Disturbances of glucose metabolism, cognitive decline, and neuroimaging changes related to Alzheimer's disease

Insulin resistance is a common abnormal metabolic state related to obesity and many other health problems where target organs cannot respond normally to insulin. Insulin resistance and the dysfunction of the pancreatic insulin-secreting β-cells are the basic features of type 2 diabetes and its preceding stages, i.e. prediabetes. Diabetes is a risk factor for cognitive decline and progressive memory disorders, of which Alzheimer’s disease (AD) is the most common. Presumably, the risk for cognitive decline begins increasing at the prediabetic stages. This thesis aimed to clarify the associations between midlife insulin resistance, late-life cognitive performance, and neuroimaging changes related to AD among individuals with and without insulin resistance in midlife. Vascular changes were assessed with magnetic resonance imaging (MRI), and neuroinflammation and beta-amyloid (A) deposition, which is an early marker of AD pathology, with positron emission tomography (PET) (n=60). This thesis also evaluated if measures from an oral glucose tolerance test (OGTT) can predict cognitive decline in the Finnish nationwide Health 2000 survey and its follow-up, the Health 2011 study (n=961). Midlife insulin resistance was associated with poorer executive functions and slower processing speed but not with brain vascular changes after 15 years. A deposits, but not vascular lesions, were related to slower processing speed. A was associated with neuroinflammation among those with only small amounts of A accumulation. Insulin resistance, low-grade systemic inflammation, and a higher body mass index (BMI) were associated with higher levels of neuroinflammation in brain regions where A is first detected in AD. Higher 2-hour glucose (reflecting impaired glucose tolerance) and a decreased early insulin response (an indicator of β-cell function) in an OGTT predicted poorer performance and greater decline in a test of episodic memory after ten years. These results indicate that midlife insulin resistance, impaired glucose tolerance, and decreased early insulin secretion – all related to prediabetic stages – are risk factors for cognitive decline. These results also suggest that early amyloid accumulation is associated with neuroinflammation

Association of Early β-Amyloid Accumulation and Neuroinflammation Measured With [11C]PBR28 in Elderly Individuals Without Dementia

OBJECTIVE: To examine whether early β-amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia. METHODS: We examined 54 volunteers (mean age 70.0 years, 56% women, 51% APOE ɛ4 carriers) with the translocator protein (TSPO) tracer [11C]PBR28 to assess neuroinflammation and with [11C] Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in 6 regions of interests by using the cerebellar cortex as a pseudo-reference and reference region, respectively. Fasting venous glucose, insulin, and high-sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n = 11) underwent CSF sampling, and Aβ40, Aβ42, total tau, phospho-tau, soluble TREM2, and YKL-40 levels were measured. RESULTS: Among the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p = 0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid-negative ([11C]PiB composite score ≤1.5) (TSPO genotype-, age- and sex-adjusted slope 0.26, p = 0.008) but not among amyloid-positive (slope -0.004, p = 0.88) participants. Higher CSF soluble TREM2 (rs = 0.72, p = 0.01) and YKL-40 (rs = 0.63, p = 0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer disease. CONCLUSIONS: While there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.</p

Oral Glucose Tolerance Test Predicts Episodic Memory Decline : A 10-Year Population-Based Follow-up Study

Tutkimusaineistona THL-aineistoThis study is based on a subpopulation of the Finnish population-based Health 2000 Survey and its follow-up, the Health 2011 study. Altogether, 961 individuals aged 45-74 (mean 55.6 years; 55.8% women) underwent OGTT in 2001-2002. Categorical verbal fluency, word-list learning, and word-list delayed recall were tested at baseline and at follow-up in 2011. Statistical analyses were performed with multivariable linear models adjusted for previously reported risk factors for cognitive declin

Association of Early β-Amyloid Accumulation and Neuroinflammation Measured With [11C]PBR28 in Elderly Individuals Without Dementia

OBJECTIVE: To examine whether early β-amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia. METHODS: We examined 54 volunteers (mean age 70.0 years, 56% women, 51% APOE ɛ4 carriers) with the translocator protein (TSPO) tracer [11C]PBR28 to assess neuroinflammation and with [11C] Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in 6 regions of interests by using the cerebellar cortex as a pseudo-reference and reference region, respectively. Fasting venous glucose, insulin, and high-sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n = 11) underwent CSF sampling, and Aβ40, Aβ42, total tau, phospho-tau, soluble TREM2, and YKL-40 levels were measured. RESULTS: Among the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p = 0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid-negative ([11C]PiB composite score ≤1.5) (TSPO genotype-, age- and sex-adjusted slope 0.26, p = 0.008) but not among amyloid-positive (slope -0.004, p = 0.88) participants. Higher CSF soluble TREM2 (rs = 0.72, p = 0.01) and YKL-40 (rs = 0.63, p = 0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer disease. CONCLUSIONS: While there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology

Midlife Insulin Resistance as a Predictor for Late-Life Cognitive Function and Cerebrovascular Lesions

Background: Type 2 diabetes (T2DM) increases the risk for Alzheimer’s disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline. Objective: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning. Methods: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n = 6062) to attend follow-up examinations in 2014–2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOE ɛ4 carriers per group. Statistical analyses were performed with multivariable linear models. Results: At follow-up the IR+group performed worse on executive functions (p = 0.02) and processing speed (p = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed. Conclusion: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here