Heterogeneous treatment effects of sodium-glucose cotransporter 2 inhibitors on risk of dementia in people with type 2 diabetes: A population-based cohort study.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit potential benefits in reducing dementia risk, yet the optimal beneficiary subgroups remain uncertain. METHODS: Individuals with type 2 diabetes (T2D) initiating either SGLT2 inhibitor or sulfonylurea were identified from OneFlorida+ Clinical Research Network (2016-2022). A doubly robust learning was deployed to estimate risk difference (RD) and 95% confidence interval (CI) of all-cause dementia. RESULTS: Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all-cause dementia over a 3.2-year follow-up, yielding a lower risk for SGLT2 inhibitors (RD, -2.5%; 95% CI, -3.0% to -2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from -4.3% (-5.5 to -3.2) to -0.9% (-1.9 to 0.2). DISCUSSION: Compared to sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of all-cause dementia, but the association varied among different subgroups. HIGHLIGHTS: New users of sodium-glucose cotransporter 2 (SGLT2) inhibitors were significantly associated with a lower risk of all-cause dementia as compared to those of sulfonylureas. The association varied among different subgroups defined by Hispanic ethnicity and chronic kidney disease. A significantly lower risk of Alzheimer's disease and vascular dementia was observed among new users of SGLT2 inhibitors compared to those of sulfonylureas.

Racial, Ethnic, and Geographic Diversity in Population Neuroscience.

In this chapter, we consider lack of racial, ethnic, and geographic diversity in research studies from a public health perspective in which representation of a target population is critical. We review the state of the research field with respect to racial, ethnic, and geographic diversity in study participants. We next focus on key factors which can arise from the lack of diversity and can negatively impact external validity. Finally, we argue that the public's health, and future research, will ultimately be served by approaches from both recruitment and representation science and population neuroscience, and we close with recommendations from these two fields to improve diversity in studies.

How are early-career dementia researchers considered and supported on a national level by dementia plans and organizations? An overview of global policy approaches.

INTRODUCTION: Despite representing an essential workforce, it is unclear how global policy efforts target early-career dementia researchers (ECDRs). Thus, this study aimed to provide an overview of policies through which ECDRs are considered and supported by dementia plans and organizations. METHODS: G20 member states were evaluated for their national dementia plan alongside policies of leading dementia organizations. Data targeting support for ECDRs were extracted and subject to content analysis using inductive coding. Findings were categorized and narratively synthesized. RESULTS: Only China, Denmark, England, Greece, Northern Ireland, Scotland, Spain, and the United States mentioned ECDRs in their national plan. Additionally, 17 countries formalized ECDR support via dementia organizations. Support efforts included research funding, dissemination and networking, career development, and research advice. DISCUSSION: Few nations formally recognized ECDRs in dementia plans or through dementia organizations. To facilitate equal prospects for ECDRs, top-down approaches are urged to enhance and align their efforts. HIGHLIGHTS: Few G20 countries (8/46) had national dementia plans for early-career researchers. Targeted support comes from government and nongovernmental dementia organizations. Support includes funding, training, advice, research dissemination, and networking. Inconsistent definitions and eligibility criteria are barriers to accessing support. Global coordination and top-down policy will aid early-career dementia researchers.

COVID-19 pandemic's relationship with enrollment at US Alzheimer's Disease Research Centers.

INTRODUCTION: We aimed to characterize the COVID-19 pandemic's relationship with enrollment in US Alzheimer's Disease Research Centers (ADRCs). METHODS: Using data on 10,105 participants from 30 ADRCs, we conducted interrupted time series analyses to assess the relationship of the pandemic with enrollment and calculate projected dates of enrollment recovery. RESULTS: Participants enrolled during the pandemic (vs pre-pandemic) were more likely to have dementia and be referred by health professionals. The pandemic was associated with a 77% drop in enrollment, with projected trend recovery in March 2024 and 100% recovery in September 2024. COVID was associated with a 91% drop in Black/African American participants, compared to 71% in White participants. Enrollment of both Hispanic and female participants was declining 1.4% and 0.3%/month pre-pandemic. DISCUSSION: Funders and researchers should account for ongoing COVID-19 impact on ADRD research enrollment. Strategies to speed enrollment recovery are needed, especially for Black/African American and Hispanic groups. HIGHLIGHTS: Tested COVID pandemic association with enrollment at Alzheimer's Disease Research Centers. During versus pre-pandemic enrollees differed on demographic and clinical variables. Interrupted time series analyses: immediate 77% drop in enrollment related to COVID. Recovery projections: trend recovery in March 2024, 100% recovery in September 2024. Enrollment of African American and Hispanic participants should be prioritized.

