Association Between Plasma Amyloid-β and Neuropsychological Performance in Patients With Cognitive Decline
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SUBMITTER: Yun G
PROVIDER: S-EPMC8573146 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesRecent studies regarding the relationships between plasma amyloid-β (Aβ) levels and cognitive performance had inconsistent results. In this study, we aimed to characterize the relationship between cognitive decline and plasma Aβ levels in a large-sample cognitively normal population.MethodsThis population-based, prospective cohort study included 1,240 participants with normal cognition. The Mini-Mental State Examination (MMSE) was used to assess cognitive function at baseline and 2 years later. Restricted cubic splines, multivariate logistic regression, and multivariate linear regression models were used to evaluate the type of relationship between cognitive decline during the 2-year follow-up period and plasma Aβ levels (Aβ40, Aβ42, and Aβ42 / 40).ResultsParticipants with moderate Aβ40 levels had the highest risk of cognitive decline during a 2-year follow-up relative to individuals with low Aβ40 [odds ratio (OR): 0.60, 95% confidence interval (CI): 0.45-0.81, p < 0.001] or high Aβ40 (OR: 0.65, 95% CI: 0.49-0.87, p = 0.004) levels. The association between Aβ40 and cognitive decline did not depend on sex, education level, or APOE ε4 status. There was an interaction found between age (≤ 65 and > 65 years) and Aβ40 (p for interaction = 0.021). In individuals older than 65 years, there was a positive linear relationship between plasma Aβ40 and cognitive decline (OR: 1.02, 95% CI: 1.00-1.04, p = 0.027). For participants ≤ 65 years old, the lower Aβ40 and higher Aβ40 groups had a lower risk of cognitive decline than the medium Aβ40 group (OR: 0.69, 95% CI: 0.50-0.94, p = 0.02; OR: 0.63, 95% CI: 0.45-0.86, p = 0.004). None of relationship between plasma Aβ42, Aβ42 / 40 and cognitive decline was found during a 2-year follow-up.ConclusionThe relationship between plasma Aβ40 and cognitive decline was not linear, but an inverted-U shape in a cognitively normal population. The underlying mechanism requires further investigation.
| S-EPMC7516983 | biostudies-literature
Project description:ObjectiveHIV-associated neurocognitive disorder (HAND) occurs in a significant percentage of HIV-infected (HIV+) adults. Increased intraindividual variability (IIV) in cognitive function may be an early marker of emerging neurocognitive disorder, which suggests that IIV may be a sensitive measure of neurologic compromise in HIV. In the current study, we hypothesize that increased IIV may predict impending morbidity, including future cognitive decline and death.MethodIn 708 HIV+ participants followed longitudinally for up to 14 years, we assessed the role of dispersion in forecasting death and cognitive decline. Incident neurocognitive impairment was predicted in a mixed-effects ordinal logistic regression model using age, gender, baseline mean cognitive functioning, CD4+, time followed, years of education, and dispersion at the previous visit. Death before the next visit was predicted in a binomial mixed-effects regression model using age, gender, baseline mean cognitive functioning, CD4+, time followed, years of education, and dispersion.ResultsPoint-in-time dispersion and change in dispersion between visits predict future cognitive decline and death in HIV+ individuals. Individuals with greater dispersion at a visit or who had larger changes in dispersion between visits were more likely to demonstrate greater neurocognitive impairment at the subsequent visit. Greater IIV was also associated with an increased risk of death prior to the subsequent visit, even after controlling for HAND severity and global cognitive functioning.ConclusionsWe conclude that the IIV in cognitive functioning may be more predictive of future disease consequence than mean level of cognitive functioning. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
| S-EPMC6234088 | biostudies-literature
Project description:BackgroundPeripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aβ) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aβ species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results.MethodsThe Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(18F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aβ40 and Aβ42 peptides. The association between Aβ40 and Aβ42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aβ levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aβ plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis.ResultsFBB-PET global SUVR correlated weakly but significantly with Aβ42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R2 = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aβ measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aβ FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aβ measurements (p value for interaction = 0.105).ConclusionBrain and plasma Aβ levels are partially correlated in individuals diagnosed with SCD. Aβ plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.
