Insulin resistance, cognition, and brain amyloid accumulation : an epidemiological and a positron emission tomography study

Insulin resistance is a common phenomenon, closely associated with obesity, and defined as the inability of target tissues to respond normally to insulin. Insulin resistance typically precedes the onset of type 2 diabetes by several years. Type 2 diabetes is a risk factor for dementia and for Alzheimer´s disease (AD), the most common type of dementia. Some epidemiological studies suggest that insulin resistance increases the risk for dementia and AD, even in non-diabetic populations. In vitro and animal studies indicate that insulin resistance can contribute to the pathogenesis of AD through multiple different pathways. This thesis was set out to explore the cross-sectional and longitudinal associations between insulin resistance and cognitive functioning in the Finnish large, nationwide Health 2000 survey, and its follow-up, Health 2011. The possible modulating effects of sex and apolipoprotein E ε4 genotype (APOEε4), the most significant genetic risk factor for sporadic AD, were of specific interest. The aim of this thesis was also to investigate whether midlife insulin resistance increases the risk for brain amyloid accumulation, which is considered an early sign of AD. Insulin resistance was associated with poorer verbal fluency in women and in non-carriers of APOEε4 cross-sectionally (n=5935). Insulin resistance was an independent predictor of poorer verbal fluency performance after 11 years, and of a steeper decline in verbal fluency during the follow-up in both men and women, and in carriers and non-carriers of APOEε4 (n=3695). Midlife insulin resistance increased the risk for brain amyloid accumulation, measured with positron emission tomography (PET), after a 15-year follow-up (n=60). The risk was similar in both carriers and non-carriers of APOEε4. These results indicate that midlife insulin resistance is an independent risk factor for cognitive decline, and for late-onset AD.Insuliiniresistenssi, kognitio ja aivojen amyloidikertymä Insuliiniresistenssi on tavallinen, keskivartalolihavuuteen liittyvä ilmiö, jolla tarkoitetaan eri kudosten heikentynyttä vastetta insuliinille. Insuliiniresistenssi edeltää tyypillisesti tyypin 2 diabeteksen puhkeamista vuosien ajan. Tyypin 2 diabetes lisää riskiä sairastua vanhuusiän muistisairauteen ja sen yleisimpään muotoon, Alzheimerin tautiin (AT). Joidenkin seurantatutkimusten perusteella insuliiniresistenssi lisäisi riskiä sairastua muistisairauteen myös henkilöillä, joille ei vielä ole kehittynyt tyypin 2 diabetesta. Insuliiniresistenssi voi vaikuttaa AT:lle tyypillisten aivomuutosten kehittymiseen useiden eri mekanismien kautta. Tämän tutkimuksen tarkoituksena oli selvittää, onko insuliiniresistenssin ja muistin tai muiden tiedonkäsittelytoimintojen välillä yhteyttä väestötasolla, perustuen laajoihin Terveys 2000 ja 2011 -tutkimuksiin. Lisäksi selvitettiin, säätelevätkö sukupuoli ja/tai AT:n tavallisin geneettinen riskitekijä eli apolipoproteiini E -geenin ε4-geenimuoto (APOEε4) insuliiniresistenssin ja tiedonkäsittelytoimintojen välistä yhteyttä. Positroniemissiotomografia (PET)-kuvausten avulla tutkittiin, lisääkö keski-iän insuliiniresistenssi riskiä aivojen amyloidikertymälle, jota pidetään AT:n varhaisena merkkinä. Tutkimuksessa osoitettiin, että insuliiniresistenssi oli yhteydessä heikompaan suoriutumiseen kielellistä sujuvuutta mittaavassa testissä poikkileikkausaineistossa (n=5935). Tämä yhteys havaittiin vain naisilla, ja vain niillä, jotka eivät kantaneet APOEε4-geenimuotoa. Sen sijaan 11 vuoden seurannassa insuliiniresistenssi ennusti heikompaa suoriutumista ko. testissä sekä naisilla että miehillä, APOEε4-geenimuodosta riippumatta (n=3695). Keski-iän insuliiniresistenssi lisäsi myös riskiä aivojen amyloidikertymälle 15 vuoden seurannassa APOEε4-geenimuodosta riippumatta (n=60). Löydösten perusteella näyttää siltä, että keski-iän insuliiniresistenssi on itsenäinen tiedonkäsittelytoimintojen heikentymisen ja AT:n riskitekijä

Proteomic correlates of cortical thickness in cognitively normal individuals with normal and abnormal cerebrospinal fluid beta-amyloid1-42