Unhealthy white matter connectivity, cognition, and racialization in older adults.

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta-amyloid (Aß) or tau pathology-affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aß- and tau-affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC-and-cognition associations, may drive clinical AD disparities between racialized groups. HIGHLIGHTS: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology-affected brain regions is associated with cognition. Relationships between UWMC and cognition are similar between Black American (BA) and non-Hispanic White (nHW) individuals. More UWMC may partially drive higher clinical AD burden in BA versus nHW populations. UWMC risk factors, particularly social and environmental, should be identified.

Heterogeneous treatment effects of metformin on risk of dementia in patients with type 2 diabetes: A longitudinal observational study.

INTRODUCTION: Little is known about the heterogeneous treatment effects of metformin on dementia risk in people with type 2 diabetes (T2D). METHODS: Participants (≥ 50 years) with T2D and normal cognition at baseline were identified from the National Alzheimer's Coordinating Center database (2005-2021). We applied a doubly robust learning approach to estimate risk differences (RD) with a 95% confidence interval (CI) for dementia risk between metformin use and no use in the overall population and subgroups identified through a decision tree model. RESULTS: Among 1393 participants, 104 developed dementia over a 4-year median follow-up. Metformin was significantly associated with a lower risk of dementia in the overall population (RD, -3.2%; 95% CI, -6.2% to -0.2%). We identified four subgroups with varied risks for dementia, defined by neuropsychiatric disorders, non-steroidal anti-inflammatory drugs, and antidepressant use. DISCUSSION: Metformin use was significantly associated with a lower risk of dementia in individuals with T2D, with significant variability among subgroups.

Biostatistical Estimation of Tau Threshold Hallmarks (BETTH) Algorithm for Human Tau PET Imaging Studies.

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either 18F-flortaucipir or 18F-MK-6240 PET scans. Methods: 18F-flortaucipir (n = 798) and 18F-MK-6240 (n = 216) scans were processed and sampled to obtain regional SUV ratios. Subsamples of the cohorts were based on participant diagnosis, age, amyloid-ß status (positive or negative), and neurodegeneration status (positive or negative), creating older-adult (age ≥ 55 y) cognitively unimpaired (amyloid-ß-negative, neurodegeneration-negative) and cognitively impaired (mild cognitive impairment/Alzheimer disease, amyloid-ß-positive, neurodegeneration-positive) groups, and then were further subsampled via matching to reduce significant differences in diagnostic prevalence, age, and Mini-Mental State Examination score. We used the biostatistical estimation of tau threshold hallmarks (BETTH) algorithm to determine sensitivity and specificity in 6 composite regions. Results: Parametric double receiver operating characteristic analysis yielded the greatest joint sensitivity in 5 of the 6 regions, whereas hierarchic clustering, gaussian mixture modeling, and k-means clustering all yielded perfect joint specificity (2.00) in all regions. Conclusion: When 18F-flortaucipir and 18F-MK-6240 are used, Alzheimer disease-related tau status is best assessed using 2 thresholds, a sensitivity one based on parametric double receiver operating characteristic analysis and a specificity one based on gaussian mixture modeling, delimiting an uncertainty zone indicating participants who may require further evaluation.

Discordant Biological and Chronological Age: Implications for Cognitive Decline and Frailty.

