Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.

Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD+/-/human APOE ɛ3 or ɛ4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral ß-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aß deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aß oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aß production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.

Advanced brain aging: relationship with epidemiologic and genetic risk factors, and overlap with Alzheimer disease atrophy patterns.

We systematically compared structural imaging patterns of advanced brain aging (ABA) in the general-population, herein defined as significant deviation from typical BA to those found in Alzheimer disease (AD). The hypothesis that ABA would show different patterns of structural change compared with those found in AD was tested via advanced pattern analysis methods. In particular, magnetic resonance images of 2705 participants from the Study of Health in Pomerania (aged 20-90 years) were analyzed using an index that captures aging atrophy patterns (Spatial Pattern of Atrophy for Recognition of BA (SPARE-BA)), and an index previously shown to capture atrophy patterns found in clinical AD (Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease (SPARE-AD)). We studied the association between these indices and risk factors, including an AD polygenic risk score. Finally, we compared the ABA-associated atrophy with typical AD-like patterns. We observed that SPARE-BA had significant association with: smoking (P<0.05), anti-hypertensive (P<0.05), anti-diabetic drug use (men P<0.05, women P=0.06) and waist circumference for the male cohort (P<0.05), after adjusting for age. Subjects with ABA had spatially extensive gray matter loss in the frontal, parietal and temporal lobes (false-discovery-rate-corrected q<0.001). ABA patterns of atrophy were partially overlapping with, but notably deviating from those typically found in AD. Subjects with ABA had higher SPARE-AD values; largely due to the partial spatial overlap of associated patterns in temporal regions. The AD polygenic risk score was significantly associated with SPARE-AD but not with SPARE-BA. Our findings suggest that ABA is likely characterized by pathophysiologic mechanisms that are distinct from, or only partially overlapping with those of AD.

In vivo human amyloid imaging.

PET imaging agents such as Pittsburgh compound B (PiB) allow detection of fibrillar ß-amyloid (Aß) in vivo. In addition to quantification of Aß deposition in mild cognitive impairment and Alzheimer's disease, PiB has also increased our understanding of Aß deposition in older adults without cognitive impairment. In vivo Aß deposition has been studied in relation to genotype, structural and functional brain changes, as well as alterations in biomarker levels. To date, several studies have reported changes in Aß burden over time. This, together with investigation of the relationship between Aß deposition and cognition, sets the stage for elucidation of the temporal sequence of the neurobiological events leading to cognitive decline. Furthermore, correlation of Aß levels detected by PiB PET and those obtained from biopsy or postmortem specimens will allow more rigorous quantitative interpretation of PiB PET data in relation to neuropathological evaluation. Since the first human study in 2004, in vivo amyloid imaging has led to advances in our understanding of the role of Aß deposition in human aging and cognitive decline, as well as provided new tools for patient selection and therapeutic monitoring in clinical trials.

Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study.

OBJECTIVES: To determine whether menopausal hormone therapy (HT) affects regional brain volumes, including hippocampal and frontal regions. METHODS: Brain MRI scans were obtained in a subset of 1,403 women aged 71-89 years who participated in the Women's Health Initiative Memory Study (WHIMS). WHIMS was an ancillary study to the Women's Health Initiative, which consisted of two randomized, placebo-controlled trials: 0.625 mg conjugated equine estrogens (CEE) with or without 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet. Scans were performed, on average, 3.0 years post-trial for the CEE + MPA trial and 1.4 years post-trial for the CEE-Alone trial; average on-trial follow-up intervals were 4.0 years for CEE + MPA and 5.6 years for CEE-Alone. Total brain, ventricular, hippocampal, and frontal lobe volumes, adjusted for age, clinic site, estimated intracranial volume, and dementia risk factors, were the main outcome variables. RESULTS: Compared with placebo, covariate-adjusted mean frontal lobe volume was 2.37 cm(3) lower among women assigned to HT (p = 0.004), mean hippocampal volume was slightly (0.10 cm(3)) lower (p = 0.05), and differences in total brain volume approached significance (p = 0.07). Results were similar for CEE + MPA and CEE-Alone. HT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores <90). CONCLUSIONS: Conjugated equine estrogens with or without MPA are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women experiencing cognitive deficits before initiating hormone therapy.

Free testosterone and risk for Alzheimer disease in older men.

