Hamish M. Evans

Effects of Resveratrol on Cognitive Performance, Mood and Cerebrovascular Function in Post-Menopausal Women; A 14-Week Randomised Placebo-Controlled Intervention Trial

We tested whether chronic supplementation with resveratrol (a phytoestrogen) could improve cerebrovascular function, cognition and mood in post-menopausal women. Eighty post-menopausal women aged 45–85 years were randomised to take trans-resveratrol or placebo for 14 weeks and the effects on cognitive performance, cerebral blood flow velocity and pulsatility index (a measure of arterial stiffness) in the middle cerebral artery (using transcranial Doppler ultrasound), and cerebrovascular responsiveness (CVR) to both cognitive testing and hypercapnia were assessed. Mood questionnaires were also administered. Compared to placebo, resveratrol elicited 17% increases in CVR to both hypercapnic (p = 0.010) and cognitive stimuli (p = 0.002). Significant improvements were observed in the performance of cognitive tasks in the domain of verbal memory (p = 0.041) and in overall cognitive performance (p = 0.020), which correlated with the increase in CVR (r = 0.327; p = 0.048). Mood tended to improve in multiple measures, although not significantly. These results indicate that regular consumption of a modest dose of resveratrol can enhance both cerebrovascular function and cognition in post-menopausal women, potentially reducing their heightened risk of accelerated cognitive decline and offering a promising therapeutic treatment for menopause-related cognitive decline.

Clinical evaluation of effects of chronic resveratrol supplementation on cerebrovascular function, cognition, mood, physical function and general well-being in postmenopausal women-rationale and study design

Background: This methodological paper presents both a scientific rationale and a methodological approach for investigating the effects of resveratrol supplementation on mood and cognitive performance in postmenopausal women. Postmenopausal women have an increased risk of cognitive decline and dementia, which may be at least partly due to loss of beneficial effects of estrogen on the cerebrovasculature. We hypothesise that resveratrol, a phytoestrogen, may counteract this risk by enhancing cerebrovascular function and improving regional blood flow in response to cognitive demands. A clinical trial was designed to test this hypothesis. Method: Healthy postmenopausal women were recruited to participate in a randomised, double-blind, placebo-controlled (parallel comparison) dietary intervention trial to evaluate the effects of resveratrol supplementation (75 mg twice daily) on cognition, cerebrovascular responsiveness to cognitive tasks and overall well-being. They performed the following tests at baseline and after 14 weeks of supplementation: Rey Auditory Verbal Learning Test, Cambridge Semantic Memory Battery, the Double Span and the Trail Making Task. Cerebrovascular function was assessed simultaneously by monitoring blood flow velocity in the middle cerebral arteries using transcranial Doppler ultrasound. Conclusion: This trial provides a model approach to demonstrate that, by optimising circulatory function in the brain, resveratrol and other vasoactive nutrients may enhance mood and cognition and ameliorate the risk of developing dementia in postmenopausal women and other at-risk populations.

Poor cerebrovascular function is an early marker of cognitive decline in healthy postmenopausal women

Impairment of cerebrovascular function becomes evident after menopause. No study has yet explored relationships between deficits in cerebrovascular function, cognitive performance, and mood in postmenopausal women.

Resveratrol supplementation reduces pain experience by postmenopausal women

Objective: Pain is a common complaint among postmenopausal women. It has been postulated that vascular dysfunction caused by estrogen decline at menopause plays a key role in the initiation and progression of degradative joint disease, namely age-related osteoarthritis. We evaluated whether supplementation with resveratrol, a phytoestrogen, could improve aspects of well-being such as chronic pain that is commonly experienced by postmenopausal women. Methods: A 14-week randomized, double-blind, placebo-controlled intervention with trans-resveratrol (75 mg, twice daily) was conducted in 80 healthy postmenopausal women. Aspects of well-being, including pain, menopausal symptoms, sleep quality, depressive symptoms, mood states, and quality of life were assessed by Short form-36 at baseline and at the end of treatment. Rating scales were averaged to provide a composite score representing overall well-being. Cerebral vasodilator responsiveness to hypercapnia was also assessed as a surrogate marker for cerebrovascular function. Results: Compared with placebo treatment, there was a significant reduction in pain and an improvement in total well-being after resveratrol supplementation. Both benefits, including measures of quality of life, correlated with improvements in cerebrovascular function. Conclusions: Our preliminary findings indicate potential for resveratrol treatment to reduce chronic pain in age-related osteoarthritis. Resveratrol consumption may also boost perceptions of well-being in postmenopausal women. Further investigation to elucidate underlying mechanisms is warranted.