BACKGROUND: Older adults with discordant biological and chronological ages (BA and CA) may vary in cognitive and physical function from those with concordant BA and CA. METHODS: To make our approach clinically accessible, we created easy-to-interpret participant groups in the Health, Aging, and Body Composition Study (N = 2 458, 52% female participants, 65% White participants, age: 73.5 ±â€…2.8) based on medians of CA, and a previously validated BA index comprised of readily available clinical tests. Joint models estimated associations of BA-CA group with cognition (Modified Mini-Mental State Examination [3MS] and Digit Symbol Substitution Test [DSST]) and frailty over 10 years. RESULTS: The sample included the following: 32%, Young group (BA and CA < median); 21%, Prematurely Aging group (BA ≥ median, CA < median), 27%, Old group (BA and CA ≥ median), and 20%, Resilient group (BA < median, CA ≥ median). In education-adjusted models of cognition, among those with CA < median, the Prematurely Aging group performed worse than the Young at baseline (3MS and DSST p < .0001), but among those with CA ≥ median, the Resilient group did not outperform the Old group (3MS p = .31; DSST p = .25). For frailty, the Prematurely Aging group performed worse than the Young group at baseline (p = .0001), and the Resilient group outperformed the Old group (p = .003). For all outcomes, groups did not differ on change over time based on the same pairwise comparisons (p ≥ .40). CONCLUSIONS: Discordant BA and CA identify groups who have greater cognitive and physical functional decline or are more protected than their CA would suggest. This information can be used for risk stratification.

Clinical trials in vascular cognitive impairment following SPRINT-MIND: An international perspective.

A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP < 120 vs. <140 mm Hg). In this perspective, we discuss key questions and make recommendations for clinical practice and for clinical trials, following SPRINT-MIND. Future trials should embody cognitive endpoints appropriate to the participant group, ideally with adaptive designs that ensure robust answers for cognitive and cardiovascular endpoints. Reliable data from diverse populations, including the oldest-old (age > 80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.

Hypertensive disorders of pregnancy and subsequent risk of Alzheimer's disease and other dementias.

Introduction: Women with hypertensive disorders of pregnancy (HDP) have an increased risk of cardiovascular disease. Whether HDP is also associated with later-life dementia has not been fully explored. Methods: Using the Utah Population Database, we performed an 80-year retrospective cohort study of 59,668 parous women. Results: Women with, versus without, HDP, had a 1.37 higher risk of all-cause dementia (95% confidence interval [CI]: 1.26, 1.50) after adjustment for maternal age at index birth, birth year, and parity. HDP was associated with a 1.64 higher risk of vascular dementia (95% CI: 1.19, 2.26) and 1.49 higher risk of other dementia (95% CI: 1.34, 1.65) but not Alzheimer's disease dementia (adjusted hazard ratio = 1.04; 95% CI: 0.87, 1.24). Gestational hypertension and preeclampsia/eclampsia showed similar increased dementia risk. Nine mid-life cardiometabolic and mental health conditions explained 61% of HDP's effect on subsequent dementia risk. Discussion: Improved HDP and mid-life care could reduce the risk of dementia.

Newer glucose-lowering drugs and risk of dementia: A systematic review and meta-analysis of observational studies.

