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Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease.

ABSTRACT: Introduction:As the role of biomarkers is increasing in Alzheimer's disease (AD) clinical trials, it is critical to use a comprehensive temporal biomarker profile that reflects both baseline and longitudinal assessments to establish a more precise association between the change in biomarkers and change in cognition. Because age of onset of dementia symptoms is highly predictable, and there are relatively few age-related comorbidities, the Dominantly Inherited Alzheimer Network autosomal dominant AD population affords a unique opportunity to investigate these relationships in a well-characterized population. Methods:A novel joint statistical model was used to simultaneously evaluate how a comprehensive AD biomarker profile predicts change in cognition using amyloid positron emission tomography (PET), CSF A?42, CSF total tau and Ptau181, cortical metabolism using [F-18] fluorodeoxyglucose-PET, and hippocampal volume from participants enrolled in the Dominantly Inherited Alzheimer Network (n = 262) with mean (SD) duration of follow-up of 2.7 (1.2) years. Results:Baseline amyloid PET levels and CSF biomarkers were associated with change in cognition in contrast to the rate of change of brain metabolism and hippocampal volume, which predicted change in cognition. Conclusions:This study suggests that the baseline value of amyloid PET and CSF A?42 measures may be useful for screening participants for AD trials; however, brain hippocampus atrophy and hypometabolism are only useful as repeated longitudinal assessments for tracking cognition and disease progression. This suggests that measures of amyloid plaques predict future cognitive decline, but only longitudinal measures of neurodegeneration correlate with cognitive decline. The novel statistical model used in this study can be easily applied to any pair of outcomes and has potential to be widely used by the AD research community.

SUBMITTER: Wang G

PROVIDER: S-EPMC6288312 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease.

Wang Guoqiao G Xiong Chengjie C McDade Eric M EM Hassenstab Jason J Aschenbrenner Andrew J AJ Fagan Anne M AM Benzinger Tammie L S TLS Gordon Brian A BA Morris John C JC Li Yan Y Bateman Randall J RJ

Alzheimer's & dementia (New York, N. Y.) 20181207

<h4>Introduction</h4>As the role of biomarkers is increasing in Alzheimer's disease (AD) clinical trials, it is critical to use a comprehensive temporal biomarker profile that reflects both baseline and longitudinal assessments to establish a more precise association between the change in biomarkers and change in cognition. Because age of onset of dementia symptoms is highly predictable, and there are relatively few age-related comorbidities, the Dominantly Inherited Alzheimer Network autosomal ...[more]

PMID: 30569014

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Project description:Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.

Project description:The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.Concentrations of amyloid-beta (A?)(42) in the CSF appeared to decline 25 years before expected symptom onset. A? deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Project description:See Li and Donohue (doi:10.1093/brain/awy089) for a scientific commentary on this article.Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer's disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1.35 years versus 5.54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.

Project description:BackgroundIn fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations.MethodsClinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios.ResultsWe identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation.ConclusionsOur study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD.

Project description:Background: National Institute on Aging-Alzheimer's Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer's disease (AD) as a biological construct. However, the associations between different AT(N) combinations and cognitive progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Methods: A total of 341 participants were classified into cognitively unimpaired (CU; n = 200) and cognitively impaired (CI; n = 141) groups according to the clinical manifestations and neuropsychological tests. Cerebrospinal fluid (CSF) Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), hippocampal volume, temporal cortical thickness, [18F]fluorodeoxyglucose (FDG) PET, and plasma neurofilament light (NfL) were used as biomarkers for (N). Binary biomarkers were obtained from the Youden index and publicly available cutoffs. Prevalence of AT(N) categories was compared between different biomarkers within the group using related independent sample non-parametric test. The relationship between AT(N) combinations and 12-year longitudinal cognition was assessed using linear mixed-effects modeling. Results: Among the CU participants, A-T-(N)- was most common. More T+ were detected using p-tau than tau PET (p < 0.05), and more (N)+ were observed using fluid biomarkers (p < 0.001). A+T+(N)+ was more common in the CI group. Tau PET combined with cortical thickness best predicted cognitive changes in the CI group and MRI predicted changes in the CU group. Conclusions: These findings suggest that optimal AT(N) combinations to determine longitudinal cognition differ by cognitive status. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for future studies.

Project description:IntroductionWhite matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer's disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD.Participants and methodsParticipants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds.ResultsMutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds.DiscussionAlthough there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.

Dataset Information

Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease.

Publications

Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease.

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