Coupling relationship between glucose and oxygen metabolisms to differentiate preclinical Alzheimer's disease and normal individuals.
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ABSTRACT:
SUBMITTER: Ding C
PROVIDER: S-EPMC8449101 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveA National Institute on Aging-sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.MethodsSeventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups.ResultsThere was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups.ConclusionsAlthough cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design.
| S-EPMC3700591 | biostudies-literature
Project description:IntroductionSensitive detection of cognitive decline over the course of preclinical Alzheimer's disease is critical as the field moves toward secondary prevention trials.MethodsWe examined amyloid β (Aβ)-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer's Disease Cooperative Study Prevention Instrument Study as a replication cohort.ResultsAβ+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aβ group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression.DiscussionThis independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer's disease, which may prove advantageous in the prevention trial design.
| S-EPMC5573651 | biostudies-literature
Project description:BackgroundBoth Alzheimer's disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition.MethodsAnalyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function.ResultsIn mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition.ConclusionsThese results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.
| S-EPMC10045505 | biostudies-literature
Project description:While detecting and validating correlations among the contributing factors to the preclinical phase of Alzheimer's disease (pAD) has been a focus, a potent meta-analysis method to integrate current findings is essential. The entity-relationship diagram with nodes as entities and edges as relationships is a graphical representation that summarizes the relationships among multiple factors in an intuitive manner. Based on this concept, a new meta-analysis approach with this type of diagram is proposed to summarize research about contributing factors of pAD and their interactions. To utilize the information for enriched visualization, width and color of the edges are encoded with reporting times, number of pAD subjects, correlation coefficient, and study design (cross-sectional or longitudinal). The proposed Probabilistic Entity-Relationship Diagram (PERD) demonstrated its effectiveness in this research for studying pAD. Another kind of diagram with occurrence order for some factors was also proposed to provide sequential information of the factors. In addition, PERD could potentially develop into an online application named PERD-online, which would help researchers to pool findings on the same relationships and guide further tests to validate uncertain relationships in PERD. PERD as a generic graphical meta-analysis tool can also be applied in studying other multifactorial diseases.
| S-EPMC4507140 | biostudies-other
Project description:Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer's disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using the postmortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression patterns in MCI are not an extension of aging, and for the most part, are not intermediate between aged controls and AD. Functional enrichment analysis of significant genes revealed prominent upregulation in MCI brains of genes associated with anabolic and biosynthetic pathways (notably transcription, protein biosynthesis, protein trafficking, and turnover) as well as mitochondrial energy generation. In addition, many synaptic genes showed altered expression in MCI, predominantly upregulation, including genes for central components of the vesicle fusion machinery at the synapse, synaptic vesicle trafficking, neurotransmitter receptors, and synaptic structure and stabilization. These data suggest that there is a rebalancing of synaptic transmission in the MCI brain. To investigate if synaptic gene expression levels in MCI were related to cognitive function, Pearson correlation coefficient between the Mini Mental State Examination (MMSE) and region-specific messenger RNA expression were computed for MCI cases. A number of synaptic genes showed strong significant correlations (r > 0.8, p < 0.01) most notably in the entorhinal cortex, with fewer in the hippocampus, and very few in neocortical regions. The synaptic genes with highly significant correlations were predominantly related to synaptic transmission and plasticity, and myelin composition. Unexpectedly, we found that gene expression changes that facilitate synaptic excitability and plasticity were overwhelmingly associated with poorer MMSE, and conversely that gene expression changes that inhibit plasticity were positively associated with MMSE. These data suggest that there are excessive excitability and apparent plasticity in limbic brain regions in MCI, that is associated with impaired synaptic and cognitive function. Such changes would be predicted to contribute to increased excitability, in turn leading to greater metabolic demand and ultimately progressive degeneration and AD, if not controlled.
