Norca Maritza Dowling

Subjective cognitive decline (SCD) refers to cognitive concerns that may occur with or without objective impairment on standardized testing. Studies suggest that SCD may be an early clinical marker of Alzheimer's disease and related dementias, and that it can predict future objective cognitive decline and progression to dementia. However, the research that supports these conclusions is primarily based on samples with homogeneous socioeconomic and cultural backgrounds. The limited studies in samples with more diverse representations of racial, ethnic, gender, and sexual orientation characteristics show varying SCD prevalence, correlates, and outcomes. Here, we review this literature, focusing on how to apply the findings to advance our understanding of SCD. We further evaluate how our findings inform a roadmap for future research. Overall, we conclude that broader investigations across more diverse populations enhance our understanding of the factors that may differentially contribute to SCD and shape its utility as a clinical metric.

As the demand for care for those living with Alzheimer's disease and related dementias (ADRD) increases, effective instruments to assess the impact of caregiving among a diverse population of family and friend caregivers are needed to inform tailored interventions. This scoping review evaluated instruments used to measure the experiences of caregivers for individuals with ADRD, aiming to assess their psychometric properties, utility, and inclusivity. Searching five databases from 1980 to 2024, we identified 141 studies reporting on 157 instruments. Most tools emphasized negative caregiving aspects like burden and distress, while fewer addressed positive elements such as resilience or satisfaction. Instruments varied widely in psychometric rigor, and validation samples often lacked diversity, typically involving spousal or child caregivers, thus limiting generalizability. The review underscores a critical need for updated, culturally sensitive tools that reflect the broad, multifaceted experiences of today's caregivers across diverse racial, ethnic, and family backgrounds.

Objective: To determine associations between central adiposity, cognitive function, and randomized menopausal hormone therapy (MHT) in a reanalysis of the Kronos Early Estrogen Prevention Study-Cognitive and Affective (KEEPS-Cog) sub-study participants. Methods: KEEPS randomized 727 women (ages 42-58) who were 35 kg/m ² , coronary artery calcium score >50 Agatston Units, and other cardiometabolic disease risk indicators were excluded from enrollment. In the ancillary KEEPS-Cog study, cognitive tests were completed at baseline, 18-, 36-, and 48-month post-randomization. In these analyses, cognitive variables were summarized as four cognitive domain-specific factor scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and speeded language and mental flexibility. Waist-hip-ratio (WHR), an indicator of central adiposity, was measured at screening (baseline) and modeled as a covariate in linear latent growth models assessing associations of MHT with cognitive functions at baseline and over time. Results: Higher baseline WHR was associated with poorer performance on all domain-specific cognitive outcomes at baseline and with changes in visual attention and executive function across time. Models including interaction effects were not significant for either o-CEE x WHR or t-E2 x WHR. Conclusion: Central adiposity is a risk factor for domain-specific cognitive decline, and thus, cognitive health effects should be investigated in early postmenopausal women, even in women with low cardiovascular risk statuses.

Objectives: To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain’s white matter architecture in women who initiated mHT within 3 years of menopause onset. Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms. Results: There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo. Conclusions: We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.

BACH1 has been identified as a functional regulator of cancer metastasis and metabolic signaling in breast cancer cells. However, the clinical relevance of BACH1 expression in breast tumors remains poorly understood. Using a tissue microarray from a cohort of 130 patients, we assessed the expression of BACH1 and its known target gene, MCT1 (encoded by SLC16A1), through immunohistochemistry (IHC). The expression data were then analyzed in relation to clinical variables, including breast cancer subtypes, tissue types, tumor size and grade, patient racial background, and age group. We found positive associations between BACH1 expression and tumor size, tumor grade, and the basal-like subtype. Importantly, BACH1 expression was significantly higher in tumors from Black women compared to those from White women, as well as in the basal-like subtype of breast tumors from Black women. Additionally, a positive correlation was observed between BACH1 and MCT1 IHC scores in tumors from Black women, while a weak association was noted in tumors from White women. Our study provides compelling evidence that BACH1 expression is evident based on the race and subtypes of breast cancer patients.