| S-EPMC6267075 | biostudies-literature
Project description:BackgroundStage 1 of the National Institute on Aging-Alzheimer's Association's proposed Alzheimer's disease continuum is defined as amyloid-β (Aβ) positive but cognitively normal. Identifying at-risk individuals before Aβ reaches pathological levels could have great benefits for early intervention. Although Aβ levels become abnormal long before severe cognitive impairments appear, increasing evidence suggests that subtle cognitive changes may begin early, potentially before Aβ surpasses the threshold for abnormality. We examined whether baseline cognitive performance would predict progression from normal to abnormal levels of Aβ.MethodsWe examined the association of baseline cognitive composites (Preclinical Alzheimer Cognitive Composite, Alzheimer's Disease Neuroimaging Initiative (ADNI) memory factor composite) with progression to Aβ positivity in 292 nondemented, Aβ-negative ADNI participants. Additional analyses included continuous cerebrospinal fluid biomarker levels to examine the effects of subthreshold pathology.ResultsForty participants progressed to Aβ positivity during follow-up. Poorer baseline performance on both cognitive measures was significantly associated with increased odds of progression. More abnormal levels of baseline cerebrospinal fluid phosphorylated tau and subthreshold Aβ were associated with increased odds of progression to Aβ positivity. Nevertheless, baseline ADNI memory factor composite performance predicted progression even after controlling for baseline biomarker levels and APOE genotype (Preclinical Alzheimer Cognitive Composite was trend level). Survival analyses were largely consistent: controlling for baseline biomarker levels, baseline Preclinical Alzheimer Cognitive Composite still significantly predicted progression time to Aβ positivity (ADNI memory factor composite was trend level).ConclusionsThe possibility of intervening before Aβ reaches pathological levels is of obvious benefit. Low-cost, noninvasive cognitive measures can be informative for determining who is likely to progress to Aβ positivity, even after accounting for baseline subthreshold biomarker levels.
| S-EPMC7166153 | biostudies-literature
Project description:Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later Alzheimer-related cognitive decline.To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).Individuals were classified at baseline as having normal (n?=?243) or elevated (n?=?202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid ?.Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30 [best] points), Clinical Dementia Rating Sum of Boxes (CDR-Sum of Boxes; 0 [best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to 25 [best] story units).Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR-Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points [95% CI, 0.94-2.10]; P?<?.001), MMSE (mean difference, 0.56 points [95% CI, 0.32-0.80]; P?<?.001), and CDR-Sum of Boxes (mean difference, 0.23 points [95% CI, 0.08-0.38]; P?=?.002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units [95% CI, -0.02 to 1.48]; P?=?.056).Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.
| S-EPMC5736301 | biostudies-literature
Project description:BackgroundThis study tested if central obesity, hypertension, or depressive symptoms moderated the relationship between β-amyloid (Aβ) and longitudinal cognitive performance in late middle-aged adults enriched for Alzheimer's disease (AD) risk.MethodsParticipants (n = 207; ages = 40-70 years; 73% parental AD) in the Wisconsin Registry for Alzheimer's Prevention study completed 3+ neuropsychological evaluations and a [11C]PiB positron emission tomography scan or lumbar puncture. Linear mixed-effects regression models tested interactions of risk factor × Aβ × visit age on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores.ResultsThe relationship between Aβ and Verbal Learning & Memory decline was moderated by hypertension (χ2(1) = 3.85, P = .04) and obesity (χ2(1) = 6.12, P = .01); those with both elevated Aβ and the risk factor declined at faster rates than those with only elevated Aβ or elevated risk factors.ConclusionIn this cohort, hypertension and obesity moderated the relationship between Aβ and cognitive decline.
| S-EPMC6408972 | biostudies-literature
Project description: We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer's disease (AD) quantitative clinical outcome measures, including amyloid-? (A?), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of A? (A?40, A?42) showed significant but weak trends with cognitive decline (MWM: slope?=?0.336, R2?=?0.149, n?=?259, p?<?0.001; NOR: slope?=?0.156, R2?=?0.064, n?=?116, p?<?0.05); only soluble A? or directly measured A? meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope?=?0.408, R2?=?0.275, n?=?371, p?< <?0.01) and NOR (slope?=?0.319, R2?=?0.176, n?=?113, p?<?0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope?=?0.586, R2?=?0.521, n?=?185, p?< <?0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than A?. Despite pTau's lower physical concentration than A?, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after A? levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3?, GSK3?, CDK5), identified phosphorylated ser9 GSK3? as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than A?. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between A? and pTau, possibly through the GSK3 pathway.
