Gene L. Bowman

Nutrient Biomarker Patterns, Cognitive Function, and Mri Measures of Brain Aging

Objective: To examine the cross-sectional relationship between nutrient status and psychometric and imaging indices of brain health in dementia-free elders. Methods: Thirty plasma biomarkers of diet were assayed in the Oregon Brain Aging Study cohort (n = 104). Principal component analysis constructed nutrient biomarker patterns (NBPs) and regression models assessed the relationship of these with cognitive and MRI outcomes. Results: Mean age was 87 ± 10 years and 62% of subjects were female. Two NBPs associated with more favorable cognitive and MRI measures: one high in plasma vitamins B (B1, B2, B6, folate, and B12), C, D, and E, and another high in plasma marine ω-3 fatty acids. A third pattern characterized by high trans fat was associated with less favorable cognitive function and less total cerebral brain volume. Depression attenuated the relationship between the marine ω-3 pattern and white matter hyperintensity volume. Conclusion: Distinct nutrient biomarker patterns detected in plasma are interpretable and account for a significant degree of variance in both cognitive function and brain volume. Objective and multivariate approaches to the study of nutrition in brain health warrant further study. These findings should be confirmed in a separate population. Neurology® 2012;78:241–249

Uric Acid as a CNS Antioxidant

Oxidative damage is a consistent finding in a number of central nervous system (CNS) disorders. Uric acid (UA) is a potent hydrophilic antioxidant that is modified by diet and drug. Several lines of evidence suggest that plasma UA may modulate outcomes in neurologic disease, but little attention has been paid to CNS levels of UA. Our objective was to test the hypothesis that cerebrospinal fluid (CSF) UA is determined by plasma UA, modified by blood-brain barrier (BBB) integrity and associated with rate of cognitive decline in Alzheimers disease (AD). Also, since UA and ascorbic acid may act as antioxidants for one another, we also explored a potential interaction between them in the brain. Thirty-two patients with mild to moderate AD (Mini-Mental Status Exam 19 +/- 5) participated in a longitudinal biomarker study for one year involving standardized clinical assessments. CSF and blood were collected at baseline for UA, ascorbic acid, and albumin. Cognitive measures were collected at baseline and again one year later. CSF UA was independent of age, gender, and AD severity. CSF and plasma UA were positively correlated (r=0.669, p=0.001) and BBB impairment was associated with higher CSF levels of UA (p=0.028). Neither plasma nor CSF UA reached significant association with rates of cognitive decline over 1 year. CSF UA and CSF ascorbic acid were positively correlated (r=0.388, p=0.001). The hypothesis that CSF UA is determined by plasma UA and BBB integrity is supported, as is the hypothesis that UA and ascorbic acid are associated in CSF but not plasma. Adequately powered prospective studies would help assess any role for UA in primary and secondary prevention of AD.

Ascorbic acid, cognitive function, and Alzheimer's disease: A current review and future direction

This narrative review appraises the human and animal studies implicating ascorbic acid (AA) in normal cognitive function and Alzheimers disease. A research framework for how nutrition affects brain aging is proposed with emphasis on AA intake, status, metabolism, and transport into brain tissue. A final synopsis highlights areas for future research regarding AA nourishment and healthy brain aging.

Ascorbic Acid and Rates of Cognitive Decline in Alzheimer’s Disease

The brain maintains high levels of ascorbic acid (AA) despite a concentration gradient favoring diffusion from brain to peripheral tissues. Dietary antioxidants, including AA, appear to modify the risk of Alzheimers disease (AD). The objective of this study was to test the hypothesis that neurodegeneration in AD is modified by brain levels of AA. Thirty-two patients with mild to moderate AD participated in a biomarker study involving standardized clinical assessments over one year. Cerebrospinal fluid (CSF) and serum were collected at baseline for AA and albumin content. Cognitive measures were collected at baseline and one year. CSF and plasma AA failed to predict cognitive decline independently, however, CSF: plasma AA ratio did. After adding CSF Albumin Index (an established marker of blood-brain barrier integrity) to the regression models the effect of CSF: plasma AA ratio as a predictor of cognitive decline was weakened. CSF: plasma AA ratio predicts rate of decline in AD. This relationship may indicate that the CSF: plasma AA ratio is an index of AA availability to the brain or may be an artifact of a relationship between blood-brain barrier impairment and neurodegeneration.