OBJECTIVE: To investigate the relationships between age-associated decreases in endogenous serum total testosterone (T) and a free T index (FTI) in men and the subsequent development of Alzheimer disease (AD). METHOD: The authors used a prospective, longitudinal design with follow-up in men since 1958. Participants were from the Baltimore Longitudinal Study of Aging, a community-dwelling volunteer sample with baseline ages of 32 to 87 years. All subjects were free of AD at baseline T assessment. Five hundred seventy-four men assessed at multiple time points were followed for a mean of 19.1 years (range, 4 to 37 years). Diagnoses of AD were based on biennial physical, neurologic, and neuropsychological evaluations. RESULTS: Diagnosis of AD was associated inversely with FTI by itself and after adjustments for age, education, smoking status, body mass index, diabetes, any cancer diagnoses, and hormone supplements. In separate analyses, total T and sex hormone binding globulin were not significant predictors after adjustment with covariates. Increases in the FTI were associated with decreased risk of AD (hazard ratio = 0.74; 95% CI = 0.57 to 0.96), a 26% decrease for each 10-nmol/nmol FTI increase. CONCLUSIONS: Calculated free testosterone concentrations were lower in men who developed Alzheimer disease, and this difference occurred before diagnosis. Future research may determine whether higher endogenous free testosterone levels offer protection against a diagnosis of Alzheimer disease in older men.

Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy.

OBJECTIVE: This study examined the effects of hormone-replacement therapy on memory and other cognitive abilities in cognitively intact older women. METHOD: This prospective observational study in nondemented postmenopausal women aged 50-89 from the Baltimore Longitudinal Study of Aging involved study groups consisting of 103 women who were receiving oral or transdermal estrogen-replacement therapy (44 of whom were receiving adjuvant progesterone) and 81 women who had never received such therapy. Groups were naturally matched on education, health status, depressive symptoms, annual income, and general verbal ability. To restrict the study group to cognitively healthy women, prospective clinical data were used to exclude women who developed dementia up to 5 years after assessment. Data were cross-sectional. Multivariate analysis of variance and follow-up univariate analyses of variance were performed to compare those women who were receiving and those who had never received hormone-replacement therapy on measures of verbal memory, figural memory, mental rotations, attention, and working memory. RESULTS: The women receiving hormone-replacement therapy performed significantly better on measures of verbal learning and memory than did those who had never received hormones, but there were no significant differences in scores on other cognitive tests. Specific aspects of memory performance, including encoding and retrieval, were superior among the women receiving hormone therapy. CONCLUSIONS: These findings, based on groups of women who were receiving and had never received hormone-replacement therapy and who were naturally matched on health and cognitive status, suggest that hormone-replacement therapy may have a selective beneficial effect on verbal memory in older nondemented women.

In vitro ATP regeneration from polyphosphate and AMP by polyphosphate:AMP phosphotransferase and adenylate kinase from Acinetobacter johnsonii 210A.

In vitro enzyme-based ATP regeneration systems are important for improving yields of ATP-dependent enzymatic reactions for preparative organic synthesis and biocatalysis. Several enzymatic ATP regeneration systems have been described but have some disadvantages. We report here on the use of polyphosphate:AMP phosphotransferase (PPT) from Acinetobacter johnsonii strain 210A in an ATP regeneration system based on the use of polyphosphate (polyP) and AMP as substrates. We have examined the substrate specificity of PPT and demonstrated ATP regeneration from AMP and polyP using firefly luciferase and hexokinase as model ATP-requiring enzymes. PPT catalyzes the reaction polyP(n) + AMP --> ADP + polyP(n-1). The ADP can be converted to ATP by adenylate kinase (AdK). Substrate specificity with nucleoside and 2'-deoxynucleoside monophosphates was examined using partially purified PPT by measuring the formation of nucleoside diphosphates with high-pressure liquid chromatography. AMP and 2'-dAMP were efficiently phosphorylated to ADP and 2'-dADP, respectively. GMP, UMP, CMP, and IMP were not converted to the corresponding diphosphates at significant rates. Sufficient AdK and PPT activity in A. johnsonii 210A cell extract allowed demonstration of polyP-dependent ATP regeneration using a firefly luciferase-based ATP assay. Bioluminescence from the luciferase reaction, which normally decays very rapidly, was sustained in the presence of A. johnsonii 210A cell extract, MgCl(2), polyP(n=35), and AMP. Similar reaction mixtures containing strain 210A cell extract or partially purified PPT, polyP, AMP, glucose, and hexokinase formed glucose 6-phosphate. The results indicate that PPT from A. johnsonii is specific for AMP and 2'-dAMP and catalyzes a key reaction in the cell-free regeneration of ATP from AMP and polyP. The PPT/AdK system provides an alternative to existing enzymatic ATP regeneration systems in which phosphoenolpyruvate and acetylphosphate serve as phosphoryl donors and has the advantage that AMP and polyP are stabile, inexpensive substrates.