Effects of Long Chain Omega-3 Polyunsaturated Fatty Acids on Brain Function in Mildly Hypertensive Older Adults

Purported benefits of long chain omega-3 polyunsaturated fatty acid (LCn-3PUFA) for brain function may be attributable, at least in part, to improved cerebral perfusion. A pilot randomised controlled trial was undertaken to investigate effects of taking a DHA-rich fish oil supplement for 20 weeks on cerebrovascular function, mood and cognitive performance. Borderline hypertensives aged 40–85 years with low habitual LCn-3PUFA intake took four capsules/day of EPAX (1600 mg DHA + 400 mg EPA) or placebo (corn oil). Cerebrovascular function was assessed at baseline and after 20 weeks in 38 completers (19 on each supplement) using transcranial Doppler ultrasound of blood flow in the middle cerebral artery at rest and whilst performing a battery of cognitive tasks (neurovascular coupling). The primary outcome, cerebrovascular responsiveness (CVR) to hypercapnia, increased 26% (p = 0.024) in women; there was no change in men. In contrast, neurovascular coupling increased significantly (p = 0.01 for the overall response) in men only; the latter correlated with an increase of EPA in erythrocytes (r = 0.616, p = 0.002). There was no associated improvement of mood or cognition in either men or women. These preliminary observations indicate that LCn-3PUFA supplementation has the potential to enhance blood flow in the brain in response to both hypercapnic and cognitive stimuli. Future studies should examine differential effects of EPA and DHA and take account of the gender differences in responsiveness to supplementation.

SUBJECTIVE MEMORY COMPLAINT IS ASSOCIATED WITH CEREBROVASCULAR DYSFUNCTION IN HEALTHY OLDER WOMEN

tertiles. Cox proportional hazard models were used to determine the predictive value of nutritional markers. All models were corrected for sex, age, BMI, history of cardiovascular disease and lipid lowering medication. Results: Twenty-one (20%) SCD patients and 43 (33%)MCI patients showed progression toMCI or dementia during follow-up. Vitamin B6, betaine and HDL cholesterol in blood, and homocysteine in CSF were associated with clinical progression in the SCD group (p for trend <0.05). Low levels of vitamin B6, betaine and HDL cholesterol and high levels of CSF homocysteine were protective for progression ((HR 95%CI1⁄4 3.9 (1.0-14.6), 4.4 (1.1-17.3), 6.0 (1.2-30.6), 0.3 (0.1-1.0), highest vs. lowest tertile). Within the MCI group only CSF S-adenosylmethionine was associated with clinical progression (p for trend ˂0.05), high levels were protective for progression to dementia (HR 95% CI1⁄4 0.4(0.2-1.0), highest vs. lowest tertile). Conclusions: In this large panel of nutritional markers we found subtle associations between various nutritional markers and clinical progression. In contrast to previous studies, higher HDL cholesterol levels and lower homocysteine levels were associated with an increased risk on clinical progression. The mild alterations shown here might reflect early metabolic changes prior to clinical progression. More distinct change in nutritional status and metabolism found in dementia patients is perhaps a consequence rather than a cause of cognitive impairment.

OBJECTIVE-SUBJECTIVE DISPARITY IN COGNITIVE IMPAIRMENT: A CROSS-SECTIONAL INVESTIGATION IN POSTMENOPAUSAL WOMEN

ive impa volume Background:Alzheimer’s disease (AD) is a neurodegenerative disease characterized by increasing interference in daily functioning. The first reported problems in daily life typically concern the more cognitively complex ‘instrumental activities of daily living’ (IADL). IADL functioning is often measured with informant-based questionnaires, but only few studies have directly addressed the relationship between these IADL measures and underlying AD brain pathology. In this study, we aimed to investigate the relationship between IADL functioning and neurodegeneration across the AD spectrum. Methods:We selected memory-clinic subjects from the Amsterdam Dementia Cohort with a diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and an available structural 3D T1-weigthed MRI acquired at 3.0 tesla. Preprocessing and segmentation into grey matter (GM), white matter and cerebrospinal fluid was performed using SPM-12. IADL functioning was measured with the Amsterdam IADL Questionnaire (A-IADL-Q), resulting in a total IADL score (Mean1⁄450 and SD1⁄410, with higher scores reflecting better performance). We used linear regression correcting for age, sex and education to investigate the relationship between total GM volume (normalized by total intracranial volume) and IADL score. We further performed voxel-based morphometry (VBM) to investigate whether any associations were specific for distinct regions. VBM analyses were corrected for total intracranial volume, age, sex and education. Results: A total of 162 subjects were included, consisting of 49 SCD subjects, 28 MCI subjects and 87 subjects with AD dementia (Table 1). Overall, we found that less GM volume was related to a lower IADL score (b 1⁄4 .284, p 1⁄4 .001; Figure 1). VBM showed twelve clusters in which less GM was associated with lower IADL scores, located in the left medial temporal lobe, around the left posterior cingulate cortex and precuneus and the right middle temporal gyrus (all p(FWEcorrected)<.05; Figure 2). Conclusions: Worsening IADL functioning as measured with the A-IADL-Q is related to neurodegeneration across the AD dementia spectrum. These associations were mostly specific for anatomical regions known to be involved in AD. Our findings show that informants are able to detect functional impairment related to AD specific neurodegeneration.

