Lisa Mosconi1, Valentina Berti2, Crystal Quinn2, Pauline McHugh2, Gabriella Petrongolo2, Isabella Varsavsky2, Ricardo S Osorio2, Alberto Pupi2, Shankar Vallabhajosula2, Richard S Isaacson2, Mony J de Leon2, Roberta Diaz Brinton2. 1. From the Departments of Neurology (L.M., R.S.I.) and Radiology (S.V.), Weill Cornell Medical College; Department of Psychiatry (L.M., C.Q., P.M., G.P., I.V., R.S.O., M.J.d.L.), New York University School of Medicine, New York; Department of Biomedical, Experimental and Clinical Sciences "Mario Serio" (V.B., A.P.), Nuclear Medicine Unit, University of Florence, Italy; Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson; and Departments of Pharmacology, Biomedical Engineering, and Neurology (R.D.B.), University of South California, Los Angeles. lim2035@med.cornell.edu. 2. From the Departments of Neurology (L.M., R.S.I.) and Radiology (S.V.), Weill Cornell Medical College; Department of Psychiatry (L.M., C.Q., P.M., G.P., I.V., R.S.O., M.J.d.L.), New York University School of Medicine, New York; Department of Biomedical, Experimental and Clinical Sciences "Mario Serio" (V.B., A.P.), Nuclear Medicine Unit, University of Florence, Italy; Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson; and Departments of Pharmacology, Biomedical Engineering, and Neurology (R.D.B.), University of South California, Los Angeles.
Abstract
OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Aβ deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Aβ deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
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