Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

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 17ß-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 17ß-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.

Longitudinal cognitive function and brain metabolites in women receiving chemotherapy for stage 1 to 3 breast cancer: Observational study.

Few proton magnetic resonance spectroscopy studies have explored chemotherapy-related biochemical changes in brain regions. This observational study aimed to longitudinally assess short-term cognitive changes and brain metabolite concentrations in women undergoing chemotherapy for breast cancer. We analyzed 11 women with newly diagnosed stage 1 to 3 breast cancer. Patients were evaluated via objective cognitive testing, and patient self-report tests. Patients were examined using single voxel proton magnetic resonance spectroscopy in the medial frontal cortex, posterior cingulate gyrus, and left thalamus at baseline and after the completion of chemotherapy on a 1.5 Tesla scanner. At the posttreatment evaluation as compared to baseline, 7 of the 10 (70%) patients reported worsening memory on the MD Anderson symptom inventory (annualized change = 1.82 ± 2.88, P = .08), while the delayed recall raw score of the Rey Osterrieth complex figure test did not change from pre- to post-chemotherapy (mean annualized change = 5.00 ± 14.38, P = .30). The annualized change in the creatine concentration in the posterior cingulate gyrus was statistically significant. The annualized change in the MD Anderson symptom inventory was negatively correlated with the annualized change in the medial frontal N-acetylaspartate (Spearman correlation coefficient [rho] = -0.78, P = .01) and positively correlated with the annualized change in the posterior cingulate gyrus creatine (rho = 0.66, P = .04). Annualized changes in the Rey Osterrieth complex figure test were positively correlated with annualized changes in choline (rho = 0.83, P = .01) in the medial frontal cortex, choline (rho = 0.76, P = .04) in the left thalamus, and creatine (rho = 0.73, P = .02) in the medial frontal cortex. Our data suggest that chemotherapy may lead to the worsening of self-reported memory function, which is associated with alterations in brain metabolites.

Association of raloxifene and tamoxifen therapy with cognitive performance, odds of mild cognitive impairment, and brain MRI markers of neurodegeneration.

The aim of this cross-sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical-linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z-scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.

Clinical Correlation of Multiple Sclerosis Immunopathologic Subtypes.

BACKGROUND AND OBJECTIVES: The goal of this work was to compare clinical characteristics across immunopathologic subtypes of patients with multiple sclerosis. METHODS: Immunopathologic subtyping was performed on specimens from 547 patients with biopsy- or autopsy-confirmed CNS demyelination. RESULTS: The frequency of immunopathologic subtypes was 23% for pattern I, 56% for pattern II, and 22% for pattern III. Immunopatterns were similar in terms of age at autopsy/biopsy (median age 41 years, range 4-83 years, p = 0.16) and proportion female (54%, p = 0.71). Median follow-up after symptom onset was 2.3 years (range 0-38 years). In addition to being overrepresented among autopsy cases (45% vs 19% in biopsy cohort, p < 0.001), index attack-related disability was higher in pattern III vs II (median Expanded Disability Status Scale score 4 vs 3, p = 0.02). Monophasic clinical course was more common in patients with pattern III than pattern I or II (59% vs 33% vs 32%, p < 0.001). Similarly, patients with pattern III pathology were likely to have progressive disease compared to patients with patterns I or II when followed up for ≥5 years (24% overall, p = 0.49), with no differences in long-term survival, despite a more fulminant attack presentation. CONCLUSION: All 3 immunopatterns can be detected in active lesions, although they are found less frequently later into the disease due to the lower number of active lesions. Pattern III is associated with a more fulminant initial attack than either pattern I or II. Biopsied patients appear to have similar long-term outcomes regardless of their immunopatterns. Progressive disease is less associated with the initial immunopattern and suggests convergence into a final common pathway related to the chronically denuded axon.

Sleep quality and cortical amyloid-ß deposition in postmenopausal women of the Kronos early estrogen prevention study.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17ß-estradiol may reduce the accumulation of cortical amyloid-ß. However, how menopausal hormone therapies modify the associations of amyloid-ß accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-ß deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17ß-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-ß deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-ß accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-ß accumulation.

Associations of pituitary-ovarian hormones and white matter hyperintensities in recently menopausal women using hormone therapy.

