Menopause is a sex-specific risk factor for Alzheimer’s Disease (AD); specifically, the Alzheimer’s Association reports that of the 5.3 million Americans with AD, 3.3 million are women and only 2.0 million are men. The physiologic basis for this sex difference is unknown. Although menopausal hot flashes (HF) have long been assumed to be benign, albeit uncomfortable,1 emerging evidence links higher rates of HF with both cognitive decline2 and cardiac disease.3 HF are experienced by 80% of menopausal women in the US.4 The underlying mechanism or symptom experiences that differentiate women at risk for or predict sequela is not known. Understanding HF physiology is critical to reducing their negative impact on symptomatic women, preventing cognitive and cardiac sequela, and developing relevant interventions.
Building on studies of the neuroprotective effects of estrogen5, 6 we have tested the Impaired Glucose Delivery Model of Vasomotor Symptoms.7, 8 Neuronal activation stimulates neurobarrier coupling to supply glucose; the coupling process both increases production of glucose transporter 1 (GLUT 1) and vasodilation at the blood brain barrier.7 With estrogen decline at menopause, we hypothesize that the GLUT 1 response is diminished and the neurovascular response overcompensates resulting in the HF.8 Based on this model, the principal investigator (PI) conducted a series of experimental studies demonstrating HF decrease with glucose administration. We found that HF were associated with lower blood glucose levels (less than 100 mg/dL) and were significantly reduced when blood glucose was higher, supporting the research hypothesis.
Based on our hypothesis, we propose that cognitive activity would stimulate HF by increasing brain glucose demands. The purpose of this study is it to first validate the efficacy of a protocol to reliability stimulate VMS through cognitive activity so that we could subsequently image dynamic bioenergetics in the brain during vasomotor symptoms using functional magnetic resonance imaging.
Methods:
To achieve the first aim, a time-series design study using four standardized cognitive challenge tests was developed. After Institutional Review Board approval, a sample of postmenopausal women age 45 to 65 experiencing 7 or more VMS per day was recruited. After completing the informed consent process and demographic data, each participant was oriented to both the Bahr Skin Conductance monitor for VMS and the FreeStyle Libre Pro for continuous blood glucose assessment and the monitors applied. These observational data were the first to provide continuous longitudinal assessment of VMS and blood glucose in the ambulatory setting as women conduct their activities of daily living. However, this data is not the focus of this presentation.
On the fifth day of observational assessment, participants were scheduled for the experimental cognitive activation of VMS experiment; participants were instructed to fast for a period of at least four hours before the scheduled experiment. Participants were first oriented to the research conditions and computer tests before questions were answered. Four computer-based cognitive tests were administered in random order each for a period of five minutes with a 3-minute rest period between each administration. Upon completion of the cognitive tests and related rest periods, each participant was fed a standard light meal, compensated for their participation, and the imaging study explained before the VMS and blood glucose monitors were removed.
For the second aim of this study women consenting to participate in the imaging study used RedCap to complete the standard risk assessment from used for all Magnetic Resonance Imaging at the collaborating agency conducting the fMRIs. The collaborating radiologist reviewed all risk assessment forms and collaborated with the research team to clarify any concerning information. On the scheduled date of the fMRI, participants were asked to fast for a minimum of four hours before the scheduled procedure. Upon arrival at the imaging center, fasting status was confirmed through a blood glucose test conducted via finger stick. Functional magnetic resonance imaging (fMRI) was performed on a Siemens Magnetom 3T Verio scanner. Localizer and structural T1-weighted images were first obtained. These were followed by echo-planar blood oxygen level dependent (EPI-BOLD) sequences. A total of 4 testing scans, during administration of the same psychological testing used in the cognitive stimulation of VMS phase of this study. The participants indicated the start and end of a hot flash sensation by pressing on a squeeze ball, and the times were noted. Blood glucose was evaluated upon completion of the fMRI sequences and the participant fed a standard meal.
Results:
Thirty-six women were recruited for this study. Several women were lost to the study due to difficulty scheduling for either monitor application or the psychology testing within five days, three were unresponsive after initial verbal consent to participate, and four were lost to analysis due to incomplete data. The resulting sample was twenty-seven postmenopausal women symptomatic for vasomotor symptoms in the cognitive stimulation of VMS phase. Cognitive stimulus of VMS data were analyzed using linear regression. Cognitive activity stimulated VMS in 26.06 minutes for 90.9% of participants. VMS was not related to difficulty of cognitive stimulus but was related to time in the testing conditions.
In the imaging phase of this study women with claustrophobia, metal used in surgical treatments, or physical limitations to lying on the MRI bed were excluded. As a result, nineteen women completed the imaging phase. Not all women experienced VMS during the imaging study and several were excluded due to short duration of VMS (< 20 seconds) precluding effective imaging. Of the final sample significant changes in bioenergetics (specifically activation) was noted in the anterior cingulate cortex and the corpus callosum.
Conclusion:
Advanced in technology now allow for collection of high-quality longitudinal VMS and blood glucose data. Cognitive activity can effectively stimulate VMS under fasting conditions in the laboratory setting, providing additional support for the Impaired Glucose Delivery Model of Vasomotor Symptoms. Further evaluation of the efficacy of cognitive stimulus for VMS is needed using a cross-over design comparing fasting and postprandial conditions. Additional study is also needed to examine the characteristics differentiating women who experienced VMS from those who did not. Finally, our preliminary data indicate that bioenergetic changes in the brain are evident as women experience VMS. Additional study is to: evaluate the longitudinal effect of these changes, examine the impact of stage of reproductive aging (STRAW +10) on bioenergetics both at rest and during VMS, and compare these bioenergetics in samples of symptomatic and non-symptomatic postmenopausal women.