None listed
Conditions
Brief summary
Cognitive impairment is one complication of T2DM that has gained considerable recognition in the last decade. Pooled estimates from prospective studies of people with T2DM reveal a 60% increase risk for future dementia. Over 3 million Australian suffer or are at risk of T2DM and this number is projected to rise markedly in the next 20 years; thus increasing the prevalence of diabetes-related impairments including accelerated cognitive decline and dementia later in life. A postulated underlying mechanism of T2DM-related cognitive decline is endothelial dysfunction in the cerebral microvasculature. Transcranial Doppler (TCD) ultrasound offers an economical and non-invasive assessment of the dependence of cognition on cerebral perfusion, by measuring increases of blood flow velocity in the middle cerebral arteries (MCA), resulting from downstream dilatation of cerebral arterioles, which can occur in response to acute hypercapnia or cognitive stimulation. Hypercapnia is a condition of abnormally elevated carbon dioxide (CO2) levels in the blood This technique is known as cerebral vasodilator responsiveness (CVR). There are currently no studies characterizing the CVR to hypercapnia in the posterior cerebral arteries in adults with T2DM. There is increasing evidence that certain bioactive nutrients can act on endothelial cells to enhance vasodilator function. It is also evident that consumption of these sources of vasoactive nutrients may lead to enhanced cognitive performance, yet it is only recently that the concept that nutrients can deliver cognitive benefits by improving cerebral circulation has been recognized. This study aims to determine the most efficacious dose of resveratrol to improve cerebral vasodilator responsiveness (CVR) to hypercapnia in the anterior circulation (MCA) in adults with T2DM. An acute randomised, double-blind, placebo-controlled, crossover dietary intervention will be undertaken at the Clinical Nutrition Research Centre (CNRC) at the University of Newcastle. Interested participants will be sent a Participant Information Statement and Consent Form. Upon returning the signed Consent Form, the study coordinator will send the Health and Lifestyle Questionnaire. This will determine the participant’s suitability before visiting the CNRC for a screening visit. 40 non-insulin-dependent type 2 diabetes mellitus adults aged 40-80 years old will be selected. Suitable participants will be required to attend the CNRC five times at weekly intervals. Subjects will be provided with each dose on one occasion; this dose will be consumed in the clinic. The study will also assess the dose-response effects of resveratrol supplementation on neuropsychological test performance.
Interventions
Enrolled participants will be required to consume 4 capsules, each containing varying doses of resveratrol, as follows:
1) Placebo: 4 capsules
2) Resvida 'Trademark' dietary supplement 75 mg: 1 cap @75 mg + 3 placebo cap
2) Resvida 'Trademark' dietary supplement 150 mg: 2 cap @75 mg + 2 placebo cap
3) Resvida 'Trademark' dietary supplement 300 mg: 4 cap @75 mg
Capsules will be taken orally with water, during weekly visits for four weeks. Particpants will take a single dose on 4 occasions a
Enrolled participants will be required to consume 4 capsules, each containing varying doses of resveratrol, as follows: 1) Placebo: 4 capsules 2) Resvida 'Trademark' dietary supplement 75 mg: 1 cap @75 mg + 3 placebo cap 2) Resvida 'Trademark' dietary supplement 150 mg: 2 cap @75 mg + 2 placebo cap 3) Resvida 'Trademark' dietary supplement 300 mg: 4 cap @75 mg Capsules will be taken orally with water, during weekly visits for four weeks. Particpants will take a single dose on 4 occasions at weekly intervals (one week washout between doses). Participants will be required to attend the Clinical Nutrition Research Centre (CNCR) 5 times over 5 weeks. Participants will arrive at the CNRC following a 4hr fast (no food/beverage, except water) for further screening to determine study eligibility. Anthropometric measurements of height, weight and waist circumference will be obtained before clinic Blood Pressure (BP) and Arterial Compliance (AC) measurements are assessed. Those with clinic BP not within the study inclusion range will be excluded. The dementia status of the participants will be determined using the Australian Version of the Modified Mini Mental State Examination (3MS). Participants scoring below 78/100 (considered an indicator of suspected dementia) will be excluded from this study. Participants will then be fitted with a headpiece supporting an ultrasound probe on each temporal region. An investigator will adjust the probes until a measurable blood flow signal is obtained in each middle cerebral artery (MCA). If the investigator is unable to obtain a blood flow signal in both MCAs, the participant will be excluded from the study. Otherwise, blood flow velocity changes (CVR) to hypercapnia in the MCA