CSF metabolites associated with biomarkers of Alzheimer's disease pathology.

Introduction: Metabolomics technology facilitates studying associations between small molecules and disease processes. Correlating metabolites in cerebrospinal fluid (CSF) with Alzheimer's disease (AD) CSF biomarkers may elucidate additional changes that are associated with early AD pathology and enhance our knowledge of the disease. Methods: The relative abundance of untargeted metabolites was assessed in 161 individuals from the Wisconsin Registry for Alzheimer's Prevention. A metabolome-wide association study (MWAS) was conducted between 269 CSF metabolites and protein biomarkers reflecting brain amyloidosis, tau pathology, neuronal and synaptic degeneration, and astrocyte or microglial activation and neuroinflammation. Linear mixed-effects regression analyses were performed with random intercepts for sample relatedness and repeated measurements and fixed effects for age, sex, and years of education. The metabolome-wide significance was determined by a false discovery rate threshold of 0.05. The significant metabolites were replicated in 154 independent individuals from then Wisconsin Alzheimer's Disease Research Center. Mendelian randomization was performed using genome-wide significant single nucleotide polymorphisms from a CSF metabolites genome-wide association study. Results: Metabolome-wide association study results showed several significantly associated metabolites for all the biomarkers except Aß42/40 and IL-6. Genetic variants associated with metabolites and Mendelian randomization analysis provided evidence for a causal association of metabolites for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), amyloid ß (Aß40), α-synuclein, total tau, phosphorylated tau, and neurogranin, for example, palmitoyl sphingomyelin (d18:1/16:0) for sTREM2, and erythritol for Aß40 and α-synuclein. Discussion: This study provides evidence that CSF metabolites are associated with AD-related pathology, and many of these associations may be causal.

Identification of plasma metabolites associated with modifiable risk factors and endophenotypes reflecting Alzheimer's disease pathology.

Modifiable factors can influence the risk for Alzheimer's disease (AD) and serve as targets for intervention; however, the biological mechanisms linking these factors to AD are unknown. This study aims to identify plasma metabolites associated with modifiable factors for AD, including MIND diet, physical activity, smoking, and caffeine intake, and test their association with AD endophenotypes to identify their potential roles in pathophysiological mechanisms. The association between each of the 757 plasma metabolites and four modifiable factors was tested in the wisconsin registry for Alzheimer's prevention cohort of initially cognitively unimpaired, asymptomatic middle-aged adults. After Bonferroni correction, the significant plasma metabolites were tested for association with each of the AD endophenotypes, including twelve cerebrospinal fluid (CSF) biomarkers, reflecting key pathophysiologies for AD, and four cognitive composite scores. Finally, causal mediation analyses were conducted to evaluate possible mediation effects. Analyses were performed using linear mixed-effects regression. A total of 27, 3, 23, and 24 metabolites were associated with MIND diet, physical activity, smoking, and caffeine intake, respectively. Potential mediation effects include beta-cryptoxanthin in the association between MIND diet and preclinical Alzheimer cognitive composite score, hippurate between MIND diet and immediate learning, glutamate between physical activity and CSF neurofilament light, and beta-cryptoxanthin between smoking and immediate learning. Our study identified several plasma metabolites that are associated with modifiable factors. These metabolites can be employed as biomarkers for tracking these factors, and they provide a potential biological pathway of how modifiable factors influence the human body and AD risk.

Crosswalk study on blood collection-tube types for Alzheimer's disease biomarkers.

INTRODUCTION: Blood-based Alzheimer's disease (AD) biomarkers show promise, but pre-analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [ A ß ] 42 , A ß 40 , phosphorylated tau [ p - ta u 181 , total tau [t-tau], neurofilament light chain [NfL], A ß 42 40 , and p - ta u 181 A ß 42 ) in three collection tube types (ethylenediaminetetraacetic acid [EDTA] plasma, heparin plasma, serum). METHODS: Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography-positive and -negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis. RESULTS: Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL ( R 2 = 0.94), adequate for amyloid ( R 2 = 0.40-0.69), and weaker for t-tau ( R 2 = 0.04-0.42) and p - ta u 181 ( R 2 = 0.22-0.29). Brain amyloidosis differentiated several measures, especially EDTA plasma pTa u 181 A ß 42 ( d = 1.29). DISCUSSION: AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood.

