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Commonalities in biomarkers and phenotypes between mild cognitive impairment and cerebral palsy: a pilot exploratory study.

ABSTRACT: Clinically, individuals with cerebral palsy (CP) experience symptoms of accelerated biological aging. Accumulative deficits in both molecular underpinnings and functions in young adults with CP can lead to premature aging, such as heart disease and mild cognitive impairment (MCI). MCI is an intermediate stage between healthy aging and dementia that normally develops at old age. Owing to their intriguingly parallel yet "inverted" disease trajectories, CP might share similar pathology and phenotypes with MCI, conferring increased risk for developing dementia at a much younger age. Thus, we examined this hypothesis by evaluating these two distinct populations (MCI= 55, CP = 72). A total of nine measures (e.g., blood biomarkers, neurocognition, Framingham Heart Study Score (FHSS) were compared between the groups. Compared to MCI, upon controlling for covariates, delta FHSS, brain-derived neurotrophic factor (BDNF) levels, and systolic blood pressure were significantly lower in CP. Intriguingly, high-sensitivity CRP, several metabolic outcomes, and neurocognitive function were similar between the two groups. This study supports a shared biological underpinning and key phenotypes between CP and MCI. Thus, we proposed a double-hit model for the development of premature aging outcomes in CP through shared biomarkers. Future longitudinal follow-up studies are warranted to examine accelerated biological aging.

SUBMITTER: Ng TKS

PROVIDER: S-EPMC7880365 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Commonalities in biomarkers and phenotypes between mild cognitive impairment and cerebral palsy: a pilot exploratory study.

Ng Ted Kheng Siang TKS Tagawa Alex A Ho Roger Chun-Man RC Larbi Anis A Kua Ee Heok EH Mahendran Rathi R Carollo James J JJ Heyn Patricia C PC

Aging 20210126 2

Clinically, individuals with cerebral palsy (CP) experience symptoms of accelerated biological aging. Accumulative deficits in both molecular underpinnings and functions in young adults with CP can lead to premature aging, such as heart disease and mild cognitive impairment (MCI). MCI is an intermediate stage between healthy aging and dementia that normally develops at old age. Owing to their intriguingly parallel yet "inverted" disease trajectories, CP might share similar pathology and phenotyp ...[more]

PMID: 33497355

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Project description:<h4>INTRODUCTION Alzheimer's disease is a prevalent disease with a heavy global burden and is suggested to be a metabolic disease in the brain in recent years. The metabolome is considered to be the most promising phenotype which reflects changes in genetic, transcript, and protein profiles as well as environmental effects. Aiming to obtain a comprehensive understanding and convenient diagnosis of MCI and AD from another perspective, researchers are working on AD metabolomics. Urine is more convenient which could reflect the change of disease at an earlier stage. Thus, we conducted a cross-sectional study to investigate novel diagnostic panels.</h4>METHODS We first enrolled participants from China-Japan Friendship Hospital from April 2022 to November 2022, collected urine samples and conducted an LC-MS/MS analysis. In parallel, clinical data were collected and clinical examinations were performed. After statistical and bioinformatics analyzes, significant risk factors and differential urinary metabolites were determined. We attempt to investigate diagnostic panels based on machine learning including LASSO and SVM.RESULTS 57 AD patients, 43 MCI patients and 62 CN subjects were enrolled. A total of 2,140 metabolites were identified among which 125 significantly differed between the AD and CN groups, including 46 upregulated ones and 79 downregulated ones. In parallel, there were 93 significant differential metabolites between the MCI and CN groups, including 23 upregulated ones and 70 downregulated ones. AD diagnostic panel (30 metabolites+ age + APOE) achieved an AUC of 0.9575 in the test set while MCI diagnostic panel (45 metabolites+ age + APOE) achieved an AUC of 0.7333 in the test set. Atropine, S-Methyl-L-cysteine-S-oxide, D-Mannose 6-phosphate (M6P), Spiculisporic Acid, N-Acetyl-L-methionine, 13,14-dihydro-15-keto-tetranor Prostaglandin D2, Pyridoxal 5'-Phosphate (PLP) and 17(S)-HpDHA were considered valuable for both AD and MCI diagnosis and defined as hub metabolites. Besides, diagnostic metabolites were weakly correlated with cognitive functions.DISCUSSION In conclusion, the procedure is convenient, non-invasive, and useful for diagnosis, which could assist physicians in differentiating AD and MCI from CN. Atropine, M6P and PLP were evidence-based hub metabolites in AD.

Project description:Lithium has been used for decades to treat Bipolar Disorder. Some of its therapeutic benefits may be through inhibition of Glycogen Synthase Kinase (GSK)-3. Enhanced GSK3 activity associates with development of Alzheimer's disease (AD), therefore lithium is a currently used therapeutic with potential to be repurposed for prevention of Dementia. An important step toward a clinical trial for AD prevention using lithium is to establish the dose of lithium that blocks GSK3 in Mild Cognitive Impairment (MCI), a high-risk condition for progression to AD. We investigated volunteer recruitment, retention, and tolerance in this population, and assessed biomarkers of GSK3 in MCI compared to control and after lithium treatment. Recruitment was close to target, with higher than anticipated interest. Drop out was not related to lithium blood concentration. Indeed, 33% of the withdrawals were in the first week of very low dose lithium. Most made it through to the highest dose of lithium with no adverse events. We analyzed 18 potential biomarkers of GSK3 biology in rat PBMCs, but only four of these gave a robust reproducible baseline signal. The only biomarker that was modified by acute lithium injection in the rat was the inhibitory phosphorylation of Ser9 of GSK3beta (enhanced in PBMCs) and this associated with reduced activity of GSK3beta. In contrast to the rat PBMC preparations the protein quality of the human PBMC preparations was extremely variable. There was no difference between GSK3 biomarkers in MCI and control PBMC preparations and no significant effect of chronic lithium on the robust GSK3 biomarkers, indicating that the dose reached may not be sufficient to modify these markers. In summary, the high interest from the MCI population, and the lack of any adverse events, suggest that it would be relatively straightforward and safe to recruit to a larger clinical trial within this dosing regimen. However, it is clear that we will need an improved PBMC isolation process along with more robust, sensitive, and validated biomarkers of GSK3 function, in order to use GSK3 pathway regulation in human PBMC preparations as a biomarker of GSK3 inhibitor efficacy, within a clinical trial setting.

Dataset Information

Commonalities in biomarkers and phenotypes between mild cognitive impairment and cerebral palsy: a pilot exploratory study.

Publications

Commonalities in biomarkers and phenotypes between mild cognitive impairment and cerebral palsy: a pilot exploratory study.

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