Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000457741
Ethics application status
Approved
Date submitted
16/04/2013
Date registered
19/04/2013
Date last updated
11/10/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Cerebral blood flow and cognition in diabetes: A pilot cross-sectional investigation
Scientific title
Cerebral blood flow and cognition in diabetes: A pilot cross-sectional investigation
Secondary ID [1] 282341 0
Nil
Universal Trial Number (UTN)
U1111-1141-9203
Trial acronym
DiaCog Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cerebral blood flow pulsatility 288888 0
Cognitive performance 288943 0
Cerebral blood flow 288944 0
Condition category
Condition code
Metabolic and Endocrine 289231 289231 0 0
Diabetes
Mental Health 289232 289232 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The aim of this pilot cross-sectional study involving type 2 (non-insulin-dependent) diabetic adults and age and gender matched healthy controls is to:
(1) Evaluate cognitive performance and cerebral blood flow pulsatility (both at rest and in response to a cognitive task) in type 2 diabetes patients and in healthy controls
(2) Explore relationships between cerebral blood flow pulsatility, cognitive performance and biomarkers of insulin resistance and diabetes.

Methods and Procedures:
Subject recruitment: Participants will be recruited from the Hunter Region in NSW using media advertising approved by the University of Newcastle Media and Marketing Department. Recruitment flyers will also be placed on noticeboards at the University of Newcastle. Participants will also be recruited from the Hunter Medical Research Institute (HMRI) Volunteer Register.

Part A
Potential participants will attend a local Hunter Pathology branch to have their fasting plasma glucose levels tested to determine their eligibility before visiting the HMRI. At this visit, anthropometric measurements, i.e. height, weight and waist circumference, and blood pressure and arterial compliance will be assessed. Cognitive status will then be assessed with the Mini Mental State Examination (MMSE) instrument (to screen for potential dementia). Participants scoring less than 25 will be excluded at this stage. Participants will then be fitted with a headpiece with two ultrasound probes on both sides of the temporal region. The transcranial Doppler (TCD) device will monitor the blood flow velocity in both the middle cerebral artery. Participants will be excluded if no measurable signal is obtained after 30 minutes. Eligible participants will then proceed to have their cerebral blood flow velocity recorded at rest in a seated position after 10 mins of silence. Participants will then perform a series of cognitive tasks continuously for approximately 60 mins, whilst the TCD device records changes in blood flow.

Part B
Ten eligible volunteers from each group that have completed Part A will be invited to return to the Research Centre a week later for reassessment of the TCD at rest and during performance of the cognitive tasks to determine the reproducibility of these outcomes.
Intervention code [1] 286957 0
Not applicable
Comparator / control treatment
Healthy controls (fasting plasma glucose less than or equal to 5.5mM)
Control group
Uncontrolled

Outcomes
Primary outcome [1] 289353 0
Cerebral blood flow pulsatility in type 2 diabetes versus age-matched controls, assessed by TCD ultrasound (peak systolic flow - end-diastolic flow/mean blood velocity in the middle cerebral artery).
Timepoint [1] 289353 0
Four continuously recording of blood flow velocity through 10 cardiac cycles, after 10 mins of seated rest in silence at baseline and 1 week later in a subset of volunteers.
Secondary outcome [1] 302292 0
Cerebral blood flow responsiveness to cognitive stimuli in type 2 diabetes versus age-matched controls, assessed by TCD ultrasound.
Timepoint [1] 302292 0
Measured continuously throughout the 60min cognitive test battery at baseline and 1 week later in a subset of volunteers.
Secondary outcome [2] 302293 0
Cognitive performance in type 2 diabetes versus age-matched controls, assessed using a cognitive test battery (Digit forward span, digit backward span, digit symbol coding, N-back task, Stroop colour word task, serial subtraction 7, letter-number sequencing, symbol digit coding and concept shifting test).
Timepoint [2] 302293 0
Cognitive performance assessed after baseline anthropometric assessment, blood pressure, MMSE, 10 mins of seated rest in silence and resting cerebral pulsatility measurements and 1 week later in a subset of volunteers.
Secondary outcome [3] 302294 0
Relationship between biomarkers of insulin resistance (HOMA) and diabetes severity (HbA1c) and the extent of cerebrovascular dysfunction, as determined by cerebral blood flow pulsatility using TCD ultrasound, in type 2 diabetes.
Timepoint [3] 302294 0
HOMA and HbA1c values of volunteers will be obtained 1 week before study enrollment from the Hunter Area Pathology Services (HAPS). Cerebral blood flow pulsatility of type 2 diabetics will be measured at baseline and 1 week later in a subset of volunteers.
Secondary outcome [4] 302329 0
Relationship between biomarkers of insulin resistance (HOMA) and diabetes severity (HbA1c) and the extent to which cerebrovascular dysfunction, as determined by cerebral blood flow pulsatility using TCD ultrasound, account for the cognitive impairment in type 2 diabetes.
Timepoint [4] 302329 0
HOMA and HbA1c values of volunteers will be obtained 1 week before study enrollment from the Hunter Area Pathology Services (HAPS). Cerebral blood flow pulsatility of type 2 diabetics will be measured at baseline and 1 week later in a subset of volunteers.