OBJECTIVE: Little is known about how menopausal hormone treatment (HT) may influence the development of white matter hyperintensities (WMHs) in the brain. This study evaluated the associations of changes in levels of pituitary-ovarian hormones during HT and changes in WMH. METHODS: Women (n = 78 adherent to treatment) enrolled in the Kronos Early Estrogen Prevention Study underwent brain magnetic resonance imaging, and blood collection before and after 48 months of randomization to 0.45 mg/d oral conjugated equine estrogen (oCEE) daily, 50 µg/d transdermal 17ß estradiol (tE2), or placebo pills and patches. Women in the active treatment groups also received oral 200 mg/d micronized progesterone the first 12 days of the month. Estradiol (E2), estrone (E1), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum by high sensitivity liquid chromatography/mass spectrometry at baseline and following 48 months of HT. Longitudinal change in WMH volume was determined from fluid-attenuated inversion recovery magnetic resonance imaging using a semiautomated image segmentation algorithm. RESULTS: Serum levels of FSH, LH, E1, or E2 did not associate with WMH volume at baseline. After 48 months of treatment, smaller increases in WMH associated with decreases in FSH from baseline in the tE2 group and increases in E1 in both tE2 and oCEE groups. Changes in LH did not associate with changes in WMH in any group. CONCLUSIONS: Circulating levels of pituitary-ovarian hormones associate with changes in WMH volume in recently menopausal women using HT. Whether these relationships would be influenced by different doses of tE2 or oCEE remains to be determined. : Video Summary:http://links.lww.com/MENO/A590.

Video Summary:http://links.lww.com/MENO/A590.

Association of Bilateral Salpingo-Oophorectomy Before Menopause Onset With Medial Temporal Lobe Neurodegeneration.

Importance: There is an increased risk of cognitive impairment or dementia in women who undergo bilateral salpingo-oophorectomy (BSO) before menopause. However, data are lacking on the association of BSO before menopause with imaging biomarkers that indicate medial temporal lobe neurodegeneration and Alzheimer disease pathophysiology. Objective: To investigate medial temporal lobe structure, white matter lesion load, and ß-amyloid deposition in women who underwent BSO before age 50 years and before reaching natural menopause. Design, Setting, and Participants: This nested case-control study of women in the population-based Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) and in the Mayo Clinic Study of Aging (MCSA) in Olmsted County, Minnesota, included women who underwent BSO from 1988 through 2007 and a control group from the intersection of the 2 cohorts. Women who underwent BSO and control participants who underwent a neuropsychological evaluation, magnetic resonance imaging (MRI), and Pittsburgh compound B positron emission tomography (PiB-PET) were included in the analysis. Data analysis was performed from November 2017 to August 2018. Exposure: Bilateral salpingo-oophorectomy in premenopausal women who were younger than 50 years. Main Outcomes and Measures: Cortical ß-amyloid deposition on PiB-PET scan was calculated using the standard uptake value ratio. White matter hyperintensity volume and biomarkers for medial temporal lobe neurodegeneration (eg, amygdala volume, hippocampal volume, and parahippocampal-entorhinal cortical thickness) on structural MRI and entorhinal white matter fractional anisotropy on diffusion tensor MRI were also measured. Results: Forty-one women who underwent BSO and 49 control participants were recruited. One woman was excluded from the BSO group after diagnosis of an ovarian malignant condition, and 6 women were excluded from the control group after undergoing BSO after enrollment. Twenty control participants and 23 women who had undergone BSO completed all examinations. The median (interquartile range [IQR]) age at imaging was 65 (62-68) years in the BSO group and 63 (60-66) years in the control group. Amygdala volume was smaller in the BSO group (median [IQR], 1.74 [1.59-1.91] cm3) than the control group (2.15 [2.05-2.37] cm3; P < .001). The parahippocampal-entorhinal cortex was thinner in the BSO group (median [IQR], 3.91 [3.64-4.00] mm) than the control group (3.97 [3.89-4.28] mm; P = .046). Entorhinal white matter fractional anisotropy was lower in the BSO group (median [IQR], 0.19 [0.18-0.22]) than the control group (0.22 [0.20-0.23]; P = .03). Women were treated with estrogen in both groups (BSO, n = 22 of 23 [96%]; control, n = 10 of 19 [53%]). Global cognitive status test results did not differ between the groups. Conclusions and Relevance: Abrupt hormonal changes associated with BSO in premenopausal women may lead to medial temporal lobe structural abnormalities later in life. Longitudinal evaluation is needed to determine whether cognitive decline follows.

