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.

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

Healthy individuals from the general population

There is no current plan to share individual participant data (IPD) with external researchers. While data reuse within the study team is permitted, external data sharing is subject to sponsor agreement and may be considered on a case-by-case basis in the future.