| S-EPMC5734131 | biostudies-literature
Project description:OBJECTIVE: Herpes simplex virus (HSV) reactivation has been identified as a possible risk factor for Alzheimer's disease (AD) and plasma amyloid-beta (A?) levels might be considered as possible biomarkers of the risk of AD. The aim of our study was to investigate the association between anti-HSV antibodies and plasma A? levels. METHODS: The study sample consisted of 1222 subjects (73.9 y in mean) from the Three-City cohort. IgM and IgG anti-HSV antibodies were quantified using an ELISA kit, and plasma levels of A?(1-40) and A?(1-42) were measured using an xMAP-based assay technology. Cross-sectional analyses of the associations between anti-HSV antibodies and plasma A? levels were performed by multi-linear regression. RESULTS: After adjustment for study center, age, sex, education, and apolipoprotein E-e4 polymorphism, plasma A?(1-42) and A?(1-40) levels were specifically inversely associated with anti-HSV IgM levels (??=?-20.7, P=0.001 and ??=?-92.4, P=0.007, respectively). In a sub-sample with information on CLU- and CR1-linked SNPs genotyping (n=754), additional adjustment for CR1 or CLU markers did not modify these associations (adjustment for CR1 rs6656401, ??=?-25.6, P=0.002 for A?(1-42) and ??=?-132.7, P=0.002 for A?(1-40;) adjustment for CLU rs2279590, ??=?-25.6, P=0.002 for A?(1-42) and ??=?-134.8, P=0.002 for A?(1-40)). No association between the plasma A?(1-42)-to-A?(1-40) ratio and anti-HSV IgM or IgG were evidenced. CONCLUSION: High anti-HSV IgM levels, markers of HSV reactivation, are associated with lower plasma A?(1-40) and A?(1-42) levels, which suggest a possible involvement of the virus in the alterations of the APP processing and potentially in the pathogenesis of AD in human.
| S-EPMC3247269 | biostudies-literature
Project description:Subjective cognitive decline (SCD) as an indicator of preclinical Alzheimer's disease (AD) may precede mild cognitive impairment (MCI) over several decades. Self-reported cognitive decline as a typical clinical manifestation is critical in preclinical AD. Metacognition represents a person's ability to accurately assess cognition. Our study aimed to examine (1) the alternations of metamemory in a cohort across the Alzheimer's continuum, (2) the association between metamemory and cognition, and (3) the relationship of cortical thickness in four regions of interest (ROI) with metamemory scores. Six hundred ninety-seven participants were classified as 79 AD dementia, 161 aMCI, 261 SCD, and 196 cognitively unimpaired (CU) individuals, in which 418 participants aged above 65, 131 participants with Aβ+ after receiving positron emission tomography, and 602 participants received sMRI. The degree of confidence (DOC) was measured by calculating discrepancies between judgments and memory performance. We assessed the relationships between DOC tertiles and cognition and analyzed the screening power, then investigated the partial correlation between DOC and ROIs, controlled by age, sex, and cognition. In the Aβ+ subgroup, SCD showed significantly higher DOC scores than the CU group. There was an increasing trend of overconfidence with the decline of cognition across the AD spectrum (P for trend < 0.001). After adjusting for age, sex, and education, the lower degree of confidence-long-term delay recall (DOC-LD) tertiles were associated with lower odds ratio in SCD, aMCI, and AD in the Aβ+ subgroup (all P for trend < 0.05). The area under the curves of DOC scores for screening SCD from CU in the Aβ+ subgroup was better than that in all participants and the age ≥65 subgroup. Partial correlation showed that in the Aβ+ subgroup, DOC-SD (degree of confidence-short-term delay recall) was negatively correlated with the anterior cingulate cortex; DOC-LD was negatively correlated with the cortices of parahippocampal, anterior cingulate, posterior cingulate, and medial orbitofrontal. In individuals with Aβ+, SCD exhibited a detectable metamemory alternation before objective cognitive impairment could be tested, indicated by the overestimation in the memory performance. The pattern of an increasing trend of overconfidence across SCD, aMCI, and AD dementia supports the view of a continuum in Alzheimer's disease.
| S-EPMC9640736 | biostudies-literature
Project description:ObjectiveTo assess in a longitudinal study whether subjective cognitive decline (SCD) and brain β-amyloid (Aβ) contribute unique information to cognitive decline.MethodsOne hundred thirty-six healthy elderly from the Berkeley Aging Cohort Study were followed up for a mean of 4 years. SCD and affective measures were generated from the Geriatric Depression Scale (GDS) with factor analysis on data from a larger set of 347 healthy, nondepressed (GDS <11) elderly individuals. Cognition was summarized with previously validated factor scores. Pittsburgh compound B (PiB)-PET scans were acquired to determine the presence (PiB+) or absence (PiB-) of Aβ pathology. Mixed models were used to assess the independent and interactive effects of SCD, affective features, PiB status, and time on cognition, with adjustment for demographic variables.ResultsSCD score demonstrated good construct validity compared to an existing measure of subjective memory and was partially explained by several lower-order measurements. Mixed models revealed that SCD interacted with PiB status to predict change in episodic memory and global cognition over time, with adjustment for affective features. PiB+ individuals with more severe SCD demonstrated the steepest cognitive decline. Worse SCD predicted faster decline in working memory independently of PiB status. No such effects were seen for affective scores when adjusted for SCD.ConclusionsPiB+ individuals with SCD are at greatest risk of cognitive decline. Evidence for amyloid alone is not sufficient to indicate risk of rapid cognitive decline in healthy elderly. Effects of GDS on cognitive decline in nondepressed cohorts may be driven by SCD rather than subsyndromal depression.
| S-EPMC5679415 | biostudies-literature