will be assessed. The investigator will adjust the ultrasound probes to locate the posterior cerebral arteries [either the posterior cerebral arteries (PCA) or the basilar artery (BA)] on either side of the temporal window. Due to the anatomical depth of the BA, the transforaminal (occipital) window is usually the site of insonation; however, it may be possible to detect a blood flow signal from the transtemporal window (same window as the MCA). In the event that the BA cannot be detected, the posterior cerebral artery will be located. Studies have confirmed that the PCA and BA responsiveness to hypercapnia is similar and therefore can be used as its own surrogate (Skow RJ, MacKay CM, Tymko MM, Willie CK, Smith KJ, Ainslie PN, et al. Differential cerebrovascular carbon dioxide (CO2) reactivity in anterior and posterior cerebral circulations. Resp Physiol Neurobi. 2013 Oct 1;189(1):76-86). Once a suitable blood flow signal is located, CVR to hypercapnia in the posterior arteries will be assessed. Participants will not be excluded if blood flow signals from the posterior arteries are not found. To minimize learning effects and to control cognitive test duration in the latter visits, participants will be familiarized with the computerized cognitive test battery at this visit. Here, participants will be given instructions for each cognitive test and a couple of practice trials. Participants will have the opportunity to break fast before undergoing the practice session. This gives the study investigators and the participants the opportunity to clarify test instructions. The anticipated duration for this visit including the practice test is estimated for 2.5 hr. Eligible participants will then be given a blood request form for a blood sample analysis of fasting glucose, insulin and glycated hemoglobin (HbA1C) at the Hunter Area Pathology Service (HAPS) Centre at the end of the initial visit. Participants will have to visit their nearest HAPS Centre the following day or any day before their scheduled visit 2, after an overnight fast of 8 hr. Visits 2 to 5: Participants will arrive at the CNRC after a 4hr fast. Assessment of clinic BP will be obtained. A blood sample will be taken and assessment of AC and CVR to hypercapnia in the MCA and PCA/BA will be obtained. Participants will then consume their assigned resveratrol dose capsules on site with water in the presence of the study investigator. The order of treatment for each subject will be determined by a Latin Square design. During the 45 minute absorption phase, participants will be reminded of the computerized multi-tasking test battery instructions and if necessary have a few trial practices. Pharmacokinetics studies of single dose consumption of resveratrol showed that plasma resveratrol peaks around 36-48mins for older adults (Nunes T, Almeida L, Rocha JF, Falcao A, Fernandes-Lopes C, Loureiro AI, et al. Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J Clin Pharmacol. 2009 Dec;49(12):1477-82). Therefore, post-consumption CVR to hypercapnia in the MCA will be obtained at 45min post-consumption and CVR to neuropsychological test battery will commence at the 55min post-consumption time point. Continuous recordings of changes in mean blood flow velocities in the MCA during the neuropsychological test battery will be obtained. Time taken to complete the neuropsyschological tests is 30min. CVR to hypercapnia in the posterior arteries will be assessed in participants who have successful blood flow signal in the PCA/BA. A second blood sample will be taken at the conclusion of each visit. This protocol is repeated at weekly intervals with different resveratrol doses. Duration of each visit may last up to 3hr 30min. Light refreshments will be served at the conclusion of each visit.
Sponsors
Dementia Collaborative Research Centre
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Non-insulin-dependent type 2 diabetes mellitus adults; non-smoking; women must be postmenopausal; dementia-free, Clinic SBP between 130-160mmHg ; BMI less than 40kg/m2; computer literate; have measurable ultrasound signal on both sides of the head; unlikely to change medication/supplements during the intervention.
Exclusion criteria
Suspected dementia (3MS score of less than 78/100 determined at screening); Smokers or currently on nicotine therapy; Neurological conditions; Kidney/liver disease; Insulin therapy ; Major depression as diagnosed by a health care professional; Visual problems including the inability to distinguish the colours of red, green, blue and yellow; Illiterate; Physical difficulty in both hands that will impede on motor performance of the hand/arm; Unable to obtain a measurable signal in the MCA; Unwilling to provide two blood samples at each visit; Unwilling to maintain pre-enrolment physical activity levels and dietary habits for the duration of the trial.; Unwilling to fast for 4hr; Currently consuming resveratrol or other grape extract supplements.
Outcome results
None listed