Cortical atrophy is an early feature of Alzheimer´s disease (AD). The biological processes associated with variability in cortical thickness remain largely unknown. We studied 220 cerebrospinal fluid (CSF) proteins to evaluate biological pathways associated with cortical thickness in 34 brain regions in 79 cognitively normal older individuals with normal (>192 ng/L, n = 47), and abnormal (≤192 ng/L, n = 32) CSF beta-amyloid1-42 (Aβ42). Interactions for Aβ42 status were tested. Panther GeneOntology and Cytoscape ClueGO analyses were used to evaluate biological processes associated with regional cortical thickness. 170 (77.3 %) proteins related with cortical thickness in at least 1 brain region across the total group, and 171 (77.7 %) proteins showed Aβ42 specific associations. Higher levels of proteins related to axonal and synaptic integrity, amyloid accumulation, and inflammation were associated with thinner cortex in lateral temporal regions, the rostral anterior cingulum, the lateral occipital cortex and the pars opercularis only in the abnormal Aβ42 group. Alterations in CSF proteomics are associated with a regional cortical atrophy in the earliest stages of AD.</p

Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review

Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([F-18]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer's disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes-two diseases characterized by systemic insulin resistance-are associated with an increased risk for AD. Along with the well-defined patterns of fasting [F-18]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [F-18]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders

Iäkkäiden muistisairaudet tarvitsevat erikoisosaajia

On korkea aika varmistaa, että hyvinvointialueet sekä yliopistosairaalat saavat geriatrian yksiköt ja niihin riittävät resurssit.</p

Head-to-head comparison of plasma p-tau181, p-tau231 and glial fibrillary acidic protein in clinically unimpaired elderly with three levels of APOE4-related risk for Alzheimer's disease

Plasma phosphorylated tau (p-tau) and glial fibrillary acidic protein (GFAP) both reflect early changes in Alzheimer's disease (AD) pathology. Here, we compared the biomarker levels and their association with regional β-amyloid (Aβ) pathology and cognitive performance head-to-head in clinically unimpaired elderly (n = 88) at three levels of APOE4-related genetic risk for sporadic AD (APOE4/4 n = 19, APOE3/4 n = 32 or non-carriers n = 37). Concentrations of plasma p-tau181, p-tau231 and GFAP were measured using Single molecule array (Simoa), regional Aβ deposition with 11C-PiB positron emission tomography (PET), and cognitive performance with a preclinical composite. Significant differences in plasma p-tau181 and p-tau231, but not plasma GFAP concentrations were present between the APOE4 gene doses, explained solely by brain Aβ load. All plasma biomarkers correlated positively with Aβ PET in the total study population. This correlation was driven by APOE3/3 carriers for plasma p-tau markers and APOE4/4 carriers for plasma GFAP. Voxel-wise associations with amyloid-PET revealed different spatial patterns for plasma p-tau markers and plasma GFAP. Only higher plasma GFAP correlated with lower cognitive scores. Our observations suggest that plasma p-tau and plasma GFAP are both early AD markers reflecting different Aβ-related processes

Episodic memory and cortical amyloid pathology: PET study in cognitively discordant twin pairs

We studied the association between episodic memory and cortical fibrillar beta-amyloid pathology within twin pairs. Using telephone-administered cognitive screening of 1415 twin pairs in a population-based older Finnish Twin Cohort study, we identified 45 (mean [SD] age 72.9 [4.0] years, 40% women) cognitively discordant same-sex twin pairs (24 dizygotic and 21 monozygotic) without neurological or psychiatric disorders other than AD or mild cognitive impairment. In-person neuropsychological testing was conducted. Cortical amyloid was measured with carbon 11-labelled Pittsburgh compound B ([11C]PiB) positron emission tomography imaging and quantified as the average standardized uptake value ratio in cortical regions affected in AD. Larger within-twin pair differences in verbal immediate (r = -0.42) and delayed free recall (r = -0.41), and visual delayed free recall (r = -0.46) were associated with larger within-twin pair differences in [11C]PiB uptake (p's < 0.01). Correlations were not significantly different in dizygotic and monozygotic pairs suggesting that the episodic memory-cortical amyloid relationship is not confounded by genetic effects. However, larger samples are needed to draw more definitive conclusions. (C) 2021 The Authors. Published by Elsevier Inc.</p

The Obesity Risk SNP (rs17782313) near the MC4R Gene Is Not Associated with Brain Glucose Uptake during Insulin Clamp-A Study in Finns

The melanocortin system is involved in the control of adiposity through modulation of food intake and energy expenditure. The single nucleotide polymorphism (SNP) rs17782313 near the MC4R gene has been linked to obesity, and a previous study using magnetoencephalography has shown that carriers of the mutant allele have decreased cerebrocortical response to insulin. Thus, in this study, we addressed whether rs17782313 associates with brain glucose uptake (BGU). Here, [F-18]-fluorodeoxyglucose positron emission tomography (PET) data from 113 Finnish subjects scanned under insulin clamp conditions who also had the rs17782313 determined were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. Statistical analysis was performed with statistical parametric mapping. There was no difference in age, BMI, and insulin sensitivity as indexed by the M value between the rs17782313-C allele carriers and non-carriers. Brain glucose uptake during insulin clamp was not different by gene allele, and it correlated with the M value, in both the rs17782313-C allele carriers and non-carriers. The obesity risk SNP rs17782313 near the MC4R gene is not associated with brain glucose uptake during insulin clamp in humans, and this frequent mutation cannot explain the enhanced brain glucose metabolic rates in insulin resistance

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