Association of Cardiovascular Risk Factors with Cerebral Perfusion in Whites and African Americans.

BACKGROUND: Midlife cardiovascular risk factors increase risk for Alzheimer's disease (AD). Despite disproportionately high cardiovascular disease and dementia rates, African Americans are under-represented in studies of AD risk and research-based guidance on targeting vascular risk factors is lacking. OBJECTIVE: This study investigated relationships between specific cardiovascular risk factors and cerebral perfusion in White and African American adults enriched for AD risk. METHODS: Participants included 397 cognitively unimpaired White (n = 330) and African American (n = 67) adults enrolled in the Wisconsin Alzheimer's Disease Research Center who underwent pseudo-continuous arterial spin labeling MRI. Multiple linear regression models examined independent relationships between cardiovascular risk factors and mean cerebral perfusion. Subsequent interaction and stratified models assessed the role for APOE genotype and race. RESULTS: When risk factor p-values were FDR-adjusted, diastolic blood pressure was significantly associated with mean perfusion. Tobacco use, triglycerides, waist-to-hip ratio, and a composite risk score were not associated with perfusion. Without FDR adjustment, a relationship was also observed between perfusion and obesity, cholesterol, and fasting glucose. Neither APOE genotype nor race moderated relationships between risk factors and perfusion. CONCLUSION: Higher diastolic blood pressure predicted lower perfusion more strongly than other cardiovascular risk factors. This relationship did not vary by racial group or genetic risk for AD, although the African American sample had greater vascular risk burden and lower perfusion rates. Our findings highlight the need to prioritize inclusion of underrepresented groups in neuroimaging studies and to continue exploring the link between modifiable risk factors, cerebrovascular health, and AD risk in underrepresented populations.

Measuring longitudinal cognition: Individual tests versus composites.

INTRODUCTION: Longitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aß). METHODS: Analyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aß modified cognitive trajectories. RESULTS: Global and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aß interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics. DISCUSSION: These results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.

Comparison of different MRI-based morphometric estimates for defining neurodegeneration across the Alzheimer's disease continuum.

BACKGROUND: Several neurodegeneration (N) metrics using structural MRI are used for the purpose of Alzheimer's disease (AD)-related staging, including hippocampal volume, global atrophy, and an "AD signature" composite consisting of thickness or volumetric estimates derived from regions impacted early in AD. This study sought to determine if less user-intensive estimates of global atrophy and hippocampal volume were equivalent to a thickness-based AD signature from FreeSurfer for defining N across the AD continuum (i.e., individuals who are amyloid-positive (A+)). METHODS: Cognitively unimpaired (CU) late middle-aged and older adults, as well as A+ mild cognitive impairment (MCI) and A+ AD dementia individuals, with available CSF and structural MRI scan <1.5 years apart, were selected for the study (n = 325, mean age = 62). First, in a subsample of A+ AD dementia and matched biomarker-negative (i.e., A- and tau tangle pathology (T)-) CU controls (n = 40), we examined ROC characteristics and identified N cut-offs using Youden's J for neurofilament light chain protein (NfL) and each of three MRI-based measures: a thickness-based AD signature from FreeSurfer, hippocampal volume (using FIRST), and a simple estimate of global atrophy (the ratio of intracranial CSF segmented volume to brain tissue volume, using SPM12). Based on the results from the ROC analyses, we then examined the concordance between NfL N positivity and N positivity for each MRI-based metric using Cohen's Kappa in the remaining subsample of 285 individuals. Finally, in the full sample (n = 325), we examined the relationship between the four measures of N and group membership across the AD continuum using Kruskal-Wallis tests and Cliff's deltas. RESULTS: The three MRI-based metrics and CSF NfL similarly discriminated between the A-T- CU (n = 20) and A+ AD (n = 20) groups (AUCs ≥0.885; ps < 0.001). Using the cut-off values derived from the ROCs to define N positivity, there was weak concordance between NfL and all three MRI-derived metrics of N in the subsample of 285 individuals (Cohen's Kappas ≤0.429). Finally, the three MRI-based measures of N and CSF NfL showed similar associations with AD continuum group (i.e., Kruskal-Wallis ps < 0.001), with relatively larger effect sizes noted when comparing the A-T- CU to the A+ MCI (Cliff's deltas ≥0.741) and A+ AD groups (Cliff's deltas ≥0.810) than to the A+T- CU (Cliff's deltas = 0.112-0.298) and A + T+ CU groups (Cliff's deltas = 0.212-0.731). CONCLUSIONS: These findings suggest that the three MRI-based morphometric estimates and CSF NfL similarly differentiate individuals across the AD continuum on N status. In many applications, a simple estimate of global atrophy may be preferred as an MRI marker of N across the AD continuum given its methodological robustness and ease of calculation when compared to hippocampal volume or a cortical thickness AD signature.

