Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery.

After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.

Single voxel proton magnetic resonance spectroscopy in post-stroke depression.

Mood disorders are associated with structural, metabolic and spectroscopic changes in prefrontal regions. In the case of depression associated with stroke, there is little information about the biochemical profile of these regions, as assessed by proton magnetic resonance spectroscopy ((1)H-MRS). In a group of first-ever stroke patients, we studied the association between post-stroke depression and (1)H-MRS measurements in unaffected frontal lobes. Twenty-six patients with a first ischemic stroke located outside the frontal lobes were included in the study. Single voxel proton magnetic resonance spectroscopy ((1)H-MRS) was performed to assess N-acetylaspartate/creatine (NAA)/Cr, glutamate+glutamine (Glx)/Cr, choline (Cho)/Cr and myo-inositol (mI)/Cr ratios. Patients were assessed within the first 10 days after stroke and again four months later. The diagnosis of depression was made on the basis of clinical observation, interview and Hamilton Depression Rating Scale scores. In a group of 26 patients, eight (31%) met criteria for depression at the first assessment, and nine (35%) met criteria for depression at follow-up. Patients with depression in the immediate post-stroke phase had significantly higher Glx/Cr ratios in the contralesional hemisphere than non-depressive patients. No biochemical differences were found between the groups at 4-month follow-up. These findings suggest that post-stroke depression is accompanied by changes in frontal lobe glutamate/glutamine levels, perhaps reflecting abnormalities in glutamatergic transmission in the immediate post-stroke period.