BACKGROUND: Preclinical studies have suggested potential beneficial effects of newer glucose-lowering drugs (GLDs) including dipeptidyl peptidase (DPP)-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors, in protecting humans against cognitive decline and dementia. However, population studies aiming to demonstrate such cognitive benefits from newer GLDs have produced mixed findings. This meta-analysis aimed to evaluate the association between newer GLDs and risk of dementia in adults with type 2 diabetes (T2D). METHODS: Electronic databases were searched up to March 11, 2022 to include observational studies that examined the association between DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors and risk of dementia (including all-cause dementia, Alzheimer's disease [AD], and vascular dementia [VD]) in people with T2D. We conducted a random-effects meta-analysis to calculate the relative risk (RR) with 95% confidence interval (CI) for each class of newer GLD. RESULTS: Ten studies (from nine articles) involving 819,511 individuals with T2D were included. Three studies found that SGLT2 inhibitor users had a lower risk of all-cause dementia than non-SGLT2 inhibitor users (RR, 0.62; 95% CI, 0.39-0.97). Five studies found that users versus nonusers of GLP-1RAs were associated with a significant reduction in the risk of all-cause dementia (RR, 0.72; 95% CI, 0.54-0.97). However, a meta-analysis for AD and VD was unavailable for SGLT2 inhibitors and GLP-1RAs because only one study was included for each drug. In seven studies, users vs. nonusers of DPP-4 inhibitors were significantly associated with a decreased risk of all-cause dementia (RR, 0.84; 95% CI, 0.74-0.94) and VD (RR, 0.59; 95% CI, 0.47-0.75) but not AD (RR, 0.82; 95% CI, 0.63-1.08). CONCLUSION: Newer GLDs were associated with a decreased risk of all-cause dementia in people with T2D. Because of the observational nature and significant heterogeneity between studies, the results should be interpreted with caution. Further research is warranted to confirm our findings.

Impact of the COVID-19 pandemic on early career dementia researchers: A global online survey.

INTRODUCTION: The World Health Organization recognizes dementia as a public health priority and highlights research as an action to respond to the consequences, with early career dementia researchers (ECDRs) representing the key driving force. Due to the COVID-19 pandemic, however, biomedical and psychosocial dementia research was strained worldwide. The aim of this study was to understand the impact of the pandemic on ECDRs. METHODS: In autumn 2021, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Professional Interest Area to Elevate Early Career Researchers (PEERs) and University College London conducted an online survey querying ECDRs' experiences during the COVID-19 pandemic. The survey was shared through the ISTAART network, social media, podcasts, and emailing lists. Data were analyzed using descriptive and inferential statistics. RESULTS: Survey data from n = 321 ECDRs from 34 countries were analyzed (67.6% women; 78.8% working in academia). Overall, 77.8% of ECDRs surveyed indicated research delays, 53.9% made project adjustments, 37.9% required additional or extended funding, and 41.8% reported a negative impact on career progression. Moreover, 19.9% felt unsupported by their institutions and employers (33% felt well supported, 42.7% somewhat supported). ECDR's conference attendance remained the same (26.5%) or increased (More: 28.6%; a lot more: 5.6%) since the start of the pandemic. Continental differences were visible, while the impact of the pandemic did not differ greatly based on ECDRs' sociodemographic characteristics. CONCLUSIONS: The COVID-19 pandemic had a substantial impact on ECDRs worldwide and institutions, employers, and funding bodies are urged to consider the implications and lessons-learned when working with, managing, and promoting ECDRs. Strategies related to the pandemic and general career support to improve ECDRs career progression are discussed, including social media training, digital networking, and benefits of hybrid events. Global resources specific for ECDRs are highlighted.

Retention, mobility, and successful transition to independence of health sciences postdocs.

INTRODUCTION: Obtaining a tenure track faculty position (TTFP) after postdoctoral appointment (PDA) completion is considered an indicator of successful transition to independence (TTI). Whether cross-institutional mobility (CIM)-moving to a different institution from that of the PDA-contributes to TTI is unclear, as data evaluating retention and mobility is lacking. We tested the hypothesis that, for postdocs (PDs) at R1 institutions, CIM is a significant predictor of successful TTI defined as TTFP-status 3 years post-PDA. MATERIALS AND METHODS: Using University of Pittsburgh data for health sciences PDs we tested the association of CIM at PDA completion (moved to a different institution (CIM = 1) or retained at Pitt (CIM = 0)) with TTFP-status 3 years post-PDA (TTFP, non-TTFP, or left faculty position) using multinomial logistic regression models. RESULTS: Among all 622 Pitt PDs, 3-year retention in a faculty position at Pitt was 21%, while 14% had a faculty position outside of Pitt. Among the analytic sample of PDs with an academic career outcome during the study period (N = 238; 50% women, 8% underrepresented minorities (URM)), at baseline PDA completion 39% moved to a different institution (CIM = 1), and 61% remained at Pitt (CIM = 0) in any job type. Those with CIM = 1 had greater odds of having a TTFP at follow-up than those with CIM = 0 [adjusted OR (95% CI): 4.4 (2.1, 9.2)]. DISCUSSION: One fifth of Pitt PDs were retained by Pitt as faculty. While Pitt PDs were equally likely to get a faculty position whether they were retained at Pitt or left, those who left had greater odds of obtaining a TTFP. Future work with longer follow-up times, expanded markers of TTI, and samples from other R1 institutions is needed to better understand the reason for these results. This knowledge can lead to better support for the next generation of PDs as they successfully transition to faculty.