Ascorbic Acid and the Brain: Rationale for the Use against Cognitive Decline

This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer’s disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration.

Dyslipidemia and Blood-Brain Barrier Integrity in Alzheimer's Disease

Background. Blood-brain barrier (BBB) dysfunction may have a significant role in the pathogenesis of Alzheimers disease (AD). Modifiable factors associated with BBB function may have therapeutic implication. This study tested the hypothesis that dyslipidemia is associated with BBB impairment in mild-to-moderate AD. Methods. Thirty-six subjects with AD were followed for 1 year. Fasting CSF and plasma were collected with clinical assessments at baseline and 12 months. BBB impairment was defined as CSF albumin index ≥9. Independent t-tests and linear regression assessed the relationship between plasma lipoproteins and BBB integrity. Results. Dyslipidemia was prevalent in 47% of the population, and in 75% of those with BBB impairment. Subjects with BBB impairment had significantly higher mean plasma triglyceride and lower HDL cholesterol (TG, P = 0.007; HDL, P = 0.043). Plasma triglycerides explained 22% of the variance in BBB integrity and remained significant after controlling for age, gender, ApoE-4 genotype, blood pressure, and statin use. Conclusion. Dyslipidemia is more prevalent in AD subjects with BBB impairment. Plasma triglyceride and HDL cholesterol may have a role in maintaining BBB integrity in mild-to-moderate Alzheimers disease.

Serum vitamin d concentrations are associated with falling and cognitive function in older adults

ObjectivesTo elucidate the mechanism through which vitamin D is associated with decreased falls.DesignThis was a convenience sample from a larger observational study examining correlations between vitamin D and 1) falls, 2) motor function, and 3) cognition (n=159).SettingFalls data were collected via weekly on-line surveys completed in the participants’ homes. Yearly evaluations of motor and cognitive function were conducted in an out-patient setting of a large tertiary medical center.ParticipantsParticipants from the Intelligent Systems for Assessment of Aging Changes Study (ISAAC), a community-based cohort study of independently living older adults over age 70, who had vitamin D concentration within 6 months of clinical evaluations were included in the analysis.ResultsParticipants mean age was 85 years and 74% were women. Fallers (n=37) had significantly lower vitamin D concentration (32.9ng/ml) compared to non-fallers (39.2ng/ml) (p<0.01). The relationship between vitamin D and falls remained significant after adjusting for age, health status (via CIRS), and supplement use (p=0.004). Vitamin D concentration were significantly associated with cognitive impairment (Clinical Dementia Rating = 0.5) (p=0.02) and MMSE (p<0.01) after adjusting for age, gender, and education. Vitamin D concentrations did not correlate with any motor measures.ConclusionVitamin D concentrations correlated with cognition and falls, but not with motor measures. Further research is needed to demonstrate a causal relationship between vitamin D and cognitive function and determine if cognition plays a role in falls reduction.

