Health, Imaging, and Cognition Across the Menopausal Transition

Official title

Santé, Imagerie et Cognition à Travers la Transition ménopausique

Overview

This observational cross-sectional study aims to better understand how the menopausal transition affects brain energy metabolism and cognition. Menopause, a natural stage in a woman's life, is typically divided into three phases: premenopause, perimenopause, and postmenopause. This transition involves hormonal fluctuations and a decline in estrogen levels, which can impact physical, emotional, and cognitive well-being. Common symptoms include hot flashes, sleep disturbances, mood changes, and difficulties with memory and concentration. Emerging evidence suggests that the decline in estrogen may impair how the brain uses glucose, its primary energy source. This reduction in glucose metabolism is thought to contribute to cognitive difficulties reported during midlife. In contrast, the brain's capacity to use ketones-alternative energy substrates produced during fasting or low-carbohydrate intake-appears preserved during aging and hormonal changes. Increasing circulating ketones may offer a promising strategy to support brain energy and cognitive function. To explore these relationships, the study will employ advanced brain imaging (PET scans) to assess glucose and ketone uptake in the brain. Additional measures will include hormone levels, cognitive testing, continuous glucose monitoring, and MRI. PET tracers will also be used to evaluate estrogen receptor distribution, providing insight into how the brain responds to hormonal changes. A total of 45 women aged 35-60 will be enrolled and categorized into three groups (15 per group): premenopause, perimenopause, and postmenopause. Each participant will attend four study visits that include questionnaires, blood tests, cognitive assessments, metabolic measurements, and imaging procedures. The results may help identify early neurobiological and metabolic markers associated with the menopausal transition. These findings could inform new approaches to preserve brain health and prevent cognitive decline in aging women. Improving understanding of how the female brain adapts to hormonal shifts may ultimately support more targeted strategies for promoting healthy aging.

Primary outcome measures

• cerebral metabolic rates (μmol/100 g/min) measured by PET (11C-AcAc +18F-FDG) [Time frame: 1 day at baseline]
• Tracer influx rates (k) measured by PET (11C-AcAc +18F-FDG) [Time frame: 1 day at baseline]

Secondary outcome measures (5)

• Time-activity curves of the estrogen receptor in the brain (by 18F-4FMFES PET) [Time frame: 1 day at baseline]
• distribution volume ratio of the estrogen receptor in the brain (by 18F-4FMFES PET) [Time frame: 1 day at baseline]
• Glucose variability (SD of glucose measured by continuous glucose monitoring) [Time frame: Over 5 days following sensor placement et stabilisation]
• Glucose average (mean of glucose measured by continuous glucose monitoring) [Time frame: Over 5 days following sensor placement et stabilisation]
• Time in range [Time frame: Over 5 days following sensor placement et stabilisation]

Eligibility criteria

Inclusion criteria

• Able to read and speak French
• Capable of understanding and signing informed consent GROUP SPECIFIC INCLUSION CRITERIA Premenopause: • Women aged 35 to 55; No change in menstrual cycle regularity over the past 10 months (variation less than 7 days per cycle)

Perimenopause: Women aged 40 to 60; Menstrual cycles varying by more than 7 days per cycle for at least 10 cycles, or no period for 3 to 11 months

postmenopause: Women aged 45 to 65; No menstrual period for ≥ 12 months

Exclusion criteria

• Pregnancy, childbirth within the past 12 months, or breastfeeding
• Use of hormone replacement therapy or hormonal contraceptives in the past 6 months
• contraindications to MRI (e.g., presence of non-compatible metallic objects)
• Claustrophobia
• Type 1 diabetes
• Adherence to a ketogenic intervention (e.g., ketone supplements, intermittent fasting, ketogenic diet) in the past 3 months
• Engaging in intense physical activity 5 times per week or more
• Any significant neurological disorder (e.g., dementia, brain tumor, seizure disorder, history of significant head trauma with persistent neurological deficits, known structural brain abnormalities)
• History of oophorectomy or hysterectomy
• Any significant psychiatric disorder (e.g., major depression within the past 2 years, bipolar disorder, schizophrenia)
• Systemic diseases or unstable/uncontrolled medical conditions (e.g., cardiovascular disease, uncontrolled diabetes, kidney or liver disorders)
• Any other condition that may interfere with participation, as judged by the study physician