Brain structure and cognition 3 years after the end of an early menopausal hormone therapy trial.

OBJECTIVE: The effects of 2 frequently used formulations of menopausal hormone therapy (mHT) on brain structure and cognition were investigated 3 years after the end of a randomized, placebo-controlled trial in recently menopausal women with good cardiovascular health. METHODS: Participants (aged 42-56 years; 5-36 months past menopause) were randomized to one of the following: 0.45 mg/d oral conjugated equine estrogen (oCEE); 50 µg/d transdermal 17ß-estradiol (tE2); or placebo pills and patch for 4 years. Oral progesterone (200 mg/d) was given to mHT groups for 12 days each month. MRIs were performed at baseline, at the end of 4 years of mHT, and 3 years after the end of mHT (n = 75). A subset of participants also underwent Pittsburgh compound B-PET (n = 68). RESULTS: Ventricular volumes increased more in the oCEE group compared to placebo during the 4 years of mHT, but the increase in ventricular volumes was not different from placebo 3 years after the discontinuation of mHT. Increase in white matter hyperintensity volume was similar in the oCEE and tE2 groups, but it was statistically significantly greater than placebo only in the oCEE group. The longitudinal decline in dorsolateral prefrontal cortex volumes was less in the tE2 group compared to placebo, which correlated with lower cortical Pittsburgh compound B uptake. Rates of global cognitive change in mHT groups were not different from placebo. CONCLUSIONS: The effects of oCEE on global brain structure during mHT subside after oCEE discontinuation but white matter hyperintensities continue to increase. The relative preservation of dorsolateral prefrontal cortical volume in the tE2 group over 7 years indicates that mHT may have long-term effects on the brain. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the rates of change in global brain volumes and cognitive function in recently menopausal women receiving mHT (tE2 or oCEE) were not significantly different from women receiving placebo, as measured 3 years after exposure to mHT.

Brain tau deposition linked to systemic causes of death in normal elderly.

The relationship between causes of death and 4 major neurodegenerative brain proteins (beta-amyloid, tau, alpha-synuclein, and the TAR DNA-binding protein of 43 kDa (TDP-43) were assessed in 94 cognitively normal elderly participants that died without a neurodegenerative disease. There was an association between tau and causes of death (p = 0.01). Tau in the brain was associated with a reduced likelihood of dying from systemic cancers (p = 0.046), and with an increased likelihood of dying from pulmonary (p = 0.03) and gastrointestinal (p = 0.049) diseases. There were no associations between beta-amyloid, alpha-synuclein, or TDP-43 and causes of death. Tau deposition in the brain may have a relationship with systemic causes of death, including cancer, in the cognitively normal elderly.

Effects of hormone therapy on brain structure: A randomized controlled trial.

OBJECTIVE: To investigate the effects of hormone therapy on brain structure in a randomized, double-blinded, placebo-controlled trial in recently postmenopausal women. METHODS: Participants (aged 42-56 years, within 5-36 months past menopause) in the Kronos Early Estrogen Prevention Study were randomized to (1) 0.45 mg/d oral conjugated equine estrogens (CEE), (2) 50 µg/d transdermal 17ß-estradiol, or (3) placebo pills and patch for 48 months. Oral progesterone (200 mg/d) was given to active treatment groups for 12 days each month. MRI and cognitive testing were performed in a subset of participants at baseline, and at 18, 36, and 48 months of randomization (n = 95). Changes in whole brain, ventricular, and white matter hyperintensity volumes, and in global cognitive function, were measured. RESULTS: Higher rates of ventricular expansion were observed in both the CEE and the 17ß-estradiol groups compared to placebo; however, the difference was significant only in the CEE group (p = 0.01). Rates of ventricular expansion correlated with rates of decrease in brain volume (r = -0.58; p ≤ 0.001) and with rates of increase in white matter hyperintensity volume (r = 0.27; p = 0.01) after adjusting for age. The changes were not different between the CEE and 17ß-estradiol groups for any of the MRI measures. The change in global cognitive function was not different across the groups. CONCLUSIONS: Ventricular volumes increased to a greater extent in recently menopausal women who received CEE compared to placebo but without changes in cognitive performance. Because the sample size was small and the follow-up limited to 4 years, the findings should be interpreted with caution and need confirmation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that brain ventricular volume increased to a greater extent in recently menopausal women who received oral CEE compared to placebo.