Reliability and Validity of Food Frequency Questionnaire and Nutrient Biomarkers in Elders With and Without Mild Cognitive Impairment

IntroductionThere is great interest in the nutritional strategies for the prevention of age-related cognitive decline, yet the best methods for nutritional assessment in the populations at risk for dementia are still evolving. Our study objective was to examine the reliability and validity of the 2 common nutritional assessments (plasma nutrient biomarkers and Food Frequency Questionnaire) in the people at risk for dementia. MethodsThirty-eight elders, half with amnestic—mild cognitive impairment were recruited. Nutritional assessments were collected together at the baseline and again at 1 month. Intraclass and Pearson correlation coefficients quantified reliability and validity. ResultsTwenty-six nutrients were examined. The reliability was very good or better for 77% (20/26, intraclass correlation coefficients or ICC ≥0.75) of the plasma nutrient biomarkers and for 88% of the food frequency questionnaires (FFQ) estimates. Twelve of the nutrient biomarkers were as reliable as the commonly measured plasma cholesterol (ICC≥0.92). FFQ and plasma long-chain fatty acids (docosahexaenoic acid, r=0.39, eicosapentaenoic acid, r=0.39) and carotenoids (&agr;-carotene, r=0.49; lutein + zeaxanthin, r=0.48; &bgr;-carotene, r=0.43; &bgr;-cryptoxanthin, r=0.41) were correlated, but these significant correlations were present only in non-impaired elders. ConclusionThe reliability and validity of the FFQ and nutrient biomarkers vary according to the nutrient of interest. Memory deficit attenuates validity and inflates reliability of FFQ reports. Many plasma nutrient biomarkers have very good reliability over 1-month, regardless of memory state. This objective method can circumvent sources of error seen in other less direct and subjective methods of nutritional assessment.

Alzheimer’s disease and the blood–brain barrier: past, present and future

Successful prevention and treatment of late-onset Alzheimer’s disease (AD) is a high priority for industrialized societies where the incidence is growing rapidly. Much of the underlying biology leading to AD is unknown, and the more knowledge we gain the more we appreciate the complexities involved. Popular etiologic hypotheses have largely ignored the blood–brain barrier (BBB) as an important factor contributing to the pathologic hallmarks of this most common form of dementia. Evidence identifying BBB dysfunction in AD or patients at risk (i.e., those with mild cognitive impairment) continue to escalate. This review highlights methodological issues facing investigators assessing BBB integrity in living patients while also discussing whether the BBB dysfunction is a cause, effect or epiphenomenon in AD. Rationale for future research pursuits aimed at describing the role of BBB function in AD pathogenesis is also presented.

Memory, mood, and vitamin D in persons with Parkinson's disease.

BACKGROUND Research in recent years has suggested a role of vitamin D in the central nervous system. The final converting enzyme and the vitamin D receptor are found throughout the human brain. From animal studies vitamin D appears important in neurodevelopment, up-regulation of neurotrophic factors, stabilization of mitochondrial function, and antioxidation. OBJECTIVE To examine the relationship between serum vitamin D and neuropsychiatric function in persons with Parkinsons disease (PD). METHODS This is an add-on study to a longitudinal study following neuropsychiatric function in persons with PD. Baseline neuropsychiatric performance and serum 25-hydroxyvitamin D were examined for 286 participants with PD. Measures of global cognitive function (MMSE, MOCA, Mattis Dementia Scale), verbal memory (Hopkins Verbal Learning Test), fluency (animals, vegetables, and FAS words), visuospatial function (Benton Line Orientation), executive function (Trails Making Test and Digit-Symbol Substitution), PD severity (Hoehn & Yahr and Unified Parkinsons Disease Rating Scale) and depression (Geriatric Depression Scale (GDS)) were administered. Multivariate linear regression assessed the association between vitamin D concentration and neuropsychiatric function, in the entire cohort as well as the non-demented and demented subsets. RESULTS Using a multivariate model, higher vitamin D concentrations were associated with better performance on numerous neuropsychiatric tests in the non-demented subset of the cohort. Significant associations were specifically found between vitamin D concentration and verbal fluency and verbal memory (t = 4.31, p < 0.001 and t = 3.04, p = 0.0083). Vitamin D concentrations also correlated with depression scores (t = -3.08, p = 0.0083) in the non-demented subset. CONCLUSIONS Higher plasma vitamin D is associated with better cognition and better mood in this sample of PD patients without dementia. Determination of causation will require a vitamin D intervention study.