Anti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer’s disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity.

Objective: To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations. Methods: Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models. Results: The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001‐0.01] and DBP: β = 0.01 [95% CI, 0.003‐0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes. Conclusion: Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life.

Background: The growing number of people living with Alzheimer’s disease and related dementias (ADRD) has led to an increased interest in the experiences of informal caregivers. Effective instruments to measure both negative and positive aspects of caregiving and validated with diverse caregiver populations, are needed to inform the design and evaluation of targeted interventions. This study (a) reviews extant literature on instruments developed to measure the range of roles and experiences of unpaid caregivers of people living with ADRD, (b) describes characteristics of the populations used to validate these instruments, and (c) discusses the usefulness, applicability, and generalizability of current measuresMethod: A scoping review was performed following the methodological framework of Aromataris and Munn (2020). In November 2023, five databases (PubMed, Scopus, Embase, PsycINFO, CINAHL) were searched including publications from 1980‐2023. We included studies that (a) described the development of instruments to assess informal (unpaid) ADRD caregiver experiences, (b) discussed their psychometric properties, and (c) described the sample used in the validation process. Covidence software was used to screen the retrieved studies and relevant data were extracted and summarized using an a priori data extraction tool.Result: The search yielded 11,928 articles; 90 met inclusion criteria. The majority of instruments measured negative aspects of caregiving (burden, hassles, psychological distress, strain, dysfunctional thoughts, isolation, grief) although a growing number of instruments focused on positive aspects of caregiving (personal growth, self‐actualization, rewards and satisfaction, resilience, hope, self‐efficacy, reciprocity). The psychometric rigor of the instruments varied widely with most samples being relatively small and mainly including spouses or children, possibly limiting generalizability of construct‐relevant interpretations. While recent instruments have focused on new constructs associated with caregiving (loss of personhood, discrimination, stigma), validation studies have not been conducted with representative populations of caregivers from both traditional and non‐traditional family structures or diverse racial/ethnic groups.Conclusion: The interpretability and meaningfulness of inferences from existing ADRD caregiving measures depend on the relevance and utility of those instruments in the applied setting. This review highlights the need for developing measures that capture the multifaceted experiences of a diverse and more representative sample from the full spectrum of ADRD caregivers.

Background: Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial. Methods and findings: The KEEPS-Cog (2005–2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017–2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline. Conclusions: In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population.

Background: Poststroke cognitive impairment (PSCI) occurs in about 60% of patients with stroke in the first year after stroke. However, the question regarding risks of recurrent stroke and mortality in patients with PSCI remains controversial. The goal of this study was to conduct a meta‐analysis of published literature to estimate the risks of stroke recurrence and mortality associated with PSCI. Methods and Results: Electronic databases were screened for eligible studies published from 1990 to 2023. The primary end points of this study were recurrent stroke and mortality. Pooled estimates were calculated as hazard ratios (HR) with 95% CIs. Meta‐regression analyses evaluated moderating effects of PSCI severity, study design, and study period on recurrent stroke and mortality. Pooled data from 27 studies comprised 39 412 patients with ischemic stroke. Nine studies evaluated the association between PSCI and risk of stroke recurrence that showed the hazard of recurrent stroke risk was significantly higher in patients with PSCI compared with those without it (HR, 1.59 [95% CI, 1.29–1.94]; I ² =52.2%). Eighteen studies examined the impact of PSCI on mortality risk. The pooled hazard of mortality was significantly higher in the group with PSCI relative to the non‐PSCI group (HR, 2.07 [95% CI, 1.65 –2.59]; I ² =89.3%). Meta‐regressions showed that the average effect of PSCI on mortality risk differed across study period and study design. Conclusions: Based on this meta‐analysis PSCI was statistically significantly associated with increased risks of recurrent stroke and all‐cause mortality. Poststroke neurocognitive assessment may identify patients at a higher risk who may require more aggressive interventions for secondary prevention.