after the first memory visit, and socio-demographic, clinical, cognitive, functional, and behavioral characteristics were analyzed. Results: Among 2,746 patients (mean ± SD age 79.9 ± 8 years, 42.4% of patients with dementia), the total direct cost was on average € 9,885 per patient during the year after the first memory visit: € 7,897 for patients with subjective cognitive complaint, € 9,600 for patients with MCI, and € 11,505 for patients with dementia. A higher functional and cognitive impairment, greater behavioral disorders, and a higher caregiver burden were independently associated with a higher total direct cost. A one-point decrease in the Instrumental Activities of Daily Living score was associated with a € 1,211 cost increase. The cost was higher in patients with Parkinson’s disease, and Lewy body disease compared to patients with AD. Diabetes mellitus, anxiety disorders and number of drugs were also significantly associated with greater costs. Conclusions: Higher real medical direct costs were independently associated with cognitive, functional, and behavioral impairment, diabetes mellitus, anxiety disorders, number of drugs, etiologies as well as caregiver burden in patients attending a memory center. The identification of factors associated to higher direct costs of care offers additional direct targets to evaluate how interventions conducted in patients with NCD impact direct costs of care.