INTERRELATIONSHIPS BETWEEN BLOOD VESSEL FUNCTION, COGNITION AND FRACTURE RISK

DLB (24/26, 92%), while two others were categorized as DLBMCI.MeanMontreal Cognitive Assessment scorewas 20.6. Significant motor parkinsonism was been observed in this subject sample with an average Unified Parkinson’s Disease Rating Scale Part III score of 28.4. Conclusions: The DLBC cohort will be a valuable tool for the research community with deep phenotyping of subjects including imaging and biomarker characterization. The data and biofluids will be available through the PDBP for use by investigators. Further enrollment characteristics will be described. Regression coefficients (B’s) and p-values are determined with linear regression models corrected for years of education and diagnosis. TMT: Trail Making Test. P3-215 INTERRELATIONSHIPSBETWEENBLOOD VESSEL FUNCTION, COGNITION AND FRACTURE RISK Jemima Dzator, Jay Jay Thaung Zaw, Peter RC. Howe, Hamish M. Evans, Rachel H. X. Wong, University of Newcastle, Callaghan, Australia; University of Southern Queensland, Toowoomba, Australia. Contact e-mail: rachel. wong@newcastle.edu.au

CEREBROVASCULAR RESISTANCE IS AN EARLY MARKER OF SLOW GAIT AND COGNITIVE DEFICITS IN OVERWEIGHT POSTMENOPAUSAL WOMEN

Anglicare, Sydney, Australia; KaRa Institute of Neurological Diseases, Sydney, Australia; CSIRO Health and Biosecurity, Perth, Australia; Australian Alzheimer’s Research Foundation, Perth, Australia; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M€olndal, Sweden; The Sahlgrenska Academy at the University of Gothenburg, M€olndal, Sweden; Cooperative Research Centre for Mental Health, Melbourne, Australia; University of Western Australia, Perth, Australia. Contact e-mail: pratishtha.chatterjee@mq.edu.au

MPS 12-04 RESFEM STUDY: CHRONIC TRANS-RESVERATROL SUPPLEMENTATION IMPROVES CEREBRAL VASODILATOR RESPONSIVENESS (CVR) AND COGNITION IN POST-MENOPAUSAL WOMEN

Objective: Loss of beneficial effects of estrogen on the cerebrovasculature may contribute to the heightened risk of dementia in postmenopausal women. We examined the relationship between cerebrovascular function and cognition in this population and tested whether supplementation with resveratrol (a phytoestrogen) could improve their CVR and cognitive performance. Design and Method: Eighty postmenopausal women aged 45–85 years were randomised to take resveratrol (2 × 75 mg/day) or placebo for 14 weeks and changes in the following were assessed:-. cognitive performance in domains of executive function, semantic, verbal and visuospatial working memory; transcranial Doppler ultrasound recording of blood flow velocity (BFV) in the middle cerebral artery, pulsatility index (PI, a measure of arterial stiffness) and CVR (percent increase of BFV) to both cognitive testing and hypercapnia (breathing carbogen gas for 3 min). Results: At baseline, a composite score of cognitive performance correlated with basal BFV (R = 0.340, P = 0.005), CVR to cognitive stimuli (R = 0.345, P = 0.006) and inversely with PI (R = −0299, P = 0.029). Compared to placebo, supplementation with resveratrol elicited 17% increases in CVR to both the hypercapnic (P = 0.018) and cognitive stimuli (P = 0.036). The latter was an overall response; there were also increases in CVR to individual tests of semantic (P = 0.003) verbal memory (P = 0.021) and executive function (P = 0.048). Moreover, resveratrol improved overall cognitive performance (P = 0.010). Conclusions: This is the first demonstration that regular consumption of a modest dose of resveratrol can enhance both cerebrovascular function and cognition in postmenopausal women and suggests that it may have the potential to reduce their heightened risks of stroke and cognitive impairment.