Occupational Complexity and Cognitive Reserve in a Middle-Aged Cohort at Risk for Alzheimer's Disease.

Higher occupational attainment has previously been associated with increased Alzheimer's disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition.

Long-term systemic inflammation and cognitive impairment in a population-based cohort.

OBJECTIVES: Evidence suggests inflammation is associated with cognitive impairment, but previous epidemiological studies have reported conflicting results. DESIGN: Prospective population-based cohort. SETTING: Epidemiology of Hearing Loss Study participants. PARTICIPANTS: Individuals without cognitive impairment in 1998-2000 (N = 2,422; 1,947 with necessary data). MEASUREMENTS: Cognitive impairment (Mini-Mental State Examination score <24 or diagnosis of dementia) was ascertained in 1998-2000, 2003-2005, and 2009-2010. Serum C-reactive protein (CRP) and interleukin-6 (IL-6) were measured in 1988-1990, 1998-2000, and 2009-2010; tumor necrosis factor-alpha was measured from 1998-2000. RESULTS: Participants with high CRP in 1988-1990 and 1998-2000 had lower risk of cognitive impairment than those with low CRP at both time points (hazard ratio (HR) = 0.46, 95% confidence interval (CI) = 0.26-0.80). Risk did not differ according to 10-year IL-6 profile or baseline inflammation category in the whole cohort. In sensitivity analyses restricted to statin nonusers, those with high IL-6 at both times had greater risk of cognitive impairment than those with low IL-6 at both times (HR = 3.35, 95% CI = 1.09-10.30). In secondary analyses, each doubling of IL-6 change over 20 years was associated with greater odds of cognitive impairment in 2009-2010 in the whole cohort (odds ratio (OR) = 1.40, 95% CI = 1.04-1.89), whereas a doubling of CRP change over 20 years was associated with cognitive impairment only in statin nonusers (OR = 1.32, 95% CI = 1.06-1.65). CONCLUSION: With data collected over 20 years, this study demonstrated greater likelihood of cognitive impairment in individuals with repeated high or increasing IL-6. The inconsistent CRP findings may reflect effects of statin medications, survival effects, or adverse effects associated with chronically low CRP. Further studies of long-term inflammation and cognitive impairment are needed.

The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition.

Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17ß-estradiol and oral conjugated equine estrogen on cognition. All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42-59 years), healthy, and free of cognitive dysfunction. Higher systolic BP was weakly related to poorer performance in auditory working memory and attention (p = 0.004; adjusted for multiple comparisons p = 0.10). This relationship was not associated with endogenous hormone levels, and systolic BP was not related to any other cognitive domain. BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy, recently menopausal women. Lower BP early in menopause may affect cognitive domains known to be associated with AD.

Pulse wave velocity and cognitive function in older adults.

