Kendall-Thomas, June

Introduction Neurological post-acute sequelae of COVID-19 (neuroPASC) are associated with persistent cognitive dysfunction and quality-of-life decline. We aimed to identify clinical, behavioral and sociodemographic factors associated with neuroPASC symptom burden two years after COVID-19 among individuals without prior neurological disease. Methods In this prospective, observational study, individuals with neuroPASC ( n = 102) and controls without symptomatic COVID-19 ( n = 74), all without prior neurological, psychiatric, or post-viral conditions, were enrolled between February 2022 and June 2024 across five academic sites. An unsupervised algorithm identified clusters with differing self-reported neurological symptom burden within the neuroPASC group. Functional differences between clusters were evaluated using quality-of-life, neurological and cognitive evaluations. Demographics, behavioral history, comorbidities, and blood biomarkers were compared across clusters and controls. Multivariable logistic regression assessed predictors of neuroPASC severity, including demographics, body-mass-index, Charlson Comorbidity Index, Framingham Risk Score, pre-existing endocrine/metabolic and/or gastrointestinal/hepatobiliary conditions, COVID-19 vaccination prior to infection, hospitalization during acute infection, and cumulative alcohol use. Results Two clusters emerged based on neurological symptom burden, labeled “high-burden” and “low-burden” neuroPASC, reflecting differences in the number and frequency of symptoms. Both clusters had deficits in quality-of-life and cognitive function compared to controls, with greater impairment in high-burden than low-burden neuroPASC. The clusters did not differ by sex, education, tobacco and cannabis use, blood pressure, body-mass-index, HbA1C, days since infection, hospitalization during COVID-19, pre-COVID vaccination rate, antibody-positivity, inflammation, and neurodegeneration biomarkers. The high-burden cluster was older and exhibited higher comorbidity burden and greater cumulative alcohol use compared with the low-burden cluster and controls. Pre-existing endocrine/metabolic and gastrointestinal/hepatobiliary conditions were more common in high-burden (63%) than in low-burden neuroPASC (35%). After adjusting for clinical and demographic factors, these pre-existing conditions remained the only independent predictor of severity, conferring a 3.5-fold increase in the odds of high-burden versus low-burden neuroPASC. Discussion Older age, higher comorbidity burden, greater cumulative alcohol use, and endocrine/metabolic and gastrointestinal conditions, rather than acute COVID-19 severity, were observed in the high-burden neuroPASC cluster. After multivariable adjustment, only pre-existing endocrine/metabolic and/or gastrointestinal/hepatobiliary conditions remained independently associated with high-burden neuroPASC, conferring a 3.5-fold increase in odds and highlighting the need for targeted post-infection monitoring in at-risk patients.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

The study assesses the relationship between thalamic proton-MR spectroscopy (1H-MRS) metabolites and thalamic 11C-ER176 translocator-protein positron emission tomography (TSPO-PET) standardized uptake value ratios (SUVR) to advance our understanding of thalamic involvement in multiple sclerosis (MS)-associated neurodegeneration and disability. In this prospective cross-sectional study, patients with MS (pwMS) and controls underwent 3T-MRI, 1H-MRS, and 11C-ER176-PET targeting the thalamus. MRI-derived thalamic volume was normalized by intracranial volume. 1H-MRS metabolites—N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln), total choline (tCho), and myo-inositol (mIns)—were normalized to total creatine (tCr). Clinical disability was evaluated using MS-specific tests of Expanded Disability Status Scale-EDSS and MS-functional composite-MSFC (including Paced Auditory Serial Addition Test-PASAT). Compared to controls (n = 30), pwMS (n = 21) exhibited smaller thalamic volume, higher thalamic 1H-MRS mIns/tCr (putative gliosis marker), and higher thalamic 11C-ER176-PET SUVR (glial density marker). In pwMS, higher thalamic mIns/tCr (r = −0.67) and tCho/tCr (r = −0.52) correlated with smaller thalamic volume. In pwMS, higher thalamic mIns/tCr correlated with higher thalamic 11C-ER176-PET SUVR (r = 0.48) and decreased cognitive function (PASAT, rho = −0.48). In controls, decreased thalamic NAA/tCr correlated with increased thalamic 11C-ER176-PET SUVR (r = −0.41). Thalamus, a core central nervous system relay, is affected early in MS disease course. Glial-mediated innate immune activation in the thalamus, evaluated by increased 1H-MRS mIns/tCr and 11C-ER176-PET SUVR, is associated with loss of thalamic volume and increased disability in pwMS. The multimodal imaging approach with 1H-MRS mIns/tCr and 11C-ER176-PET SUVR emerges as potential glial biomarkers, to better understand disease mechanisms and evaluate therapeutic interventions targeting glial activity in MS.

Abstract Objective This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). Methods KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. Results Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. Conclusions There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.