| S-EPMC4067010 | biostudies-literature
Project description:IntroductionFasting glucose increases with age and is linked to modifiable Alzheimer's disease risk factors such as cardiovascular disease and Type 2 diabetes (T2D).MethodsWe leveraged available biospecimens and neuroimaging measures collected during the Alzheimer's Prevention Through Exercise (APEx) trial (n = 105) to examine the longitudinal relationship between change in blood glucose metabolism and change in regional cerebral amyloid deposition and gray and white matter (WM) neurodegeneration in older adults over 1 year of follow-up.ResultsIndividuals with improving fasting glucose (n = 61) exhibited less atrophy and regional amyloid accumulation compared to those whose fasting glucose worsened over 1 year (n = 44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus and inferior parietal cortex, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by apolipoprotein E ε4 carrier status.DiscussionDysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine whether treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.
| S-EPMC8804928 | biostudies-literature
Project description:Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor for developing the disease among cognitively normal (NL) individuals. This magnetic resonance imaging (MRI) study examines whether NL with a LOAD-affected parent show preclinical brain atrophy, and whether there are parent-of-origin effects. Voxel-based morphometry (VBM) on Statistical parametric mapping (SPM8) was used to examine volumetric T1-MRI scans of 60 late-middle-aged NL subjects, divided into 3 size-matched, demographically balanced groups of 20 subjects each, including NL with a maternal (FHm), paternal (FHp), or negative family history (FH-) of LOAD. There were no group differences for clinical and neuropsychological measures, and ApoE status. On VBM, FHm showed reduced gray matter volumes (GMV) in frontal, parietal, and temporal cortices and precuneus as compared with FH-, and in precuneus compared with FHp (p < 0.05, family-wise error [FWE]-corrected). Results remained significant controlling for age, gender, education, ApoE, and total intracranial volume. No differences were observed between FHp and FH- in any regions. NL FHm showed reduced GMV in LOAD-affected brain regions compared with FH- and FHp, indicating higher risk for Alzheimer's disease. Our findings support the use of regional brain atrophy as a preclinical biomarker for LOAD among at-risk individuals.
| S-EPMC3115436 | biostudies-literature
Project description:ObjectivesEpidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease (AD) is rapidly increasing. However, there is little or no evidence for a direct association between dietary nutrients and brain biomarkers of AD. This study identifies nutrient patterns associated with major brain AD biomarkers in a cohort of clinically and cognitively normal (NL) individuals at risk for AD.DesignCross-sectional study.SettingManhattan (broader area).ParticipantsFifty-two NL individuals (age 54+12 y, 70% women, Clinical Dementia Rating=0, MMSE>27, neuropsychological test performance within norms by age and education) with complete dietary information and cross-sectional, 3D T1-weighted Magnetic Resonance Imaging (MRI; gray matter volumes, GMV, a marker of brain atrophy), 11C-Pittsburgh compound-B (PiB; a marker of fibrillar amyloid-β, Aβ) and 18F-fluorodeoxyglucose (FDG; a marker of glucose metabolism, METglc) Positron Emission Tomography (PET) scans were examined.MeasurementsDietary intake of 35 nutrients associated with cognitive function and AD was assessed using the Harvard/Willet Food Frequency Questionnaire. Principal component analysis was used to generate nutrient patterns (NP) from the full nutrient panel. Statistical parametric mapping and voxel based morphometry were used to assess the associations of the identified NPs with AD biomarkers.ResultsNone of the participants were diabetics, smokers, or met criteria for obesity. Five NPs were identified: NP1 was characterized by most B-vitamins and several minerals [VitB and Minerals]; NP2 by monounsaturated and polyunsaturated fats, including ω-3 and ω-6 PUFA, and vitamin E [VitE and PUFA]; NP3 by vitamin A, vitamin C, carotenoids and dietary fibers [Anti-oxidants and Fibers]; NP4 by vitamin B12, vitamin D and zinc [VitB12 and D]; NP5 by saturated, trans-saturated fats, cholesterol and sodium [Fats]. Voxel-based analysis showed that NP4 scores [VitB12 and D] were positively associated with METglc and GMV, and negatively associated with PiB retention in AD-vulnerable regions (p<0.001). In addition, both METglc and GMV were positively associated with NP2 scores [VitE and PUFA], and negatively associated with NP5 scores [Fats] (p<0.001), and METglc was positively associated with higher NP3 scores [Anti-oxidants and Fibers] (p<0.001). Adjusting for age, gender, ethnicity, education, caloric intake, BMI, alcohol consumption, family history and Apolipoprotein E (APOE) status did not attenuate these relationships. The identified 'AD-protective' nutrient combination was associated with higher intake of fresh fruit and vegetables, whole grains, fish and low-fat dairies, and lower intake of sweets, fried potatoes, high-fat dairies, processed meat and butter.ConclusionSpecific dietary NPs are associated with brain biomarkers of AD in NL individuals, suggesting that dietary interventions may play a role in the prevention of AD by modulating AD-risk through its effects on Aβ and associated neuronal impairment.
