Maillard, Pauline

Importance Multidomain lifestyle interventions slow cognitive decline in at-risk older adults, but effects on cerebrovascular injury and whether any effect differs by age or across magnetic resonance imaging (MRI) markers remain unclear. Objectives To test whether a structured multidomain lifestyle intervention, vs a self-guided program, alters trajectories of cerebrovascular MRI markers and whether baseline diffusion MRI estimates subsequent vascular injury. Design, Setting, and Participants POINTER Imaging was a prespecified secondary imaging analysis of the US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) randomized clinical trial conducted at multiple US sites. Starting August 1, 2020, and continuing until March 1, 2023, all newly enrolled US POINTER trial participants who met criteria, including being 60 to 79 years of age and at increased risk for cognitive decline, were given the opportunity to enroll in POINTER Imaging. Annual MRIs were performed at baseline and up to 2 follow-up visits at 12 and 24 months. The imaging study ended May 14, 2025. Interventions Structured multidomain lifestyle arm (supervised exercise, dietary counseling, cognitive and social engagement, and health coaching) vs self-guided educational arm. Main Outcomes and Measures Primary outcomes were cerebrovascular MRI markers of global white matter free water (FW), fractional anisotropy (FA), peak width of skeletonized mean diffusivity (PSMD), analysis along the perivascular space (ALPS) index, white matter hyperintensity (WMH) volume, and incident cerebral microbleeds (CMBs). Age-group analyses (<70 vs ≥70 years) were prespecified. Linear mixed-effects models tested time, intervention arm, age group, and interactions for continuous outcomes; logistic regression evaluated incident CMBs. All analyses were adjusted for sex, hypertension, diabetes, and smoking and were conducted for the evaluable population. Data were analyzed September 5 to December 11, 2025. Results For 959 participants included in the analysis, the mean (SD) age was 68 (5) years, and 594 (61.9%) were female. A significant time × arm × age group interaction was observed for FW (β = 0.050; SE = 0.018; P = .006). In participants younger than 70 years, the structured intervention, compared with the self-guided intervention, attenuated the FW increase over time (β = −0.031; SE = 0.012; P = .009); no intervention arm difference was observed in participants aged 70 years or older (β = 0.019; SE = 0.014; P = .18). No intervention-related interactions were detected (eg, time × intervention arm interaction) for WMH (β = 0.002; SE = 0.016; P = .90), FA (β = 0.016; SE = 0.016; P = .30), PSMD (β = −0.011; SE = 0.021; P = .60), or ALPS (β = 0.006; SE = 0.021; P = .79). Overall, greater odds of incident CMBs were associated with higher baseline FW (odds ratio, 1.63 [95% CI, 1.24-2.14]; P < .001) and PSMD (odds ratio, 1.40 [95% CI, 1.08-1.81]; P < .001). Greater WMH progression was associated with higher baseline FW (β = 0.014; SE = 0.006; P = .02) and lower baseline FA (β = −0.018; SE = 0.006; P = .004). Conclusions and Relevance In this secondary imaging analysis of a randomized clinical trial, FW was the cerebrovascular MRI marker most responsive to lifestyle intervention in adults 60 to 70 years of age, showing attenuated small-vessel disease–related injury. Findings suggested greater microvascular benefit when intensive lifestyle intervention is implemented earlier in late life. Trial Registration ClinicalTrials.gov Identifier: NCT03688126

