Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load

Abstract

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer’s disease (AD) in women. We conducted 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) 11C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.

Systematic review of 31P-magnetic resonance spectroscopy studies of brain high energy phosphates and membrane phospholipids in aging and Alzheimer's disease

“…We have identified 7 31 P-MRS studies investigating HEP variability with normal aging (Longo et al, 1993 ; Constans et al, 1995 ; Rae et al, 2003 ; Forester et al, 2010 ; Schmitz et al, 2018 ; Cuenoud et al, 2020 ; Rietzler et al, 2022 ), in addition to 4 studies focusing on individuals at risk for AD (e.g., family history and/or APOE4 genotype) (Mosconi et al, 2021 ; Jett et al, 2022a , 2023 ; Parasoglou et al, 2022 ). These studies are summarized in Table 2 .…”

“…The first study of 119 cognitively normal midlife individuals (74 women, 45 men) at risk for AD found higher α-ATP utilization relative to PCr in temporal and frontal regions of post-menopausal women as compared to age-controlled men (Mosconi et al, 2021 ). Another report of 216 healthy individuals (170 women, 46 men) at risk for AD aged 40–65 years found that when compared to men, peri-menopausal women exhibited lower PCr/ATP in frontal cortex, which extended to PCC, fusiform, medial and lateral temporal cortices in post-menopausal women (Jett et al, 2022a ). This study also investigated associations between PCr/ATP and fibrillar Aβ load as measured by 11 C-Pittsburgh Compound B (PiB) PET and found that participants with the highest Aβ load were peri- and post-menopausal women with lower PCr/ATP measures (Jett et al, 2022a ).…”

“…Another report of 216 healthy individuals (170 women, 46 men) at risk for AD aged 40–65 years found that when compared to men, peri-menopausal women exhibited lower PCr/ATP in frontal cortex, which extended to PCC, fusiform, medial and lateral temporal cortices in post-menopausal women (Jett et al, 2022a ). This study also investigated associations between PCr/ATP and fibrillar Aβ load as measured by 11 C-Pittsburgh Compound B (PiB) PET and found that participants with the highest Aβ load were peri- and post-menopausal women with lower PCr/ATP measures (Jett et al, 2022a ). However, another study of individuals at risk for AD found no associations between HEP metabolites with Aβ load, which warrants further investigation (Parasoglou et al, 2022 ).…”

“…However, two studies reported no sex differences in HEP metabolites in healthy individuals (Forester et al, 2010 ; Schmitz et al, 2018 ), and another study, while including both sexes in analysis, did not report on related differences (Longo et al, 1993 ). One study reported no difference in PCr/Pi between men and women at risk for AD (Jett et al, 2022a ), while two studies found no effect of sex on Pi/ATP measures in individuals at risk for AD (Jett et al, 2022a , 2023 ). Additional studies investigating the effects of sex on age-related changes in HEP metabolites are warranted.…”

“…PCr, set at 0 ppm, with PME, Pi, and PDE to the left of PCr, whereas α-ATP, β-ATP, and γ-ATP are located to the right of PCr. Images adapted from data presented in Jett et al ( 2022a ). ATP, adenosine triphosphate; PCr, phosphocreatine; PDE, phosphodiester; Pi, inorganic phosphate; PME, phosphomonoester.…”