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A prospective cohort study of prodromal Alzheimer's disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA).

ABSTRACT: This prospective cohort study, "Prospective Imaging Study of Ageing: Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

SUBMITTER: Lupton MK

PROVIDER: S-EPMC7750170 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A prospective cohort study of prodromal Alzheimer's disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA).

Lupton Michelle K MK Robinson Gail A GA Adam Robert J RJ Rose Stephen S Byrne Gerard J GJ Salvado Olivier O Pachana Nancy A NA Almeida Osvaldo P OP McAloney Kerrie K Gordon Scott D SD Raniga Parnesh P Fazlollahi Amir A Xia Ying Y Ceslis Amelia A Sonkusare Saurabh S Zhang Qing Q Kholghi Mahnoosh M Karunanithi Mohan M Mosley Philip E PE Lv Jinglei J Borne Léonie L Adsett Jessica J Garden Natalie N Fripp Jurgen J Martin Nicholas G NG Guo Christine C CC Breakspear Michael M

NeuroImage. Clinical 20201208

This prospective cohort study, "Prospective Imaging Study of Ageing: Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of d ...[more]

PMID: 33341723

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Project description:IntroductionThe number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients' cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI.Methods and analysisThe ongoing study is a 4-year randomised clinical trial comparing patients' physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve.Ethics and disseminationThis protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals.Trial registration numberNCT03138018.

Project description:Introduction: Brain plasticity, synaptic regeneration and neuroinflammation are crucial mechanisms that play important roles in the recovery from acute brain injuries, such as aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI). The p75 neurotrophic receptor (p75NTR) is a significant receptor that modulates brain plasticity, neuroinflammation and apoptosis, making it an interesting target for therapeutic interventions. However, despite the progress made in understanding the molecular mechanisms involved in brain plasticity and neuroinflammation, there are still significant knowledge gaps in identifying protein biomarkers and microRNAs (miRNAs) associated with different types of acute brain injuries. Addressing these gaps will be critical in advancing our understanding of the underlying mechanisms involved in brain injury and developing effective therapies or prognostic strategies for recovery. Hypotheses: We hypothesized that changes in serum levels of p75NTR and its linked neuroinflammatory signaling proteins could predict recovery from acute brain injuries, regardless of injury type. Differentially expressed (DE) circulating miRNAs following acute brain injuries may regulate studied protein targets and overall injury outcome. Methods: A prospective cohort of 74 patients with ischemic stroke (n=30), aneurysmal subarachnoid hemorrhage (n=31), and traumatic brain injury (n=13) was evaluated. Serum samples were collected at two time points after the injury (early at 1.9 ± 1.0 days and late at 5.9 ± 2.2 days) and outcome evaluation was performed after three months. Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1, TNF, and cyclophilin A. A 2-tailed 2-sample t-test, univariate, and multivariate linear discriminant analysis (LDA) was used to compare serum molecules between patients with favorable (modified Rankin Scale (mRS) 0-3) and unfavorable outcome (mRS 4-6). Additionally, circulating miRNAs were extracted from the samples (n=48, early and late) and DE miRNAs were identified using DESeq2. The miRNA putative target genes were predicted and LDA was performed using the normalized expression values of identified DE miRNAs. Results: In this study, p75NTR (p < 0.01) and IL1 (p < 0.05) were found to be independently associated with outcome among the six circulating protein biomarkers studied. Combinatory LDA analysis of all six biomarkers showed significant predictive value for favorable outcome (OR 2.95 (1.46-5.98); area under the curve (AUC)= 71.2%, 95% CI = (0.590-0.833), p = 0.003). Temporal alterations of miRNA expression were observed in the aSAH, TBI, and IS groups (p<0.05, FDR corrected). Twenty-three common miRNAs were identified that differentiated favorable and unfavorable outcome (p<0.05) in all three groups. LDA of four identified miRNAs with predicted targets to studied proteins showed high predictive accuracy (OR (95% CI) 11.7 (2.39-226)); AUC = 94.1%, 95% CI = (0.849 - 1.00), p = 0.016). Conclusions This study indicates that assessing serum levels of p75NTR and its mechanistically linked proteins can predict recovery outcome in patients with different types of acute brain injuries. The combined miRNA and protein biomarker models demonstrated accurate outcome prediction across diverse injury types, implying the presence of a common recovery mechanism. DE miRNAs were found to target the studied molecules, suggesting a potential mechanistical role in recovery. The identified common miRNAs may provide new targets for mechanistic validation in disease models. Further investigation is warranted to validate and explore the potential of these proteins and miRNAs in prognostication and as therapeutic targets for enhancing recovery from acute brain injuries.

Project description:Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-β aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-β in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-β aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-β aggregates, including soluble amyloid-β oligomers. Different soluble amyloid-β oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-β oligomers previously described in mouse models-amyloid-β trimers, Aβ*56 and amyloid-β dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-β trimers appear to be the fundamental amyloid-β assembly unit of Aβ*56 and are present in young mice prior to memory decline, amyloid-β trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. Aβ*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-β dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between Aβ*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between Aβ*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-β dimers or amyloid-β trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-β dimers, but the lowest levels of Aβ*56 and amyloid-β trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults Aβ*56 increased ahead of amyloid-β dimers or amyloid-β trimers, and pathological tau proteins and postsynaptic proteins correlated with Aβ*56, but not amyloid-β dimers or amyloid-β trimers. We propose that Aβ*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.

Dataset Information

A prospective cohort study of prodromal Alzheimer's disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA).

Publications

A prospective cohort study of prodromal Alzheimer's disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA).

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