Abstract Rationale The impacts of COVID-19 vaccination and SAR-CoV-2 infection on brain tissues and structures remain controversial. This study examines whether COVID-19-related exposures are associated with measurable changes in structural magnetic resonance imaging (MRI) using data from the US general population-based Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study. Methods The C4R study is an observational meta-cohort study of 14 NIH-funded population-based cohorts, with directly measured data on COVID-19-related exposures, including vaccination and infection. For this analysis, we included participants with C4R data and paired brain MRI scans from both before and after the onset of the COVID-19 pandemic (defined as March 1, 2020) from two cohorts: the Atherosclerosis Risk in Communities study (ARIC) and Framingham Heart Study (FHS). MRI features examined as outcomes were white matter volume (WMV), gray matter volume (GMV), total brain volume (BV), hippocampal volume (HV), and white matter hyperintensity volume (WMH), a marker of microvascular disease. Exposures included SARS-CoV-2 infections identified via questionnaires, serosurveys, and medical record reviews from 2020-2025. Infections resulting in hospitalization were classified as severe. Time-to-recovery, symptoms of long COVID, and vaccination status were self-reported by questionnaire. Analysis of covariance (ANCOVA) estimated associations between COVID-19-related exposures and pandemic MRI-measured outcomes, with adjustment for: the corresponding pre-pandemic MRI measure, the time between the two MRI scans, age, sex, systolic blood pressure, diabetes, and cardiovascular disease. Results Of 270 participants with available data, mean (SD) age was 80.6 years (10.6); 43.0% were male; and the mean (SD) interval between paired MRI scans was 4.2 (2.0) years. Most (90%) were vaccinated (of whom 6.7% vaccinated before infection) and 7.9% reported SARS-CoV-2 infection (of which 13.6% were severe infections) prior to their pandemic MRI (conducted March 2020 - June 2022). In fully adjusted models, there was no statistically significant association for change in WMV, GMV, BV, HV, or WMH with SAR-CoV2 infection status, infection severity, vaccination status, or vaccination timing (Table, P > 0.05 for all comparisons). Self-reported symptoms of long COVID and vaccine manufacturer were also not associated with MRI outcomes. Conclusions Based on repeated (pre-pandemic and pandemic era) structural MRI scans, we found no evidence that SARS-CoV-2 infection or COVID-19 vaccination were associated with changes in brain structure or brain microvascular disease. These findings are consistent with prior data supporting COVID-19 vaccine safety and suggest resilience of brain structures following SARS-CoV-2 exposures. Nonetheless, further research is warranted using more sensitive measures and assessing longer term effects. This abstract is funded by: OT2HL156812

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Importance Brain imaging biomarkers may (1) identify underlying mechanisms of intervention effects and (2) define brain characteristics of those most likely to benefit cognitively from the intervention. Objective To test whether (1) a lifestyle intervention is related to brain changes, (2) brain changes are correlated with intervention-specific cognition changes, and (3) brain imaging biomarkers provide information about who is likely to benefit from a lifestyle intervention. Design, Setting, and Participants In this randomized clinical trial, the POINTER Imaging study was an ancillary study of the 2-year, single-blind multicenter US POINTER clinical trial in which neuroimaging data were collected on eligible enrolled participants. The study was conducted from May 2019 to March 2023 (final follow-up, May 14, 2025). Participants were enrolled into the POINTER Imaging study following a standard procedure at 5 clinical sites in the US. Participant eligibility criteria included an age of 60 to 79 years, sedentary lifestyle, and suboptimal diet, plus at least 2 additional risk criteria for cognitive decline and no contraindications for neuroimaging. Interventions Participants were randomly assigned to receive the structured or self-guided intervention. Both interventions emphasized increased physical and cognitive activity, healthy nutrition, social engagement, and cardiovascular health monitoring, but they differed in intensity and accountability. Main Outcomes and Measures There were 4 primary imaging outcomes: global β-amyloid (Aβ) burden, tau burden in the entorhinal cortex (ERC), hippocampal (HC) volume, and white matter hyperintensity volume. The primary cognitive measure was a global cognitive composite. Results Among 1943 parent trial participants who were assessed for eligibility, 983 underwent at least 1 magnetic resonance imaging or positron emission tomography scanning session. The mean (SD) age was 68.4 (5.2) years; 605 participants (61.5%) were female and 378 male (38.5%). Five hundred sixteen participants received the structured intervention and 467 the self-guided intervention. There were no intervention group differences in longitudinal cognitive or imaging outcomes. Intervention group differences were not associated with or moderated by Aβ status or accumulation. There was a negative association between change in ERC tau and change in global cognition in the self-guided group that was attenuated in the structured group (difference in association: 0.289; 95% CI, 0.029 to 0.550; interaction P = .03). Lower baseline HC volume was associated with greater cognitive benefit for participants in the structured group vs the self-guided group (lower HC: 0.077 SD; 95% CI, 0.022 to 0.132; higher HC: 0.002 SD; 95% CI, −0.037 to 0.041; interaction P = .03). Conclusion and Relevance This study found that a high-intensity multidomain lifestyle intervention did not affect brain biomarker trajectories and was not associated with Aβ pathology, but older adults with specific at-risk brain characteristics, including lower baseline HC volume, showed a greater cognitive benefit of the structured intervention. Trial Registration ClinicalTrials.gov Identifier: NCT03688126