Research Centers Collaborative Network Workshop on Sex and Gender Differences in Aging.

Aging affects men and women differently; however, the impact of sex and gender on the aging process is not well understood. Moreover, these 2 concepts are often conflated, which further contributes to a lack of clarity on this important issue. In an effort to better understand the relevance of sex and gender in aging research, the Research Centers Collaborative Network sponsored a 1.5-day conference on sex and gender differences in aging that brought together key thought leaders from the 6 National Institute on Aging center programs. The meeting included sessions on comparing males and females, pathophysiological differences, sex/gender in clinical care, and gender and health in the social context. Presenters from a wide array of disciplines identified opportunities for multidisciplinary research to address current gaps in the field and highlighted the need for a more systematic approach to understanding the how and why of sex/gender differences, as well as the health implications of these differences and the sex/gender biases that affect clinical treatment and outcomes. This article summarizes the proceedings of the workshop and provides several recommendations to move the field forward, such as better data collection tools to assess the intersection of sex and gender in epidemiological research; a life course perspective with attention to fetal/developmental origins and key life stages; innovative animal models to distinguish contributions from sex hormones versus sex chromosomes; and integration of sex/gender into teaching and clinical practice. Ultimately, successful implementation of these recommendations will require thoughtful investigations across the translational spectrum and increased collaborations among those with expertise in sex and gender differences.

Vascular cognitive impairment and dementia: An early career researcher perspective.

The field of vascular contributions to cognitive impairment and dementia (VCID) is evolving rapidly. Research in VCID encompasses topics aiming to understand, prevent, and treat the detrimental effects of vascular disease burden in the human brain. In this perspective piece, early career researchers (ECRs) in the field provide an overview of VCID, discuss past and present efforts, and highlight priorities for future research. We emphasize the following critical points as the field progresses: (a) consolidate existing neuroimaging and fluid biomarkers, and establish their utility for pharmacological and non-pharmacological interventions; (b) develop new biomarkers, and new non-clinical models that better recapitulate vascular pathologies; (c) amplify access to emerging biomarker and imaging techniques; (d) validate findings from previous investigations in diverse populations, including those at higher risk of cognitive impairment (e.g., Black, Hispanic, and Indigenous populations); and (e) conduct randomized controlled trials within diverse populations with well-characterized vascular pathologies emphasizing clinically meaningful outcomes.

Consideration of sex and gender in Alzheimer's disease and related disorders from a global perspective.

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. HIGHLIGHTS: The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.

Brain health correlates of mobility-related confidence.

