Evidence of Pericyte Damage in a Cognitively Normal Cohort: Association With CSF and PET Biomarkers of Alzheimer's Disease.

BACKGROUND: Blood-brain barrier (BBB) dysfunction is emerging as an important pathophysiologic factor in Alzheimer's disease (AD). Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) is a biomarker of BBB pericyte injury and has been implicated in cognitive impairment and AD. METHODS: We aimed to study CSF PDGFRß protein levels, along with CSF biomarkers of brain amyloidosis and tau pathology in a well-characterized population of cognitively unimpaired individuals and correlated CSF findings with amyloid-PET positivity. We performed an institutional review board (IRB)-approved cross-sectional analysis of a prospectively enrolled cohort of 36 cognitively normal volunteers with available CSF, Pittsburgh compound B PET/CT, Mini-Mental State Exam score, Global Deterioration Scale, and known apolipoprotein E (APOE) ε4 status. RESULTS: Thirty-six subjects were included. Mean age was 63.3 years; 31 of 36 were female, 6 of 36 were amyloid-PET-positive and 12 of 36 were APOE ε4 carriers. We found a moderate positive correlation between CSF PDGFRß and both total Tau (r=0.45, P=0.006) and phosphorylated Tau 181 (r=0.51, P=0.002). CSF PDGFRß levels were not associated with either the CSF Aß42 or the amyloid-PET. CONCLUSIONS: We demonstrated a moderate positive correlation between PDGFRß and both total Tau and phosphorylated Tau 181 in cognitively normal individuals. Our data support the hypothesis that BBB dysfunction represents an important early pathophysiologic step in AD, warranting larger prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00094939.

Systematic review and meta-analysis of the effects of menopause hormone therapy on cognition.

Introduction: Despite evidence from preclinical studies suggesting estrogen's neuroprotective effects, the use of menopausal hormone therapy (MHT) to support cognitive function remains controversial. Methods: We used random-effect meta-analysis and multi-level meta-regression to derive pooled standardized mean difference (SMD) and 95% confidence intervals (C.I.) from 34 randomized controlled trials, including 14,914 treated and 12,679 placebo participants. Results: Associations between MHT and cognitive function in some domains and tests of interest varied by formulation and treatment timing. While MHT had no overall effects on cognitive domain scores, treatment for surgical menopause, mostly estrogen-only therapy, improved global cognition (SMD=1.575, 95% CI 0.228, 2.921; P=0.043) compared to placebo. When initiated specifically in midlife or close to menopause onset, estrogen therapy was associated with improved verbal memory (SMD=0.394, 95% CI 0.014, 0.774; P=0.046), while late-life initiation had no effects. Overall, estrogen-progestogen therapy for spontaneous menopause was associated with a decline in Mini Mental State Exam (MMSE) scores as compared to placebo, with most studies administering treatment in a late-life population (SMD=-1.853, 95% CI -2.974, -0.733; P = 0.030). In analysis of timing of initiation, estrogen-progestogen therapy had no significant effects in midlife but was associated with improved verbal memory in late-life (P = 0.049). Duration of treatment >1 year was associated with worsening in visual memory as compared to shorter duration. Analysis of individual cognitive tests yielded more variable results of positive and negative effects associated with MHT. Discussion: These findings suggest time-dependent effects of MHT on certain aspects of cognition, with variations based on formulation and timing of initiation, underscoring the need for further research with larger samples and more homogeneous study designs.

Sex-specific associations of serum cortisol with brain biomarkers of Alzheimer's risk.

Emerging evidence implicates chronic psychological stress as a risk factor for Alzheimer's disease (AD). Herein, we examined the relationships between serum cortisol and multimodality brain AD biomarkers in 277 cognitively normal midlife individuals at risk for AD. Overall, higher cortisol was associated with lower total brain volume, lower glucose metabolism (CMRglc) in frontal cortex, and higher ß-amyloid (Aß) load in AD-vulnerable regions; and marginally associated with phosphocreatine to ATP ratios (PCr/ATP) in precuneus and parietal regions. Sex-specific modification effects were noted: in women, cortisol exhibited stronger associations with Aß load and frontal CMRglc, the latter being more pronounced postmenopause. In men, cortisol exhibited stronger associations with gray matter volume and PCr/ATP measures. Higher cortisol was associated with poorer delayed memory in men but not in women. Results were adjusted for age, Apolipoprotein E (APOE) epsilon 4 status, midlife health factors, and hormone therapy use. These results suggest sex-specific neurophysiological responses to stress, and support a role for stress reduction in AD prevention.

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

Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aß) plaques. In vivo probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used 18F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in vivo in the human brain. 31Phosphorus-magnetic resonance spectroscopy (31P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the 31P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of 31P-MRS measures as biomarkers for the early detection of AD.

In vivo Brain Estrogen Receptor Expression By Neuroendocrine Aging And Relationships With Gray Matter Volume, Bio-Energetics, and Clinical Symptomatology.

17ß-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women's health.

Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimer's disease: A 31Phosphorus MR spectroscopy study.

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

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

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 (Aß) 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 Aß load were not significant, individuals with the highest Aß 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.

Decreased CSF clearance and increased brain amyloid in Alzheimer's disease.

BACKGROUND: In sporadic Alzheimer's disease (AD), brain amyloid-beta (Aß) deposition is believed to be a consequence of impaired Aß clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer 18F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aß levels. METHODS: In the present study, we use two PET tracers, 18F-THK5351 and 11C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants. RESULTS: we observed that the ventricular CSF clearance measures were correlated (r = 0.66, p < 0.01), with reductions in AD of 18 and 27%, respectively. We also replicated a significant relationship between ventricular CSF clearance (18F-THK5351) and brain Aß load (r = - 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance. CONCLUSIONS: Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aß deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence.

Sex-driven modifiers of Alzheimer risk: A multimodality brain imaging study.

OBJECTIVE: To investigate sex differences in late-onset Alzheimer disease (AD) risks by means of multimodality brain biomarkers (ß-amyloid load via 11C-Pittsburgh compound B [PiB] PET, neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI). METHODS: We examined 121 cognitively normal participants (85 women and 36 men) 40 to 65 years of age with clinical, laboratory, neuropsychological, lifestyle, MRI, FDG- and PiB-PET examinations. Several clinical (e.g., age, education, APOE status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences. RESULTS: Groups were comparable on clinical and cognitive measures. After adjustment for each modality-specific confounders, the female group showed higher PiB ß-amyloid deposition, lower FDG glucose metabolism, and lower MRI gray and white matter volumes compared to the male group (p < 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease. CONCLUSION: Hormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process.