Search

Background: Independent contributions of enlarged perivascular spaces (ePVS) to cognition remain elusive due to their intertwining with white matter hyperintensities (WMH). We studied the unique and shared effects of ePVS and WMH on cognitive performance in 397 subjects along the Alzheimer's disease (AD) continuum. Methods: We quantified baseline volumes of WMH, basal ganglia (BG) and centrum semiovale (CSO) ePVS in participants of the multicentre DELCODE study (Controls = 81/Subjective Cognitive Decline = 151/Mild Cognitive Impairment = 79/AD = 45/AD relatives = 41) and regressed age, sex, pTau181, and image quality out of them. We established cognitive domain scores (memory, working memory, language, executive, visuospatial) based on a comprehensive cognitive test battery and confirmatory factor analysis, and assessed preclinical Alzheimer's cognitive composite (PACC5) scores. Using principle component (PC) analysis, we estimated unique and shared variances. We began by extracting the first PC (PC1)—a weighted average of ePVS and WMH volumes—which indicated overall cerebrovascular dysfunction (Figure 1). We then regressed PC1 out of ePVS and WMH volumes to estimate their unique variances, which should reflect glymphatic function and white matter (WM) damage, respectively. For each cognitive domain, we compared null linear regression models (years of education, age, sex, pTau181, and image quality) to those enriched with the shared (PC1) and unique variances of BG‐/CSO‐ePVS and WMH. Results: Overall cerebrovascular dysfunction—PC1—substantially affected all cognitive domains negatively. BG‐ePVS' unique variance—surrogate for glymphatic function—contributed to better memory (B = 0.19, 95%‐CI[0.02;0.36]), language (B = 0.25, 95%‐CI[0.09;0.42]) and PACC5 performance (B = 0.25, 95%‐CI[0.07;0.43]) beyond overall cerebrovascular dysfunction. However, WM damage—WMH unique variance—contributed more substantially and negatively to the same cognitive domains (memory: R²PC1 = 0.365

Background: Altered fluctuations in blood oxygen level dependent (BOLD) signal during resting‐state functional magnetic resonance imaging (rs‐fMRI) have been considered indicative of decreased cerebrovascular health. Previous studies reported changes in BOLD fluctuations associated with Alzheimer's dementia (AD) and white matter hyperintensities (WMH). However, to date, there has been no large‐scale study involving patients with AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and control subjects (CON) that has explored local AD‐ and WMH‐related effects in BOLD fluctuations. Method: We calculated the voxel‐based coefficient of variation (CV: standard deviation divided by the mean) and the relative CV (rCV: CV divided by the mean CV of the whole‐brain) of the rs‐fMRI BOLD signal in the large multicentric DZNE DELCODE cohort. After spatial preprocessing, regression of movement parameters, movement spikes, and scanner drift, low‐pass filtering and exclusion of subjects with high motion, CV and rCV maps were obtained and compared with respect to (A) clinical diagnosis (AD: n = 79; MCI: n = 113; SCD: n = 314; CON: n = 192) and cerebrospinal fluid Aβ42/40 (AD: n = 41; MCI: n = 64; SCD: n = 139; CON: n = 77); and (B) effects of vascular‐related lesions, here WMH. Result: The CV and rCV of the precuneus and middle cingulum indicated increasingly reduced BOLD fluctuation across the clinical groups towards AD. Interestingly, we observed increases in rCV in the basal ganglia and frontal white matter in AD compared with CON. Of note, lower CSF Aβ42/40 (more pathological) was associated to reduced CV and rCV in the precuneus and with lower rCV in the right angular gyrus. Subjects with higher WMH volume showed widespread reductions of CV in white matter near the left angular gyrus and reduced rCV in large portions of white matter and subcortical gray matter. Conclusion: The AD spectrum exhibits altered BOLD fluctuations that are at least partially tied to actual amyloid differences. Larger WMH are associated with reduced BOLD signal fluctuations consistent with widespread white matter pathology ‐ beyond the effects of diagnosis. We argue that rCV is a useful complement to CV to detect these changes that might reflect cerebrovascular impairment. [ABSTRACT FROM AUTHOR]

Background: Perivascular spaces in the brain can become enlarged (ePVS); their temporal dynamics remain under increasing debate. We studied automatic ePVS measurements obtained from 870 subjects along the AD continuum over the course of three years. Method: We measured centrum semiovale (CSO) and basal ganglia (BG) ePVS volumes computationally in the multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) (Table 1; 870 subjects; 51% female, mean age 70.85 (SD 6.16), up to 4 annual time points; 2487 sets of T1w and FLAIR). We segmented ePVS using a multiscale Hessian‐based filtering method leveraging T1w and FLAIR imaging and validated segmentation against clinical visual ratings. We studied local longitudinal changes via the sandwich estimator toolbox and linear mixed‐effect modelling and tested for effects of age, hypertension, clinical diagnosis, ApoE4 status, pTau181, and Aβ42/40 on ePVS trajectories. Result: BG‐ePVS and CSO‐ePVS became more voluminous over time (Table 2 and Figure 1A‐C; BG: B = 0.04 [95%‐CI 0.03‐0.05], p<0.001; CSO: B = 0.02 [95%‐CI 0.00‐0.04], p<0.031). The age of the patient at baseline determined the baseline volume of ePVS in the BG (B = 0.13 [95%‐CI 0.09‐0.17], p<0.001), but not in the CSO‐ePVS (p = 0.245). WMH can form around ePVS (Figure 1D) and their progression was correlated with PVS enlargement (BG: B = 0.05 [95%‐CI 0.04‐0.07], p<0.001; CSO: B = 0.19 [95%‐CI 0.15‐0.22], p<0.001). No other predictors contributed significantly to longitudinal ePVS changes. Conclusion: Ageing is a major contributor to the volumetric expansion of ePVS over time. WMH and ePVS growth are associated, suggesting shared underlying pathological mechanisms. [ABSTRACT FROM AUTHOR]

Background: Inflammation, vascular disease and Alzheimer's Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction. Method: Leveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aβ42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory. Result: Lower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers. Conclusion: Lower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology. [ABSTRACT FROM AUTHOR]

Introduction: Cholinesterase inhibitors can enhance cognitive functions in healthy elderly and delay cognitive decline in patients with Alzheimer‘s disease (AD). However, not everyone benefits from this treatment (non-responders). Current studies show clinical meaningful improvements only in one third of AD patients treated with cholinesterase inhibitors. Methods: Here we investigate structural magnetic resonance imaging of the basal forebrain cholinergic system volume (BFvol) as a potential predictor of cognitive response to a single dose of galantamine in healthy adults (n = 18; 59 to 75 years). Results: We observed that the cognitive response to galantamine, more specifically the attention-dependent filtering performance in a delayed match-to-sample working memory task, correlated with BFvol: Only participants with high BFvol showed a significant positive effect of galantamine on the ability to filter out distracting information during the workingmemory encoding process. Discussion: Future studies need to assess whether BFvol may serve as a predictor of the galantamine response in AD patients, too. [ABSTRACT FROM AUTHOR]