BACKGROUND: Mobility is important for independence in older age. While brain health correlates of objectively measured mobility-related features like gait and balance have been reported, we aimed to test neuroimaging and cognitive correlates of subjective measures of mobility-related confidence. METHODS: We carried out a cross-sectional observational study comprised of N = 29 cognitively unimpaired older adult participants, mean age 75.8 ± 5.8, 52% female, 24% non-white. We measured cognition, hippocampal volume, white matter hyperintensities, cerebral amyloid-ß (Aß), and gait and balance confidence. We tested associations using unadjusted Spearman correlations and correlations partialling out covariates of interest one at a time. RESULTS: Greater gait confidence was associated with better attention (unadjusted ρ = 0.37, p = 0.05; partially attenuated by adjustment for age, APOE4, anxiety, motivation, gait speed, or Aß); executive performance (unadjusted ρ = 0.35, p = 0.06; partially attenuated by adjustment for age, APOE4, gait speed, or Aß); and lower Aß levels (unadjusted ρ = -0.40, p = 0.04; partially attenuated by adjustment for age, depressive symptoms, motivation, or gait speed). Greater balance confidence was associated with better global cognition (unadjusted ρ = 0.41, p = 0.03; partially attenuated by adjustment for APOE4, gait speed, or Aß); attention (unadjusted ρ = 0.46, p = 0.01; robust to adjustment); and lower Aß levels (unadjusted ρ = -0.35, p = 0.07; partially attenuated by adjustment for age, education, APOE4, depressive symptoms, anxiety, motivation, or gait speed). CONCLUSIONS: Self-reported mobility-related confidence is associated with neuroimaging and cognitive measures and would be easy for providers to use in clinical evaluations. These associations should be further evaluated in larger samples, and longitudinal studies can help determine temporality of declines.

A guide for researchers seeking training in retrospective data harmonization for population neuroscience studies of Alzheimer's disease and related dementias.

Due to needs surrounding rigor and reproducibility, subgroup specific disease knowledge, and questions of external validity, data harmonization is an essential tool in population neuroscience of Alzheimer's disease and related dementias (ADRD). Systematic harmonization of data elements is necessary to pool information from heterogeneous samples, and such pooling allows more expansive evaluations of health disparities, more precise effect estimates, and more opportunities to discover effective prevention or treatment strategies. The key goal of this Tutorial in Population Neuroimaging Curriculum, Instruction, and Pedagogy article is to guide researchers in creating a customized population neuroscience of ADRD harmonization training plan to fit their needs or those of their mentees. We provide brief guidance for retrospective data harmonization of multiple data types in this area, including: (1) clinical and demographic, (2) neuropsychological, and (3) neuroimaging data. Core competencies and skills are reviewed, and resources are provided to fill gaps in training as well as data needs. We close with an example study in which harmonization is a critical tool. While several aspects of this tutorial focus specifically on ADRD, the concepts and resources are likely to benefit population neuroscientists working in a range of research areas.

Cognition and Cerebrovascular Reactivity in Midlife Women With History of Preeclampsia and Placental Evidence of Maternal Vascular Malperfusion.

Background: Preeclampsia is emerging as a sex-specific risk factor for cerebral small vessel disease (SVD) and dementia, but the reason is unknown. We assessed the relationship of maternal vascular malperfusion (MVM), a marker of placental SVD, with cognition and cerebral SVD in women with and without preeclampsia. We hypothesized women with both preeclampsia and MVM would perform worst on information processing speed and executive function. Methods: Women (n = 45; mean 10.5 years post-delivery; mean age: 41 years; 42.2% Black) were classified as preeclampsia-/MVM-, preeclampsia+/MVM-, or preeclampsia+/MVM+. Information processing speed, executive function, and memory were assessed. In a pilot sub-study of cerebrovascular reactivity (CVR; n = 22), cerebral blood flow during room-air breathing and breath-hold induced hypercapnia were obtained via arterial spin labeling MRI. Non-parametric tests and regression models were used to test associations. Results: Between-group cognitive differences were significant for information processing speed (p = 0.02); preeclampsia+/MVM+ had the lowest scores. Cerebral blood flow increased from room-air to breath-hold, globally and in all regions in the three groups, except the preeclampsia+/MVM+ parietal region (p = 0.12). Lower parietal CVR (less change from room-air breathing to breath-holding) was correlated with poorer information processing speed (partial ρ = 0.63, p = 0.005) and executive function (ρ = 0.50, p = 0.03) independent of preeclampsia/MVM status. Conclusion: Compared to women without preeclampsia and MVM, midlife women with both preeclampsia and MVM have worse information processing speed and may have blunted parietal CVR, an area important for information processing speed and executive function. MVM in women with preeclampsia is a promising sex-specific indicator of cerebrovascular integrity in midlife.