| S-EPMC4375781 | biostudies-literature
Project description:ObjectiveAlthough the association between alanine aminotransferase (ALT) levels and risk of type 2 diabetes is well-studied, the effects of slightly increased ALT levels within the normal range on the temporal normal glucose profile remains poorly understood.MethodsA total of 322 Chinese subjects without impaired glucose tolerance or previous diagnoses of diabetes were recruited for study from 10 hospitals in urban areas across China. All subjects wore a continuous glucose monitoring (CGM) system for three consecutive days. The diurnal (06∶00-20∶00) and nocturnal (20∶00-06∶00) mean blood glucose (MBG) levels were calculated. Subjects were stratified by ALT quartile level and correlation analyses were performed.ResultsThe median ALT level was 17 IU/L, and subjects with ALT ≥17 IU/L had higher nocturnal MBG level than those with ALT <17 IU/L (P<0.05). Nocturnal MBG was positively correlated with ALT levels (Pearson correlation analysis: r = 0.187, P = 0.001), and the correlation remained significant after correction for the homeostatic model assessment of insulin resistance index (HOMA-IR) (r = 0.105, P = 0.041). No correlations were found between diurnal MBG and ALT, and nocturnal or diurnal MBG and aspartate aminotransferase or gamma-glutamyltransferase (all, P>0.05). Multivariate stepwise regression analysis of elevated nocturnal MBG identified increased HOMA-IR, elevated ALT levels, and decreased homeostatic model assessment of ß-cell function as independent factors (all, P<0.05).ConclusionsMildly elevated ALT levels, within the normal range, are associated with unfavorable nocturnal glucose profiles in Chinese subjects with normal glucose regulation.
| S-EPMC3570416 | biostudies-literature
Project description:BackgroundThe concept of metabolically obese, normal weight (MONW) has emerged to describe individuals with a normal body mass index (BMI) who are at a relatively high risk of chronic diseases. However, BMI itself is a suboptimal index for the assessment of the health risks associated with visceral fat. The triglyceride-glucose (TyG) index is considered to be a reliable and cost-effective marker of insulin resistance. Therefore, in the present study, we aimed to determine the TyG index cut-off values that could be used to define MONW in older people and to determine the usefulness of these values for the prediction of chronic diseases.MethodsA total of 4,721 participants in the Korea National Health and Nutritional Examination Survey who were ≥ 60 years of age and did not have underweight or obesity were included. MONW was defined using the criteria for metabolic syndrome (MS), and the TyG index was calculated on the basis of the fasting plasma triglyceride and glucose concentrations. Chronic diseases, including T2DM, hypertension, and non-alcoholic fatty liver disease (NAFLD), were diagnosed.ResultsThe prevalence of MS increased from the lowest to the highest TyG index tertile. The cut-off values of the TyG index for MONW were calculated as 8.88 and 8.80 for males and females, respectively. MONW, defined using these cut-off values, was associated with high odds ratios for NAFLD, T2DM, and hypertension in both males and females.ConclusionsThe TyG index cut-off values calculated in the present study can be used to discriminate individuals with MONW from other older individuals without obesity and to predict the risk of chronic diseases. These findings show that the TyG index is an effective and cost-efficient method of assessing the risk of chronic diseases in people with MONW.
| S-EPMC10837892 | biostudies-literature