Disease progression modelling from preclinical Alzheimer's disease (AD) to AD dementia.
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ABSTRACT:
SUBMITTER: Cho SH
PROVIDER: S-EPMC7893024 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Disease progression modelling from preclinical Alzheimer's disease (AD) to AD dementia.
Cho Soo Hyun SH Woo Sookyoung S Kim Changsoo C Kim Hee Jin HJ Jang Hyemin H Kim Byeong C BC Kim Si Eun SE Kim Seung Joo SJ Kim Jun Pyo JP Jung Young Hee YH Lockhart Samuel S Ossenkoppele Rik R Landau Susan S Na Duk L DL Weiner Michael M Kim Seonwoo S Seo Sang Won SW
Scientific reports 20210218 1
To characterize the course of Alzheimer's disease (AD) over a longer time interval, we aimed to construct a disease course model for the entire span of the disease using two separate cohorts ranging from preclinical AD to AD dementia. We modelled the progression course of 436 patients with AD continuum and investigated the effects of apolipoprotein E ε4 (APOE ε4) and sex on disease progression. To develop a model of progression from preclinical AD to AD dementia, we estimated Alzheimer's Disease ...[more]
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Project description:Alzheimer's disease (AD) is characterized by the progressive alterations seen in brain images which give rise to the onset of various sets of symptoms. The variability in the dynamics of changes in both brain images and cognitive impairments remains poorly understood. This paper introduces AD Course Map a spatiotemporal atlas of Alzheimer's disease progression. It summarizes the variability in the progression of a series of neuropsychological assessments, the propagation of hypometabolism and cortical thinning across brain regions and the deformation of the shape of the hippocampus. The analysis of these variations highlights strong genetic determinants for the progression, like possible compensatory mechanisms at play during disease progression. AD Course Map also predicts the patient's cognitive decline with a better accuracy than the 56 methods benchmarked in the open challenge TADPOLE. Finally, AD Course Map is used to simulate cohorts of virtual patients developing Alzheimer's disease. AD Course Map offers therefore new tools for exploring the progression of AD and personalizing patients care.
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Project description:ImportanceUndetected biological heterogeneity adversely impacts trials in Alzheimer's disease because rate of cognitive decline - and perhaps response to treatment - differs in subgroups. Recent results show that data-driven approaches can unravel the heterogeneity of Alzheimer's disease progression. The resulting stratification is yet to be leveraged in clinical trials.ObjectiveInvestigate whether image-based data-driven disease progression modelling could identify baseline biological heterogeneity in a clinical trial, and whether these subgroups have prognostic or predictive value.DesignScreening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected between April 2014 and December 2017, and longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) observational study downloaded in February 2022 were used.SettingThe A4 Study is an interventional trial involving 67 sites in the US, Canada, Australia, and Japan. ADNI is a multi-center observational study in North America.ParticipantsCognitively unimpaired amyloid-positive participants with a 3-Tesla T1-weighted MRI scan. Amyloid positivity was determined using florbetapir PET imaging (in A4) and CSF Aβ(1-42) (in ADNI).Main outcomes and measuresRegional volumes estimated from MRI scans were used as input to the Subtype and Stage Inference (SuStaIn) algorithm. Outcomes included cognitive test scores and SUVr values from florbetapir and flortaucipir PET.ResultsWe included 1,240 Aβ+ participants (and 407 Aβ- controls) from the A4 Study, and 731 A4-eligible ADNI participants. SuStaIn identified three neurodegeneration subtypes - Typical, Cortical, Subcortical - comprising 523 (42%) individuals. The remainder are designated subtype zero (insufficient atrophy). Baseline PACC scores (A4 primary outcome) were significantly worse in the Cortical subtype (median = -1.27, IQR=[-3.34,0.83]) relative to both subtype zero (median=-0.013, IQR=[-1.85,1.67], P<.0001) and the Subcortical subtype (median=0.03, IQR=[-1.78,1.61], P=.0006). In ADNI, over a four-year period (comparable to A4), greater cognitive decline in the mPACC was observed in both the Typical (-0.23/yr; 95% CI, [-0.41,-0.05]; P=.01) and Cortical (-0.24/yr; [-0.42,-0.06]; P=.009) subtypes, as well as the CDR-SB (Typical: +0.09/yr, [0.06,0.12], P<.0001; and Cortical: +0.07/yr, [0.04,0.10], P<.0001).Conclusions and relevanceIn a large secondary prevention trial, our image-based model detected neurodegenerative heterogeneity predictive of cognitive heterogeneity. We argue that such a model is a valuable tool to be considered in future trial design to control for previously undetected variance.
| S-EPMC9934776 | biostudies-literature
Project description:BackgroundWhile sex differences in incidence of Alzheimer's disease (AD) and potential explanations have received considerable attention, less attention has been paid to possible sex differences in genetic risk for AD.ObjectiveWe examined sex differences in genetic and environmental influences on disease risk and age at onset for All Dementia, AD Only, and Non-AD Dementia.MethodsTwin pairs were drawn from the Swedish Twin Registry. All Dementia analysis included 9,467 pairs; AD only, 8,696 pairs; and non-AD dementia, 8,195 pairs. APOE analyses included 1,740 individual twins with measured ɛ4 alleles. Dementia diagnoses were based on clinical workup and national health registry linkage.ResultsAlthough within-pair correlations for All Dementia and AD Only were higher for women than for men, sex differences did not statistically differ for genetic or environmental etiology of All Dementia, AD Only, and Non-AD dementia. Similar results were observed when looking at specific genetic effects (APOEɛ4). Co-twin control analyses indicated that among twin pairs discordant for dementia, female twins without dementia had approximately 40% greater risk of developing dementia, compared with their male counterparts, in the 2-5 years following the first twin's diagnosis.ConclusionFor All Dementia, AD Only, and Non-AD Dementia, genetic influences could be equated across sex. Co-twin analyses, however, suggest greater risk to female than to male co-twins of dementia cases even though sex differences in either genetic or shared environmental influences on the risk of dementia could not be differentiated.
