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Synergistic effect of ?-amyloid and neurodegeneration on cognitive decline in clinically normal individuals.

ABSTRACT: IMPORTANCE:Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes. OBJECTIVE:To determine whether neuroimaging markers of ?-amyloid (A?) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals. DESIGN, SETTING, AND PARTICIPANTS:Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). MAIN OUTCOMES AND MEASURES:The A? status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (A?-/ND-), stage 1 (A?(+)/ND-), stage 2 (A?(+)/ND(+)), and suspected non-Alzheimer disease pathology (A?-/ND(+)). Cognition was assessed with a composite of neuropsychological tests administered annually. RESULTS:The A?(+) CN individuals were more likely to be classified as ND+: 59.6% of A?(+) CN individuals were ND(+), whereas 31.9% of A?- CN individuals were ND(+) (odds ratio, 3.14; 95% CI, 1.44-7.02; P =?.004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both A? and ND, whereas diminished practice effects were observed in CN individuals positive for either A? or ND. Decline over time was observed only in CN individuals positive for both A? and ND, and decline in this group was significantly greater than that in all other groups (P

SUBMITTER: Mormino EC

PROVIDER: S-EPMC4293023 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals.

Mormino Elizabeth C EC Betensky Rebecca A RA Hedden Trey T Schultz Aaron P AP Amariglio Rebecca E RE Rentz Dorene M DM Johnson Keith A KA Sperling Reisa A RA

JAMA neurology 20141101 11

<h4>Importance</h4>Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes.<h4>Objective</h4>To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals.<h4>Design, setting, and participants</h4>Academic ...[more]

PMID: 25222039

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Project description:Importance:Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and ?-amyloid (A?) pathology commonly co-occur in older adults and are significant causes of cognitive impairment. Objective:To determine whether vascular risk and A? burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including A? burden, hippocampal volume, fludeoxyglucose F18-labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease. Design, Setting, and Participants:In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, A?-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017. Main Outcomes and Measures:Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured A? burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E ?4 status. Results:Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (??=?-0.064; 95% CI, -0.094 to -0.033; P?<?.001) and higher A? burden (??=?-0.058; 95% CI, -0.079 to -0.037; P?<?.001). The interaction of the FHS-CVD risk score and A? burden with time was significant (??=?-0.040, 95% CI, -0.062 to -0.018; P?<?.001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (??=?-0.055; 95% CI, -0.086 to -0.024; P?<?.001), even after adjustment for A? burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities. Conclusions and Relevance:In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with A? burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.

Project description:ImportanceCerebrovascular disease (CVD) and Alzheimer disease are significant causes of cognitive impairment in the elderly. However, few studies have evaluated the relationship between CVD and β-amyloid burden in living humans or their synergistic effects on cognition. Thus, there is a need for better understanding of mild cognitive impairment (MCI) before clinical deterioration begins.ObjectiveTo determine the synergistic effects of β-amyloid burden and CVD on cognition in patients with subcortical vascular MCI (svMCI).Design, setting, and participantsA cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We prospectively recruited 95 patients with svMCI; 67 of these individuals participated in the study. Forty-five patients with amnestic MCI (aMCI) were group matched with those with svMCI by the Clinical Dementia Rating Scale Sum of Boxes.Main outcomes and measuresWe measured β-amyloid burden using positron emission tomography with carbon 11-labeled Pittsburgh Compound B (PiB). Cerebrovascular disease was quantified as white matter hyperintensity volume detected by magnetic resonance imaging fluid-attenuated inversion recovery. Detailed neuropsychological tests were performed to determine the level of patients' cognitive impairment.ResultsOn evaluation, 22 of the svMCI group (33%) and 28 of the aMCI group (62%) were found to be PiB positive. The mean PiB retention ratio was lower in patients with svMCI than in those with aMCI. In svMCI, the PiB retention ratio was associated with cognitive impairments in multiple domains, including language, visuospatial, memory, and frontal executive functions, but was associated only with memory dysfunction in aMCI. A significant interaction between PiB retention ratio and white matter hyperintensity volume was found to affect visuospatial function in patients with svMCI.Conclusions and relevanceMost patients with svMCI do not exhibit substantial amyloid burden, and CVD does not increase β-amyloid burden as measured by amyloid imaging. However, in patients with svMCI, amyloid burden and white matter hyperintensity act synergistically to impair visuospatial function. Therefore, our findings highlight the need for accurate biomarkers, including neuroimaging tools, for early diagnosis and the need to relate these biomarkers to cognitive measurements for effective use in the clinical setting.

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.

Dataset Information

Synergistic effect of ?-amyloid and neurodegeneration on cognitive decline in clinically normal individuals.

Publications

Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals.

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