Arterial stiffness may be associated with cognitive function. In this study, pulse wave velocity (PWV) was measured from the carotid to femoral (CF-PWV) and from the carotid to radial (CR-PWV) with the Complior SP System. Cognitive function was measured by 6 tests of executive function, psychomotor speed, memory, and language fluency. A total of 1433 participants were included (mean age 75 y, 43% men). Adjusting for age, sex, education, pulse rate, hemoglobin A1C, high-density lipoprotein cholesterol, hypertension, cardiovascular disease history, smoking, drinking, and depression symptoms, a CF-PWV>12 m/s was associated with a lower Mini-Mental State Examination score (coefficient: -0.31, SE: 0.11, P=0.005), fewer words recalled on Auditory Verbal Learning Test (coefficient: -1.10, SE: 0.43, P=0.01), and lower score on the composite cognition score (coefficient: -0.10, SE: 0.05, P=0.04) and marginally significantly associated with longer time to complete Trail Making Test-part B (coefficient: 6.30, SE: 3.41, P=0.06), CF-PWV was not associated with Trail Making Test-part A, Digit Symbol Substation Test, or Verbal Fluency Test. No associations were found between CR-PWV and cognitive performance measures. Higher large artery stiffness was associated with worse cognitive function, and longitudinal studies are needed to confirm these associations.

Neurobiological Underpinnings of the Estrogen - Mood Relationship.

Women are at a higher risk than men to develop mood disorders and depression. The increased risk is associated with fluctuating estrogen levels that occur during reproductive cycle events, particularly during the menopausal transition, a time characterized by drastic fluctuations in estrogen levels and increases in new onset and recurrent depression. Conversely, recent data show that hormone therapy, particularly transdermal estradiol formulations, may prevent mood disorders or even serve as a treatment regimen for women with diagnosed mood disturbances via estrogen regulation. While the exact mechanism is unknown, there is compelling scientific evidence indicating the neuromodulatory and neuroprotective effects of estrogen, which are directly relevant to mood symptomotology. Specifically, affective regulation has been linked to neural structures rich in estrogen receptors and estrogenic regulation of neurotransmitters. While a wealth of basic science, observational and clinical research support this rationale, potential mediating variables, such as estrogen formulation, proximity of administration to menopause, and the addition of progestins should be considered. Furthermore, the nature of postmenopausal exogenous hormone formulations in relation to premenopausal endogenous levels, as well as the ratio of estrone to estradiol warrant consideration.

Standardized note template improves screening of firearm access and driving among veterans with dementia.

Little is known about screening used in clinical practice to assess driving and firearm safety among patients with dementia. A case-controlled study was performed, including 22 patients with dementia seen in a geriatric evaluation and management clinic and 22 matched patients with dementia seen in a memory assessment clinic. Data about prevalence of firearm use and driving were obtained. In geriatric evaluation and management clinic, 57.9% of patients had dementia, compared with 71.0% in memory assessment clinic, and more patients were diagnosed with Alzheimer dementia in memory assessment clinic (P = .005). In geriatric evaluation and management clinic, 65% of patients had driving screening compared with 100% in memory assessment clinic (P = .07). Four percent in geriatric evaluation and management clinic were screened for firearm access versus 100% in memory assessment clinic (P < .001). In memory assessment clinic, 31.8% had firearms access and 50% were driving. Many patients continued to drive and have access to firearms. The use of templates for the progress note was effective in increasing the screening rate.

Magnetic resonance imaging characterization of brain structure and function in mild cognitive impairment: a review.

Given the predicted increase in prevalence of Alzheimer's disease (AD) in the coming decades, early detection and intervention in persons with the predementia condition known as mild cognitive impairment (MCI) is of paramount importance. Recent years have seen remarkable advances in the application of neuroimaging and other biomarkers to the study of MCI. This article reviews the most recent developments in the use of magnetic resonance imaging (MRI) to characterize brain changes and to prognosticate clinical outcomes of patients with MCI. The review begins with description of methods and findings in structural MRI research, delineating findings regarding both gross atrophy and microstructural brain changes in MCI. Second, we describe the most recent findings regarding brain function in MCI, enumerating findings from functional MRI and brain perfusion studies. Third, we will make recommendations regarding the current clinical use of MRI in identification of MCI. As a conclusion, we will look to the future of neuroimaging as a tool in early AD detection.