Abstract Background Our objective is to examine the generalizability of the relationships between four MRI markers of CVD: DTI‐derived free water (FW), fractional anisotropy (FA), perivascular space (PVS) and white matter hyperintensities (WMH) volume, with vascular risk factors (VRF) and cognition in the baseline POINTER Imaging and Framingham Heart Study (FHS) cohorts. Method We studied 907 U.S. POINTER and 797 FHS Offspring participants with available baseline demographic, clinical and imaging data (Table 1). Continuous FW, FA, WMH (log‐transformed) and PVS measurements were regressed against total cranial volume (TCV). Cognitive outcomes included a Global Cognitive Composite and executive function composite score for POINTER and FHS. For each MRI marker, we used linear and logistic regressions to assess the effect of age, sex, hypertension, diabetes and smoking status, adjusting for ethnicity. We then assessed, for each cognitive outcome, the individual effect of MRI markers using separate linear regressions adjusted for demographic and clinical factors, as well as TCV‐adjusted gray matter volume to control for atrophy. Result POINTER and FHS differed across most demographic and biomarker characteristics (Table 1). Despite these differences, there were similar associations between demographic and VRF and the 4 MRI vascular markers in POINTER and FHS (Figure 1): increased age was associated with worse outcomes for the 4 markers, hypertension was associated with increased FW, PVS and lower FA, diabetes was associated with increased FW only, smoking status did not impact any of the four markers. Only exception was that female had lower FW and increased WMH in POINTER and increased PVS in FHS. Associations between CVD measures and cognition were also similar across cohorts: reduced cognitive performance was significantly associated with both decreased FA and increased FW (Figure 2), but not with WMH nor PVS. Conclusion Our study explores four imaging markers representing diverse mechanisms by which CVD could impact brain structure and function in the POINTER and FHS studies. Despite differences in cohort characteristics, we found mostly consistent CVD relationships with demographic, VRF, and cognitive measures between cohorts which supports the generalizability of the relation of these markers with VRF and cognition identified in the POINTER cohort.

Objective To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458

Background: High adherence to the Mediterranean Diet (MeDi) was associated with better cognitive performance and decreased memory decline among Hispanic or Latino adults. Objective: Investigate if higher adherence to the MeDi improves white matter (WM) integrity among Hispanic/Latino adults and if this effect is mediated by cardiovascular health (CVH). Methods: We included 2,774 participants from the Study of Latinos-Investigation of Neurocognitive Aging-MRI Ancillary Study. Participants completed 24-hour dietary recalls at baseline (2008-2011) which were used to calculate a MeDi score (MeDiS, range 0-9). Brain MRI and diffusion tensor images were collected between 2018 and 2022 on a 3T MRI scanner using a standardized protocol. WM integrity was ascertained using WM hyperintensity (WMH) volume and fractional anisotropy (FA). WMH volumes were residualized for total cranial volume and Ln-transformed prior to analysis. The association of MRI outcomes with MeDiS and its components was investigated using weighted linear regression analysis with complex survey design adjusting for age, sex, sociodemographic characteristics. Cardiovascular health was assessed using the Life’s Simple 7 (LS7, range 0-14) score. The mediating effect of LS7 on the primary outcome was reported as Average Causal Mediation Effects (ACME) and Average Direct Effects (ADE). Statistical significance was set at p<0.05. Results: Mean age (95% CI) at MRI scan was 64.0 (63.4 to 65.2) and 44% were males. Mean MeDiS was 5.01 (4.89 to 5.12) and LS7 was 7.1 (7.0 to 7.3). In our fully adjusted model, increasing MeDi adherence was associated with decreased LnWMH volume (β=-0.07, 95% CI -0.10 to -0.03) and increased FA (β=0.002, 95% CI 0.001 to 0.003). Increasing LS7 scores partially mediated the relationship between MeDiS and WMHs (ACME=-0.01, ADE=-0.08, p<0.05, percent mediation=9%) and between MeDiS and FA (ACME=0.0001, ADE=0.002, p<0.01, percent mediated=8%). Among the different MeDi components, consumption of whole grains and fish above sex-specific energy adjusted energy median intake predicted lower WMH volume and increase FA (p<0.05 for both). Conclusions: Among diverse Hispanic/Latino adults, high MeDi adherence was associated with preserved WM integrity. This association was partially mediated by CVH. This suggests that the beneficial effect of MeDi on brain health is not fully explained by vascular risk factors. A culturally tailored MeDi may preserve brain health among Hispanic/Latino adults.