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Project description:Accumulation of amyloid-? (A?) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer's disease (AD). After almost 15 years from their generation, 3xTg-AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg-AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed A? and tau load, neuroinflammation, and cognitive changes in 2-, 6-, 12-, and 20-month-old female 3xTg-AD and nontransgenic (NonTg) mice. We found that ~80% of the mice analyzed had A? plaques in the caudal hippocampus at 6 months of age, while 100% of them had A? plaques in the hippocampus at 12 months of age. Cortical A? plaques were first detected at 12 months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6-month-old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6-month-old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6 months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD-like pathology in female 3xTg-AD mice, and will facilitate the design of future studies using these mice.
| S-EPMC6351836 | biostudies-other
Project description:INTRODUCTION:Lifetime risks are the probabilities of progressing to Alzheimer's disease (AD) dementia during one's lifespan. Here, we report the first estimates of the lifetime and ten-year risks of AD dementia based on age, gender, and biomarker tests for preclinical disease. METHODS:We used a multistate model for the disease process together with US death rates. RESULTS:Lifetime risks of AD dementia vary considerably by age, gender, and the preclinical or clinical disease state of the individual. For example, the lifetime risks for a female with only amyloidosis are 8.4% for a 90-year old and 29.3% for a 65-year old. Persons younger than 85 years with mild cognitive impairment, amyloidosis, and neurodegeneration have lifetime risks of AD dementia greater than 50%. DISCUSSION:Most persons with preclinical AD will not develop AD dementia during their lifetimes. Lifetime risks help interpret the clinical significance of biomarker screening tests for AD.
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Project description:Neural cells are under immense pressure to maintain proper degradation of molecules using their endo-lysosomal pathway (ELP). In Alzheimer’s disease (AD), the gradual cognitive worsening of this age-related disorder is partially due to dysfunction of the ELP. However, AD is a complex disorder and how the genetic landscape eventually leads to AD is unclear. Sanfilippo syndrome childhood dementia (mucopolysaccharidosis type III, MPSIII) is an extreme consequence of ELP dysfunction, where inherited recessive mutations result in the inability to properly catabolise a particular polysaccharide, which ultimately accumulates and interferes with the function of the ELP. Unlike AD, Sanfilippo is genetically simple (all causative genes are identified). The primary biochemical consequences are understood and animal models of Sanfilippo are considered excellent models of the human disease. Since Sanfilippo and AD show similar pathological changes, they likely share disease-associated mechanisms. Here, we dissect the similarity between AD and Sanfilippo using RNA-seq. We have generated zebrafish knock-in models of both diseases: the early-onset familial AD-like (EOfAD-like) mutation psen1 Q96_K97del and the MPSIII-like mutation naglu A603fs. We generated a family of zebrafish containing wild type, heterozygous EOfAD-like and homozygous MPSIII-like genotypes. We raised the family until 7 days post fertilisation and performed mRNA-seq on n = 8 induvial larvae per genotype. A power calculation revealed that this experiment was only contained ~50% power to detect differentially expressed genes. Nevertheless, changes to the expression of genes encoding proteins involved in lysosomal function could be detected in the MPS-III mutant larvae, suggesting a homeostatic response as the cells which make up the larval RNA-seq samples respond to dysfunctional lysosomes.
2022-11-08 | GSE217196 | GEO
Project description:Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).
| S-EPMC8612719 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) is a common health condition affecting senile people and leads to severe cognitive dysfunctions. Acupuncture has been shown to be a possible alternative natural remedy for AD in some animal studies.ObjectiveTo perform a systematic review to identify the effect of verum-acupuncture compared with sham-acupuncture on learning and memory performance among animal models of AD.MethodsExperimental animal studies of treating AD via verum- and sham- acupuncture were searched in nine electronic databases, including Sciverse ScienceDirect, PubMed, Springer, Ebsco Medline, AMED, EMBASE (Elsevier), Scopus (Elsevier), PsycINFO (ProQuest), and OVID from the dates of the databases' inception to June 2019. The Morris water maze test was considered as an outcome measure. The software Revman 5.3 and Stata 16.0 were used to conduct the meta-analysis. Heterogeneity was examined by using I2 statistics. The publication bias was assessed via Begg's test by Stata 16.0.ResultsTwelve studies involving 229 animals met the inclusion criteria. Most of the studies had a moderate quality according to SYRCLE's risk of bias tool for animal studies. The results of the meta-analysis indicated that verum-acupuncture could reduce the escape latency (MD = -12.90, 95% CI (-17.08, -8.71), p < 0.001) and increase the time spent in the original platform quadrant (MD = 7.28, 95% CI (4.23, 10.33), p < 0.001) and frequency of the crossing former platform (MD = 2.01, 95% CI (1.53, 2.50), p < 0.001) compared with the sham-acupuncture.ConclusionsAcupuncture is effective in improving cognitive functions in AD animal models, and this benefit is more than just a placebo effect. Further clinical trials are needed to confirm the findings.
| S-EPMC7150729 | biostudies-literature