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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]

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

Cognitive performance

Cerebral blood flow

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Mental Health

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]

Not applicable

Comparator / control treatment

Healthy controls (fasting plasma glucose less than or equal to 5.5mM)

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

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]

Cerebral blood flow responsiveness to cognitive stimuli in type 2 diabetes versus age-matched controls, assessed by TCD ultrasound.

Timepoint [1]

Measured continuously throughout the 60min cognitive test battery at baseline and 1 week later in a subset of volunteers.

Secondary outcome [2]

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]

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]

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]

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]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Newcastle

Address [1]

University of Newcastle
University Drive
School of Biomedical Sciences & Pharmacy
Callaghan NSW 2308

Country [1]

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]

None

Name [1]

None

Address [1]

None

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee

Ethics committee address [1]

The University of Newcastle 
University Drive
Human Research Ethics Administration
Research Services Research Integrity Unit 
The Chancellery 
Callaghan, NSW 2308

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

11/04/2013

Ethics approval number [1]

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

Prof Peter Howe

Address

University of Newcastle
University Drive
School of Biomedical Sciences & Pharmacy
MS 304
Callaghan
NSW 2308

Country

Australia

Phone

+61 2 49217309

Fax

peter.howe@newcastle.edu.au

Contact person for public queries

Name

Rachel Wong

Address

University of Newcastle
Clinical Nutrition Research Centre
School of Biomedical Sciences and Pharmacy
University Drive, Callaghan NSW 2308

Country

Australia

Phone

61849216408

Fax

rachel.wong@mymail.unisa.edu.au

Contact person for scientific queries

Name

Peter Howe

Address

University of Newcastle
University Drive
School of Biomedical Sciences & Pharmacy
MS 304
Callaghan
NSW 2308

Country

Australia

Phone

+61 2 49217309

Fax

peter.howe@newcastle.edu.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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No additional documents have been identified.

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