AbstractBackgroundRecent advances in automatic face recognition have increased the risk that de‐identified research imaging data could be re‐identified from face imagery in brain scans.MethodAn ADNI committee of independent imaging experts evaluated 11 published techniques for face‐deidentification (“de‐facing”) and selected four algorithms (FSL‐UK Biobank, HCP/XNAT, mri_reface, and BIC) for formal testing using 183 longitudinal scans of 61 racially and ethnically diverse ADNI participants, evaluated by their facial feature removal on 3D rendered surfaces (confirming sufficient privacy protection) and by comparing measurements from ADNI routine image analyses on unmodified vs. de‐faced images (confirming negligible side effects on analyses).ResultEffects of the de‐facing methods on FreeSurfer at UCSF (Figure 1‐top), ASHS at University of Pennsylvania (Figure 1 bottom‐left), and longitudinal atrophy at Mayo Clinic (Figure 1 bottom‐right) were comparable with each other and sufficiently small vs. unmodified scans to recommend de‐facing in ADNI‐4. The FSL and mri_reface methods were more thorough in removing facial features, partly because these also removed ears (Figure 2‐top). mri_reface was recommended for ADNI‐4 primarily because fewer (zero) images had modified brain (Figure 2‐bottom), and ADNI leadership approved de‐facing with mri_reface. ADNI performed a second validation of its latest version on another diverse sample of 100 ADNI‐3 participants. These analyses included: boundary shift interval at University College London, where average differences in measurements were all <0.05%; cortical white matter hyperintensities at UC Davis, where they found “minimum impact” (R>0.97); and others.ConclusionADNI‐4 de‐faces all indicated image types (Table 1) before subsequent pre‐processing, analyses, and public release. Sites upload images to the central repository (LONI), where they are queued to the MRI Core at Mayo Clinic for de‐facing. Image types requiring de‐facing are de‐faced using mri_reface. Trained analysts inspect de‐faced images to confirm complete removal of the face and complete non‐modification of the brain, and any flagged images are re‐processed manually until issues are resolved. De‐faced images are converted back to DICOM and re‐uploaded for further distribution. Image types not requiring de‐facing are indicated to proceed directly to subsequent steps. In summary, ADNI‐4 has adopted mri_reface because it successfully de‐faces without substantially affecting brain measurements.

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aβ) peptides and tau‐protein neurofibrillary tangles, hallmark features of Alzheimer’s disease (AD) pathology, have been concomitantly associated with white matter (WM) integrity loss, while a unique effect of each pathology on WM integrity in a more demographically diverse population remains unknown.MethodTo examine the degree to which each pathology affects WM integrity in a more diverse non‐demented cohort, Aβ and tau PET, diffusion‐weighted imaging (DWI), and cognition (memory and executive function composites) were examined from the U.S. POINTER neuroimaging participants (N=608; age=68.34±5.2; 61.8% females; 29% Aβ+) and a subset of Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (N=291; age=72.85±7.3; 50% females; 39% Aβ+) (Table). Aβ‐positivity was determined using tracer‐specific standardized cut‐offs. Tau SUVR was estimated for each Braak stage. For WM integrity, voxel‐based GLMs were applied to FSL‐processed fractional anisotropy (FA) maps using Braak stage tau SUVR and Aβ‐positivity status, along with covariates of age, sex, and b‐value profiles.ResultIn U.S. POINTER, independent from Aβ‐positivity status, greater tau burden in Braak stages I and II was related to lower FA across the tracts including the superior longitudinal fasciculus, fornix (cres), corpus callosum, and anterior thalamic radiation (Figure). Average FA from supra‐threshold clusters for Braak I and II significantly predicted executive function but not episodic memory. No association between FA and tau burden in Braak stages III/IV or V/VI was found. In the ADNI sample, greater tau burden in Braak I was related to lower FA mostly in left inferior longitudinal fasciculus and left uncinate fasciculus, while negative associations with FA became more diffuse with tau load in Braak III/IV and V/VI. Average FA from supra‐threshold clusters significantly predicted both episodic memory and executive function scores. Across both samples, after accounting for tau burden in each Braak stage, there were no association between Aβ‐positivity status and WM integrity.ConclusionDistinct associations between tau burden, WM integrity, and cognition were found across the studies, indicating greater impact of early tau burden on WM integrity in U.S. POINTER, accounting for Aβ‐positivity status. Factors contributing to the distinct associations across studies need further investigation.