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Longitudinal change of biomarkers in cognitive decline.

ABSTRACT: To delineate the trajectories of A?42 level in cerebrospinal fluid (CSF), fludeoxyglucose F18 (FDG) uptake using positron emission tomography, and hippocampal volume using magnetic resonance imaging and their relative associations with cognitive change at different stages in aging and Alzheimer disease (AD).Cohort study.The 59 study sites for the Alzheimer's Disease Neuroimaging Initiative.A total of 819 participants 55 to 90 years of age with normal cognition, mild cognitive impairment, and AD who were followed up during the period from 2005 to 2007.Rates of change in level of A?42 in CSF, FDG uptake, hippocampal volume, and the Alzheimer Disease's Assessment Scale-cognitive subscale score during up to 36 months of follow-up by diagnostic group as well as prediction of cognitive change by each biomarker.Reductions in the level of A?42 in CSF were numerically greater in participants with normal cognition than in participants with mild cognitive impairment or AD; whereas both glucose metabolic decline and hippocampal atrophy were significantly slower in participants with normal cognition than in participants with mild cognitive impairment or AD. Positive APOE4 status accelerated hippocampal atrophic changes in participants with mild cognitive impairment or AD, but did not modify rates of change in level of A?42 in CSF or FDG uptake. The Alzheimer Disease's Assessment Scale-cognitive subscale scores were related only to the baseline level of A?42 in CSF and the baseline FDG uptake in participants with normal cognition, which were about equally associated with change in FDG uptake and hippocampal volume in participants with mild cognitive impairment and best modeled by change in FDG uptake in participants with AD.Trajectories of A?42 level in CSF, FDG uptake, and hippocampal volume vary across different cognitive stages. The longitudinal patterns support a hypothetical sequence of AD pathology in which amyloid deposition is an early event before hypometabolism or hippocampal atrophy, suggesting that biomarker prediction for cognitive change is stage dependent.

SUBMITTER: Lo RY

PROVIDER: S-EPMC5604752 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Longitudinal change of biomarkers in cognitive decline.

Lo Raymond Y RY Hubbard Alan E AE Shaw Leslie M LM Trojanowski John Q JQ Petersen Ronald C RC Aisen Paul S PS Weiner Michael W MW Jagust William J WJ

Archives of neurology 20110613 10

<h4>Objective</h4>To delineate the trajectories of Aβ42 level in cerebrospinal fluid (CSF), fludeoxyglucose F18 (FDG) uptake using positron emission tomography, and hippocampal volume using magnetic resonance imaging and their relative associations with cognitive change at different stages in aging and Alzheimer disease (AD).<h4>Design</h4>Cohort study.<h4>Setting</h4>The 59 study sites for the Alzheimer's Disease Neuroimaging Initiative.<h4>Participants</h4>A total of 819 participants 55 to 90 ...[more]

PMID: 21670386

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Project description:ImportanceAlzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.ObjectiveTo evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.Design, setting, and participantsThis prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.ExposuresBaseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.Main outcomes and measuresThe primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.ResultsAmong 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.Conclusions and relevanceIn this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

Project description:PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer's disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Patients and methodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer's Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

Project description:BackgroundWe explored fine motor skills (FMS) before and after brain radiotherapy (RT), analyzing associations between longitudinal FMS and imaging biomarkers of cortical and white matter (WM) integrity in motor regions of interest (ROIs).MethodsOn a prospective trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric brain MRI, diffusion tensor imaging, and FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], Grooved Pegboard Dominant Hands [PDH], and Grooved Pegboard Nondominant Hands [PNDH]) at baseline and 3-, 6-, and 12-month post-RT. Motor ROIs autosegmented included: sensorimotor cortices and superficial WM, corticospinal tracts, cerebellar cortices and WM, and basal ganglia. Volume (cc) was measured in all ROIs at each timepoint. Diffusion biomarkers (FA [fractional anisotropy] and MD [mean diffusivity]) were additionally measured in WM ROIs. Linear mixed-effects models assessed biomarkers as predictors of FMS scores. P values were corrected for multiple comparisons.ResultsHigher RT dose was associated with right paracentral cortical thinning (β = -2.42 Gy/(month × mm), P = .03) and higher right precentral WM MD (β = 0.69 Gy/(month × µm2/ms), P = .04). Higher left (β = 38.7 points/(month × µm2/ms), P = .004) and right (β = 42.4 points/(month × µm2/ms), P = .01) cerebellar WM MD, left precentral cortical atrophy (β = -8.67 points/(month × mm), P = .02), and reduced right cerebral peduncle FA (β = -0.50 points/month, P = .01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (β = -17.3 points/(month × mm), P = .02). Left (β = -0.87 points/(month × cm3), P = .001) and right (β = -0.64 points/(month × cm3), P = .02) cerebellar cortex, left pons (β = -19.8 points/(month × cm3), P = .02), and right pallidum (β = -10.8 points/(month × cm3), P = .02) atrophy and reduced right internal capsule FA (β = -1.02 points/month, P = .03) were associated with worse PNDH performance.ConclusionsBiomarkers of microstructural injury in motor-associated brain regions were associated with worse FMS. Dose avoidance in these areas may preserve FMS.

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Longitudinal change of biomarkers in cognitive decline.

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Longitudinal change of biomarkers in cognitive decline.

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