Eligibility
Key inclusion criteria
1. Age 50 – 80 years, females must be post-menopausal (self-reported cessation of menses for at least 12 months)
2. Have non-insulin-dependent diabetes as diagnosed by a doctor and fasting plasma glucose greater than or equal to 7.0mM or have fasting plasma glucose less than or equal 5.5mM, determined by the results obtained in the Hunter Pathology test.
Minimum age
50 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unwilling to fast for at least 8 hours
2. A smoker or currently on nicotine therapy
3. Have dementia or suspected dementia (MMSE score less than 25 at screening visit)
4. Have a history of serious head injury, alcoholism, stroke and/or neurological condition
5. Have no measurable TCD ultrasound signal (determined during the screening visit)
6. Unable to read and write English fluently
7. Have changed their diabetes medication in the last three months

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Case control
Timing
Prospective
Statistical methods / analysis
Outcomes from this study will be analysed by one-way ANCOVA. Baseline measures (age, HOMA, HbA1C) will be used as covariates. We will match groups by stratification of age and gender and other potential variables such as years of education and MMSE score will be added as covariates. Relationships between changes in circulatory parameters and cognitive parameters will be analysed by linear regression with appropriate pre-planned Bonferroni comparisons and the effect of biomarker status will be determined using biomarkers as covariates in a mixed model analysis.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
22/04/2013
Actual
27/05/2013
Date of last participant enrolment
Anticipated
31/12/2014
Actual
24/07/2015
Date of last data collection
Anticipated
Actual
24/07/2015
Sample size
Target
80
Accrual to date
Final
79
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 287098 0
University
Name [1] 287098 0
University of Newcastle
Country [1] 287098 0
Australia
Primary sponsor type
Individual
Name
Prof Peter Howe
Address
University of Newcastle
University Drive
School of Biomedical Sciences & Pharmacy
MS304
Callaghan NSW 2308
Country
Australia
Secondary sponsor category [1] 285875 0
None
Name [1] 285875 0
None
Address [1] 285875 0
None
Country [1] 285875 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289113 0
Human Research Ethics Committee
Ethics committee address [1] 289113 0
The University of Newcastle
University Drive
Human Research Ethics Administration
Research Services Research Integrity Unit
The Chancellery
Callaghan, NSW 2308
Ethics committee country [1] 289113 0
Australia
Date submitted for ethics approval [1] 289113 0
Approval date [1] 289113 0
11/04/2013
Ethics approval number [1] 289113 0
H-2013-0015

Summary
Brief summary
People with type 2 diabetes are at increased risk of developing arterial disease. Arteries stiffen with advancing age and this process is exacerbated in type 2 diabetes and other risk factors for heart disease. Increasing stiffness of arteries in the brain may impede regional blood flow, thus impairing brain function; those with poor mental abilities appear to have stiffer blood vessels in the brain compared to healthy individuals. This may account for the increased prevalence of cognitive decline associated with type 2 diabetes. However, no studies have yet investigated whether arterial function in the brain is related to the mental abilities of adults with type 2 diabetes.

This project will be the first of its kind to evaluate whether artery stiffness in the brain and biomarkers of insulin resistance and type 2 diabetes are indicators of impaired mental abilities, such as attention, concentration and memory. The introduction transcranial Doppler ultrasound (TCD) enables us to readily assess the pulsatility of blood flow in the middle cerebral artery, a measure of arterial stiffness in the brain. Moreover, we will also measure cerebrovascular responsiveness (CVR), i.e. the ability of blood vessels in brain regions to dilate in response to psychological stimuli. Thus, at the same time as evaluating the cognitive abilities of people with type 2 diabetes, we can assess the ability of their arteries to supply more blood to the brain during the mental tests. We will compare these capabilities in type 2 diabetes with age and gender matched healthy controls. We will also examine their relationship to indicators of the severity of diabetes, viz. insulin resistance and glycated haemoglobin. We hypothesise that a) cerebral blood flow pulsatility will be higher and CVR to cognitive stimuli will be lower in type 2 diabetes patients than in healthy controls; b) both measures will correlate with the severity of insulin resistance/diabetes and the extent of cognitive decline. The results will indicate the extent to which impaired artery function in the brain is a potential risk factor for decline in mental abilities in type 2 diabetes and will help us to devise early intervention strategies to prevent future loss of mental abilities in this at-risk population.


Trial website
Trial related presentations / publications
Impaired cerebrovascular responsiveness and cognitive performance in adults with type 2 diabetes.J Diabetes Complications. 2016 Jun 30. pii: S1056-8727(16)30254-9. doi: 10.1016/j.jdiacomp.2016.06.025. [Epub ahead of print]
Public notes

Contacts
Principal investigator
Name 39306 0
Prof Peter Howe
Address 39306 0
University of Newcastle
University Drive
School of Biomedical Sciences & Pharmacy
MS 304
Callaghan
NSW 2308
Country 39306 0
Australia
Phone 39306 0
+61 2 49217309
Fax 39306 0
Email 39306 0
[email protected]
Contact person for public queries
Name 39307 0
Dr Rachel Wong
Address 39307 0
University of Newcastle
Clinical Nutrition Research Centre
School of Biomedical Sciences and Pharmacy
University Drive, Callaghan NSW 2308
Country 39307 0
Australia
Phone 39307 0
61849216408
Fax 39307 0
Email 39307 0
[email protected]
Contact person for scientific queries
Name 39308 0
Prof Peter Howe
Address 39308 0
University of Newcastle
University Drive
School of Biomedical Sciences & Pharmacy
MS 304
Callaghan
NSW 2308
Country 39308 0
Australia
Phone 39308 0
+61 2 49217309
Fax 39308 0
Email 39308 0
[email protected]

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