Disentangling the Effect of Brain Insulin Resistance on Brain Health (BIR-BrainHealth)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 150
- 试验地点
- 3
- 主要终点
- Correlation between brain insulin response and cognitive measures
研究概览
简要总结
People with diabetes are at increased risk of developing dementia, including Alzheimer's disease and vascular dementia. In addition, persons with diabetes have more pronounced age-related brain atrophy and cognitive difficulties compared to people without diabetes. The mechanisms behind the effects on the brain of diabetes are still unclear. New research suggests that the brains of some people with diabetes do not respond normally to insulin signals, a condition known as brain insulin resistance (BIR). To date, there have been no large clinical studies investigating BIR and its impact on brain health, but several smaller studies suggest that BIR may be a cause of cognitive decline and impaired brain health in people with diabetes. Another mechanism that may contribute to impaired brain health in people with diabetes is damage to the blood vessels in the brain. Damage to blood vessels is a well-known complication of diabetes, but how it affects the brain is not fully described. In this project, we will investigate the relationship between BIR and brain blood vessel dysfunction and its relationship to cognition and brain function. This is done by examining patients with type 1 diabetes (T1D), type 2 diabetes (T2D) and healthy controls. The participants will undergo MRI brain scans to assess the impact of BIR on the brain physiology and to evaluate brain blood vessel health. Participants will undergo comprehensive assessments of their cognitive abilities and thorough health examination.
详细描述
The BIR-BrainHealth project investigates the role of brain insulin resistance (BIR) as a key mechanism linking diabetes to cognitive decline and dementia risk. By combining cognitive testing with advanced neuroimaging (MRI and PET), metabolic profiling, and multi-omics analyses, the study aims to uncover how BIR affects brain physiology, energy metabolism, and neurovascular function. The present trial registration specifically covers the MRI components of the project and does not include PET imaging.
Diabetes significantly increases the risk of mild cognitive impairment and dementia. The exact link between diabetes and cognitive decline is yet to be fully understood. Early cognitive decline in diabetes suggests a unique pathogenetic trajectory. One hypothesized mechanism involves impaired insulin signaling/transport in the brain, referred to as brain insulin resistance (BIR). Evidence indicates that in some individuals with diabetes, neuronal insulin signaling is abnormal, resulting in dysregulated cerebral metabolism and function. Another possible pathway is cerebrovascular pathology, which may compromise cerebral perfusion and energy metabolism. The present project will investigate the relationship between BIR and cerebrovascular dysfunction, and their impact on cognition and brain function.
We will set up a multicenter study in Denmark and Germany. Initially the study will include 50 participants with type 1 diabetes, 50 participants with type 2 diabetes, and 50 control participants without diabetes. All participants will undergo a comprehensive clinical evaluation to characterize diabetes duration, severity, and systemic comorbidities. The cognitive performance of the participants will be assessed using a neuropsychological test battery of following standardized tests:
- Rey Auditory Verbal Learning Test (RAVLT)
- Trail Making Test (TMT) part A and B
- Symbol Digit Modalities Test (SDMT)
- RBANS Digit Span forward (Version A)
- Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS)
- Verbal Fluency test (phonetic and semantic)
- Grooved Pegboard
- Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses
- The Montreal Cognitive Assessment (MoCA)
Tests will be grouped by cognitive domains, and each domain score is calculated as the mean of the individual component z-scores. A cognitive composite (global score) will be derived from the mean of the domains: learning and memory, executive function and working memory, processing speed, and attention.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 50 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •age 50-80 years
- •Inclusion Criteria (diabetes only):
- •Diagnosis of either type 1 diabetes or type 2 diabetes
- •Diabetes duration of ≥10 years for individuals with type 1 diabetes and ≥5 years for individuals with type 2 diabetes
排除标准
- •HbA1c >100 mmol/mol
- •Other type of diabetes
- •Weight >140 Kg
- •Treatment with drugs that cannot be paused for 12 hours
- •Diagnosis of dementia
- •Active and recent (1year) malignant disease
- •History of major stroke
- •Major depression and/or treatment with antipsychotics
- •History of traumatic brain injury
- •Other medical condition or disorder (e.g., epilepsy, recent concussion) that in the opinion of the investigator precludes compliance with the protocol, evaluation of the results or represent an unacceptable risk for the participant's safety.
- •Inability to perform neuropsychological tests (e.g., severe vision and hearing impairment that cannot be improved with aids such as glasses and hearing aids, or language barrier.)
- •Severe claustrophobia
- •Foreign bodies of metal in the body which prohibits brain MRI scans (e.g. pacemaker or screws/plates from surgery in the head or neck region)
- •Participants who do not wish to be informed about accidental findings by MRI
- •eGFR measurement <45 within 3 months of study visit
研究组 & 干预措施
Type 1 Diabetes
Individuals who have a type 1 diabetes diagnose and meet the inclusion and exclusion criteria.
Type 2 Diabetes
Individuals who have a type 2 diabetes diagnose and meet the inclusion and exclusion criteria.
Controls
Individuals who do not have a diabetes diagnose and meet the inclusion and exclusion criteria.
结局指标
主要结局
Correlation between brain insulin response and cognitive measures
时间窗: Baseline (only measured once)
Brain insulin response is assessed by measuring changes in cerebral blood flow following intranasal insulin administration, using arterial spin labelling (ASL) MRI. The neuropsychological test battery includes the following: * Rey Auditory Verbal Learning Test (RAVLT) * Trail Making Test (TMT) part A and B * Symbol Digit Modalities Test (SDMT) * RBANS Digit Span forward (Version A) * Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS) * Verbal Fluency test (phonetic and semantic) * Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)
Correlation between cerebrovascular reactivity and cognitive measures
时间窗: Baseline (only measured once)
Cerebrovascular reactivity is assessed by measuring changes in cerebral blood flow responses to inhalation of hypercapnic air (air enriched with 5% CO2). Cerebral blood flow is measured using combined blood-oxygen-level-dependent (BOLD) MRI, ASL MRI, and phase contrast mapping (PCM) MRI. The neuropsychological test battery includes the following: * Rey Auditory Verbal Learning Test (RAVLT) * Trail Making Test (TMT) part A and B * Symbol Digit Modalities Test (SDMT) * RBANS Digit Span forward (Version A) * Wechsler Adult Intelligence Scale III Letter-Number Sequencing test (WAIS-LNS) * Verbal Fluency test (phonetic and semantic) * Rapid Visual Processing (RVP) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) using A' (RVP-A) and mean latency for correct responses Motor function (Grooved Pegboard) Montreal Cognitive Assessment (MoCA)
次要结局
- Blood-brain-barrier permability(Baseline (only measured once))
- Neurovascular coupling(Baseline (only measured once))
- Hypothalamic glucose sensing(Baseline (only measured once))
研究者
Henrik Bo Wiberg Larsson
Professor
Rigshospitalet, Denmark