Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD.
Ontology highlight
ABSTRACT:
SUBMITTER: Schindler SE
PROVIDER: S-EPMC4483518 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD.
Schindler Suzanne Elizabeth SE Fagan Anne M AM
Frontiers in neurology 20150629
Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, co ...[more]
Similar Datasets
Project description:1H magnetic resonance spectroscopy (MRS) can reveal changes in brain biochemistry in vivo in humans and has been applied to late onset Alzheimer disease (AD). Carriers of mutations for autosomal dominant Alzheimer disease (ADAD) may show changes in levels of metabolites prior to the onset of clinical symptoms. Proton MR spectra were acquired at 1.5 T for 16 cognitively asymptomatic or mildly symptomatic mutation carriers (CDR?<?1) and 11 non-carriers as part of a comprehensive cross-sectional study of preclinical ADAD. Levels of N-acetyl-aspartate+N-acetyl-aspartyl-glutamate (NAA), glutamate/glutamine (Glx), creatine/phosphocreate (Cr), choline (Cho), and myo-inositol (mI) in the left and right anterior cingulate and midline posterior cingulate and precuneus were compared between mutation carriers (MCs) and non-carriers (NCs) using multivariate analysis of variance with age as a covariate. Among MCs, correlations between metabolite levels and time until expected age of dementia diagnosis were calculated. MCs had significantly lower levels of NAA and Glx in the left pregenual anterior cingulate cortex, and lower levels of NAA and higher levels of mI and Cho in the precuneus compared to NCs. Increased levels of mI were seen in these regions in association with increased proximity to expected age of dementia onset. MRS shows effects of ADAD similar to those seen in late onset AD even during the preclinical period including lower levels of NAA and higher levels of mI. These indices of neuronal and glial dysfunction might serve as surrogate outcome measures in prevention studies of putative disease-modifying agents.
| S-EPMC6295351 | biostudies-literature
Project description:Background"Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.
| S-EPMC10729487 | biostudies-literature
Project description:The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.
| S-EPMC3880800 | biostudies-literature
Project description:BackgroundHyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s).MethodsIn autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD.ResultsThe WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss.ConclusionsWe identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.
| S-EPMC9701560 | biostudies-literature
Project description:ImportanceIndividuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined.ObjectiveTo characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals.Design, setting, and participantsAs part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 (Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up.Main outcomes and measuresChanges in Aβ40, Aβ42, total tau, P-tau181, VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding.ResultsWhile there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau181, and VILIP-1) dramatically increased in some individuals in mid and late middle age (P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P ≤ .003). These patterns were more apparent in at-risk ε4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR.Conclusions and relevanceLongitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.
| S-EPMC4570860 | biostudies-literature
Project description:ObjectiveRecent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).MethodsTwo sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.ResultsBaseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.ConclusionThese results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.
| S-EPMC7238945 | biostudies-literature
Project description:IntroductionAs the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others.MethodsWe used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation.ResultsThree primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors.DiscussionThese results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.
| S-EPMC9525451 | biostudies-literature
Project description:Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-?1-42 (A?1-42) associated with the presence of A? plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.
| S-EPMC4038930 | biostudies-literature
Project description:IMPORTANCE:Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. OBJECTIVE:To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS:We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURES:For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTS:A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCE:Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.
| S-EPMC4240274 | biostudies-literature
Project description:OBJECTIVE:To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with 11C-deuterium-L-deprenyl (11C-DED)-PET, in familial autosomal-dominant Alzheimer disease (ADAD). METHODS:The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent 11C-DED-PET. RESULTS:Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between 11C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, 11C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness. CONCLUSIONS:Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.
| S-EPMC7282881 | biostudies-literature