Early Postmenopausal Transdermal 17ß-Estradiol Therapy and Amyloid-ß Deposition.

BACKGROUND: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD). OBJECTIVE: To investigate the effects of hormone therapy on amyloid-ß deposition in recently postmenopausal women. METHODS: Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50µg/day transdermal 17ß-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. RESULTS: Women (age = 52-65) randomized to transdermal 17ß-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17ß-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers. CONCLUSION: In this pilot study, transdermal 17ß-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-ß deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

Genome-wide association analyses of genetic, phenotypic, and environmental risks in the age-related eye disease study.

PURPOSE: To present genome-wide association analyses of genotypic and environmental risks on age-related macular degeneration (AMD) using 593 subjects from the age-related eye disease study (AREDS), after adjusting for population stratification and including questionable controls. METHODS: Single nucleotide polymorphism (SNP) associations with AMD for the non-Hispanic white population were investigated using a log-additive model after adjusting for population stratification. Replication of possible SNP-disease association was performed by genotyping an independent group of 444 AMD case and 300 control subjects. Logistic regression models were used to assess interaction effects between smoking and SNPs associated with AMD. Independent genetic risk effects among the disease-associated SNPs were also investigated using multiple logistic regression models. RESULTS: Population stratification was observed among the individuals having a self-reported race of non-Hispanic white. Risk allele frequencies at established AMD loci demonstrated that questionable control subjects were similar to control subjects in the AREDS, suggesting that they could be used as true controls in the analyses. Genetic loci (complement factor H [CFH], complement factor B [CFB], the age-related maculopathy susceptibility 2 locus containing the hypothetical gene [LOC387715]/the high-temperature requirement A-1 [HTRA1], and complement component 3 [C3]) that were already known to be associated with AMD were identified. An additional 26 novel SNPs potentially associated with AMD were identified, but none were definitely replicated in a second independent group of subjects. Smoking did not interact with known AMD loci, but was associated with late AMD. Statistically independent genetic signals were observed within the Pleckstrin homology domain-containing family A member 1 (PLEKHA1) region near LOC387715/HTRA1 and within a haplotype spanning exon 19 of the C3 gene. CONCLUSIONS: Population stratification among Caucasian subjects from the multicentered AREDS was observed, suggesting that it should be adjusted for in future studies. The AREDS questionable control subjects can be used as control subjects in the AREDS genome-wide association study (GWAS). Smoking was an independent risk factor for advanced AMD in the AREDS subjects. There continues to be evidence that the 10q26 (age-related maculopathy susceptibility 2 gene [ARMS2]) locus spanning PLEKHA1-LOC387715-HTRA1 and the C3 gene may contain multiple independent genetic risks contributing to AMD.

Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration.

PURPOSE: Nonsynonymous coding single nucleotide polymorphisms (nsSNPs) in complement component 3 (C3) alter the risk of age-related macular degeneration (AMD). This was a study of the effect of haplotypes across C3 on AMD risk. METHODS: Nine SNPs tagging haplotypes across C3 were genotyped on 738 subjects at the Mayo Clinic. Haplotype analyses were performed with and without conditioning on individual SNPs. Replication studies were performed using 1541 subjects from the age-related eye disease study (AREDS). RESULTS: Two nsSNPs located 5125 bp apart in the 5' end of C3 showed the highest association (rs1047286 or P314L, P = 9.2E-05; rs2230199 or R102G, P = 4.1E-05) with AMD. The minor alleles of both SNPs tagged a single risk haplotype. The effects of the two nsSNPs could not be distinguished due to high linkage disequilibrium. The risk SNPs preferentially promoted the development of advanced AMD relative to early AMD in both the Mayo and AREDS subjects. Haplotypes in the 3' end of the C3 locus were associated with AMD in both the Mayo and AREDS subjects. The effect persisted after conditioning on the nsSNPs only in the Mayo subjects. No interaction was found between rs2230199 and smoking or other AMD loci. CONCLUSIONS: nsSNPs in C3 increased the risk of developing AMD 1.8-fold for 1 risk allele or 2.4-fold for two risk alleles and were preferentially associated with advanced AMD. Further study is needed to determine whether haplotypes in the 3' end of C3 have an independent association with AMD.