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Canada · 1 center

• Centre de recherche sur le Vieillissement — Sherbrooke

Publications

• Andy C, Nerattini M, Jett S, Carlton C, Zarate C, Boneu C, Fauci F, Ajila T, Battista M, Pahlajani S, Christos P, Fink ME, Williams S, Brinton RD, Mosconi L. Systematic review and meta-analysis of the effects of menopause hormone therapy on cognition. Front Endocrinol (Lausanne). 2024 Mar 4;15:1350318. doi: 10.3389/fendo.2024.1350318. eCollection 2024. PMID 38501109
• Castellano CA, Baillargeon JP, Nugent S, Tremblay S, Fortier M, Imbeault H, Duval J, Cunnane SC. Regional Brain Glucose Hypometabolism in Young Women with Polycystic Ovary Syndrome: Possible Link to Mild Insulin Resistance. PLoS One. 2015 Dec 9;10(12):e0144116. doi: 10.1371/journal.pone.0144116. eCollection 2015. PMID 26650926
• Mosconi L, Nerattini M, Matthews DC, Jett S, Andy C, Williams S, Yepez CB, Zarate C, Carlton C, Fauci F, Ajila T, Pahlajani S, Andrews R, Pupi A, Ballon D, Kelly J, Osborne JR, Nehmeh S, Fink M, Berti V, Dyke JP, Brinton RD. In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology. Sci Rep. 2024 Jun 20;14(1):12680. doi: 10.1038/s41598-024- PMID 38902275
• Paquette M, Phoenix S, Lavallee E, Rousseau JA, Guerin B, Turcotte EE, Lecomte R. Cross-Species Physiological Assessment of Brain Estrogen Receptor Expression Using 18F-FES and 18F-4FMFES PET Imaging. Mol Imaging Biol. 2020 Oct;22(5):1403-1413. doi: 10.1007/s11307-020-01520-w. Epub 2020 Jul 22. PMID 32699974
• Arjmand S, Bender D, Jakobsen S, Wegener G, Landau AM. Peering into the Brain's Estrogen Receptors: PET Tracers for Visualization of Nuclear and Extranuclear Estrogen Receptors in Brain Disorders. Biomolecules. 2023 Sep 18;13(9):1405. doi: 10.3390/biom13091405. PMID 37759805
• Fortier M, Castellano CA, St-Pierre V, Myette-Cote E, Langlois F, Roy M, Morin MC, Bocti C, Fulop T, Godin JP, Delannoy C, Cuenoud B, Cunnane SC. A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT. Alzheimers Dement. 2021 Mar;17(3):543-552. doi: 10.1002/alz.12206. Epub 2020 Oct 26. PMID 33103819
• Fortier M, Castellano CA, Croteau E, Langlois F, Bocti C, St-Pierre V, Vandenberghe C, Bernier M, Roy M, Descoteaux M, Whittingstall K, Lepage M, Turcotte EE, Fulop T, Cunnane SC. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019 May;15(5):625-634. doi: 10.1016/j.jalz.2018.12.017. Epub 2019 Apr 23. PMID 31027873
• Croteau E, Castellano CA, Richard MA, Fortier M, Nugent S, Lepage M, Duchesne S, Whittingstall K, Turcotte EE, Bocti C, Fulop T, Cunnane SC. Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease. J Alzheimers Dis. 2018;64(2):551-561. doi: 10.3233/JAD-180202. PMID 29914035

Identifiers

NCT: NCT07021664 · 2025-58-28

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