Clinical pharmacology and differential cognitive efficacy of estrogen preparations.

Menopause is associated with a significant decline in levels of estrogen, which reportedly leads to several distressing symptoms and adverse health effects on various target tissues including those on bones, heart, and brain. Although effective, the long-term safety and feasibility of therapy with both unopposed and opposed oral conjugated equine estrogen has been questioned by the recent findings of both the Women's Health Initiative (WHI) and the Women's Health Initiative Memory Study (WHIMS). The findings of both these studies have raised several critical issues related to hormone therapy that need to be systematically evaluated in clinical studies. Specifically, these issues relate to the differential efficacy and adverse-effects profile of various forms of estrogen and progestins, the importance of the route of administration of estrogen, the best timing to initiate postmenopausal hormone therapy, and the efficacy of cyclic versus continuous hormone therapy. This article focuses on estrogen and discusses issues related to selecting the best form and route of administration of the hormone. It includes information on basic clinical pharmacology of various forms of estrogen, neuroendocrinology of the menopause, neurobiology of estradiol and estrone, and results of selected basic science and human intervention studies with relevance to identifying the best form and route of administration of estrogen.

Cardiovascular disease and the aging woman: overcoming barriers to lifestyle changes.

Coronary heart disease (CHD) is the leading cause of death in women aged 60 years and older, yet 40% of this group believe they are unlikely to have a heart attack. Recent data show that the lack of a low-risk lifestyle may account for approximately 82% of coronary events in women. Underappreciation of CHD risk may prevent aging women from making significant changes in dietary habits, activity levels, and tobacco use to decrease their risk. In addition, many physicians may not treat cardiovascular risk factors aggressively in middle-aged and older women, despite data from primary and secondary prevention trials supporting the efficacy of interventions. This article addresses age-related changes in cardiovascular risk factors in women, with a focus on lifestyle interventions.

Inaccuracy of lipid measurements with the portable Cholestech L.D.X analyzer in patients with hypercholesterolemia.

BACKGROUND: Although total cholesterol concentrations measured by portable lipid analyzers have acceptable bias and precision in young and middle-aged adults, clinically relevant differences in HDL-cholesterol (HDL-C) and triglyceride values have been described. Furthermore, the accuracy of portable lipid analyzers in older hyperlipidemic individuals, who have a high incidence of coronary heart disease, has not been validated. This study determined the biases and variability in portable lipid measurements in older patients with hypercholesterolemia and related them to National Cholesterol Education Program Adult Treatment Panel III guidelines. METHODS: Participants were > or =70 years of age with fasting serum LDL-cholesterol (LDL-C) concentrations > 1.40 g/L. Fasting fingerstick samples were analyzed on a Cholestech L.D.X desktop analyzer. Antecubital venous samples were analyzed in a proficiency-certified clinical laboratory. RESULTS: Portable measurements systematically overestimated triglycerides (0.296 g/L; P <0.001) and HDL-C (0.015 g/L; P = 0.026). LDL-C concentrations were underestimated (0.043 g/L; P = 0.046). Total and non-HDL cholesterol calculations based on the portable lipid device provided unbiased estimates, but wide variability was present. Significant variability in lipid determinations limited their clinical usefulness in individual patients, especially because 2 SD of the mean bias between the laboratory and the portable determinations of LDL-C and non-HDL cholesterol exceeded the 0.30 g/L cutoff that defines treatment targets in the current lipid guidelines. CONCLUSIONS: Lipid values obtained from portable lipid analyzers may be useful for screening, but they should not be used to make clinical decisions regarding the diagnosis and management of dyslipidemia in individual patients.