Firat Kara

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.

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.

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.

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: 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.

In vivo proton (¹H) magnetic resonance spectroscopy (MRS) is a powerful non-invasive method that can measure Alzheimer’s disease (AD)-related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by ¹H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of ¹H MRS metabolites with biofluid, PET, and postmortem AD biomarkers and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate the development of potential novel therapeutic approaches.

In vivo proton (1H) magnetic resonance spectroscopy (MRS) is a powerful noninvasive method which can measure Alzheimer’s disease (AD) related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis, but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by 1H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of 1H MRS metabolites with biofluid, PET, and postmortem AD biomarkers, and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate to develop potential novel therapeutic approaches.

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 three years of menopause onset. Long-term effects of mHT exposure during early postmenopause remain understudied. 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 the participants randomized to one of two active estrogen formulations during early postmenopause would demonstrate differential longitudinal change in cognitive performance during the approximately ten years following randomization in the parent KEEPS trial when compared to women who received placebo. Specifically, transdermal estradiol (tE2) would demonstrate benefit over placebo, and oral conjugated equine estrogens (oCEE) demonstrate no effect compared to placebo. Methods and Findings: The KEEPS-Cog was an ancillary study to the KEEPS, in which women were randomized to placebo or one of two forms of mHT, oCEE (Premarin, 0.45 mg/d) or tE2 (Climara, 50 µg/d) for 48 months. Micronized progesterone (Prometrium, 200 mg/d) was used by those in mHT arms. Approximately 10 years (M(SD)=9.57(1.08) years; range: 8-14 years) after randomization, women returned to repeat the original KEEPS-Cog test battery. Cognitive tests were analyzed as 4 factor scores and a global cognitive score. Because KEEPS-Continuation visits occurred 8-14 years post-randomization, linear latent growth models with distal outcomes tested whether cognitive performance at baseline in KEEPS and the change-in-cognition across KEEPS visits predicted “distal” KEEPS cognition, and whether mHT randomization of KEEPS modified this relationship. Covariates included education, age at continuation visit, and APOE e 4 allele carrier status. All 727 postmenopausal participants in the KEEPS interventions were eligible for the KEEPS-Continuation. Among those participants, 622 (86%) had valid contact information and were invited to the study. Of these, 194 did not respond, 10 were deceased, and 119 declined to participate, resulting in 299 participants enrolled in the KEEPS-Continuation at seven sites. Of the 299 KEEPS-Continuation participants, 275 had cognitive data to estimate cognitive factors scores both at KEEPS and KEEPS-Continuation. Similar health characteristics were observed at KEEPS randomization for KEEPS-Continuation participants and nonparticipants (i.e. women not returning for the KEEPS-Continuation). Among the women enrolled in the KEEPS-Continuation, cognitive performance was not influenced by either mHT formulation employed in KEEPS. Models showed strong associations between baseline cognition and change-in-cognition during KEEPS and the same measures in KEEPS-Continuation, i.e., the strongest predictor of cognitive performance in KEEPS-Continuation was cognitive performance in KEEPS. KEEPS-Continuation 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 women completion of the randomized treatments. Conclusions: In these KEEPS-Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause vs. placebo. These data offer reassurance regarding long term neurocognitive safety of mHT used by healthy recently postmenopausal women for symptom management. Author summary: Why was this study done?: Little is known about the long-term cognitive effects of short-term use of menopausal hormone therapies (mHT) – i.e, the use of mHT during the menopausal transition or in early postmenopause for symptoms of menopause, leaving women and their providers with concerns about long-term consequences of short-term mHT use. We invited women who participated in a study examining the cognitive effects of short-term mHT to return for re-evaluation approximately a decade after they were randomized to 4 years of treatment with one of two forms of mHT or a placebo. Importantly, the original study only enrolled women who were recently postmenopausal and at low cardiovascular risk. The goals for the follow-up study were to examine the long-term cognitive effects of using mHT for a brief period shortly after menopause onset and to assess if these effects differed for the two forms of mHT. What did the researchers do and find?: > The observational Kronos Early Estrogen Prevention Study (KEEPS)-Continuation explored cognitive effects of short-term (4 year) randomized assignment to mHT vs. placebo, initiated within 3 years of menopause onset, after an average of 10 years following randomization in the original KEEPS trial. > We tested whether long term cognitive performance was influenced by prior exposure to HT formulation (e.g., transdermal 17β-estradiol or oral conjugated equine estrogens), controlling for covariates using linear latent growth models. > Among the women enrolled in the KEEPS-Continuation, cognitive performance was not influenced by earlier exposure to either HT formulation. > Linear growth models showed strong associations between baseline cognition (intercept) and its change (slope) during KEEPS and the same measures in the KEEPS-Continuation. > KEEPS-Continuation cross-sectional comparisons confirmed that both oral and transdermal mHT groups performed similarly to placebo on cognitive measures approximately 10 years after they were randomized to either HT or placebo. What do these findings mean?: > We detected no long-term cognitive benefit or harm of short-term mHT vs placebo. > Our findings suggest that there are no long-term cognitive effects of exposure to short-term mHT vs placebo in recently postmenopausal women who have low cardiovascular risk. > These data offer reassurance to recently postmenopausal women with good cardiovascular health who are considering mHT for the management of menopausal symptoms.