Functional MRI Biomarkers of Cognitive Decrements in Diabetes

The exact neuronal mechanism underlying the cognitive decline associated with diabetes mellitus type 2 (DM2) still remains to be elucidated. Multi-parametric functional MRI can potentially provide functional, micro-structural, micro-vascular, and metabolic information on the affected brain at an earlier stage than does conventional structural MRI. The overall aim of the current proposal is to obtain a better understanding in the neuronal mechanisms that underlie cognitive decline in DM2 and the putative prediabetic condition the metabolic syndrome (MetS).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Mild Cognitive Impairment; Metabolic Syndrome X

Detailed Description

Diabetes mellitus type 2 (DM2) is a common chronic metabolic disorder that affects 4.1% of the Dutch population. In addition to vascular disease, DM2 is associated with structural brain changes visible on MRI, accelerated cognitive decline, and dementia in older individuals. The exact pathophysiological mechanisms underlying cognitive decrements in DM2 still remain to be elucidated. The 'metabolic syndrome' (MetS), defined as a cluster of cardiovascular risk factors (including obesity, hypertension, and dyslipidemia) is often considered a prediabetic condition. Individuals with MetS display similar cognitive decrements as do DM2 patients, but do not share the severity of brain injury. It has been indicated that in prediabetic MetS, cognitive problems precede structural brain changes, and that MetS and DM2 affect the brain through a shared mechanism in which vascular co-morbidity is essential.

The primary objectives are defined according to a hierarchical design: i) to tailor and apply multi-parametric, functional MRI techniques to identify cerebral abnormalities (cerebral biomarkers) in DM2 and MetS; ii) to investigate which cerebral biomarkers are shared and differ between DM2 and MetS; iii) to assess whether these cerebral biomarkers are associated with cognitive decrements.

• Study Type: Observational
• Enrollment (Actual): 106

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6202 AZ
    • Maastricht University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Matched subjects aged 40-75 years with Diabetes mellitus type 2, metabolic syndrome, and healthy controls

Description

Inclusion criteria:

• Subjects aged 40-75 years
• Subjects enrolled in the existing 'Maastricht Study' (M-Study)
• Subjects gave written consent to be approached for additional research
• Subjects belongs to the 20% of the worst and 20% of the best performing (as based on neuropsychological cognitive testing (Stroop color-word test, 15 word learning test, and Delayed recall and recognition 15 word learning test)

Individuals Diabetes type 2:

- Fasting blood glucose ≥ 7.0 mmol/l, after an oral glucose tolerance test (OGTT)blood glucose ≥ 11.1 mmol/l or used oral glucose-lowering medication or insulin

Metabolic syndrome:

• Participants should meet three out of 5 of the following criteria [8]:

  1. Waist circumference > 88 cm (women), > 102 cm (men)
  2. Triglycerides ≥ 1.7 mmol/l
  3. HDL cholesterol < 1.3 mmol/l (women), < 1.0 mmol/l (men)
  4. Blood pressure ≥ 130/85 mmHg (or medication)

  5. Fasting blood glucose ≥ 6.1 mmol/l, after an OGTT blood glucose ≥ 7.8 mmol/l

     Control participants:

• Those who fulfilled no more than 1 criterium of the metabolic syndrome, no DM2.

Exclusion criteria:

• Contra-indications for MRI examination (e.g. pacemaker; neurostimulator; medication pump; cochlear or hearing implant; tattoos or other items that cannot be removed and include metal parts (for instance from operations in the past); metal splinter in the eye; pregnancy and claustrophobia; brain vessel clamps; denture, which contains magnets).
• Psychiatric co-morbidity and inability to perform the functional MRI tests.
• Incomplete cognitive assessment data
• Diabetes mellitus type 1 (DM1)
• Subjects who are not belonging to the 20% of the worst and 20% of the best performing individuals (as based on neuropsychological cognitive testing (Stroop color-word test, 15 word learning test, and Delayed recall and recognition 15 word learning test).
• Last visit of the subjects to the M-Study should be less than one year

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
healthy controls
Diabetes mellitus type 2 (DM2)
metabolic syndrome (MetS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional and structural connectivity relationships of multiple brain regions and biomarkers of brain alterations	Differences in macro-structural, micro-structural, and metabolic concentrations between patients and healthy controls will be evaluated. These MRI measures include volumetric characteristics (e.g. hyper-intensities, white matter lesions, atrophy), quantitative measures (e.g. T2 relaxation times, mean diffusivity, fractional anisotropy), functional characteristics (e.g. activated regions, cerebral blood flow), metabolic characteristics (e.g. concentration of metabolites), network properties (e.g. functional and structural connectivity, graph-theoretical measures).	subjects will be assessed once (on 1 day)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anthropometrics	Simple anthropometric measurements will include: Body mass index will be calculated as the weight (kg) divided by the square of the height (m). Waist circumference (WC) will be taken as the minimum circumference between the umbilicus and xiphoid process and measured to the nearest 0.5 cm.	subjects will be assessed once (on 1 day)
Mental health	For assessment of mental health, specifically depression, the Cambridge Mental Disorders of the Elderly Examination will be used.	subjects will be assessed once (on 1 day)
Lifestyle	Lifestyle specifics, including alcohol consumption, smoking behavior and mobility will be obtained through a questionnaire.	subjects will be assessed once (on 1 day)
Cardiovascular risk factors	Blood samples will be assessed for: Fasting circulating levels of glucose, albumin, creatinin, total cholesterol, LDL- and HDL-cholesterol, triglycerides, HbA1c and uric acid.	subjects will be assessed once (on 1 day)

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Netherlands Organisation for Scientific Research
• Investigators: Principal Investigator: Jacobus FA Jansen, PhD, Maastricht University Medical Center

Publications and helpful links

General Publications

• van Bussel FC, Backes WH, Hofman PA, van Oostenbrugge RJ, Kessels AG, van Boxtel MP, Schram MT, Stehouwer CD, Wildberger JE, Jansen JF. On the interplay of microvasculature, parenchyma, and memory in type 2 diabetes. Diabetes Care. 2015 May;38(5):876-82. doi: 10.2337/dc14-2043. Epub 2015 Feb 17.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: June 6, 2012
• First Submitted That Met QC Criteria: October 11, 2012
• First Posted (Estimate): October 12, 2012

Study Record Updates

• Last Update Posted (Estimate): April 10, 2015
• Last Update Submitted That Met QC Criteria: April 9, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Neurocognitive Disorders; Endocrine System Diseases; Insulin Resistance; Hyperinsulinism; Cognition Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Metabolic Syndrome; Cognitive Dysfunction
• Other Study ID Numbers: NL34329.068.10 / METC 10-2-023; 916.11.059 (Other Grant/Funding Number: NWO/ZonMW VENI)