The Latest Articles on Biomarker in Alzheimer’s Disease
Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on biomarker in Alzheimer’s disease.
Title: Abnormal motor cortical plasticity as a useful neurophysiological biomarker for Alzheimer’s disease pathology
Authors: Takenobu Murakami, Mitsunari Abe, Amanda Tiksnadi, Ayaka Nemoto, Miyako Futamura, Ryo Yamakuni, Hitoshi Kubo, Naoto Kobayashi, Hiroshi Ito, Ritsuko Hanajima, Yasuhiro Hashimoto, Yoshikazu Ugawa
Type: Research Article
Abstract:
Objective
Amyloid-beta (Aβ) and tau accumulations impair long-term potentiation (LTP) induction in animal hippocampi. We investigated relationships between motor-cortical plasticity and biomarkers for Alzheimer’s disease (AD) diagnosis in subjects with cognitive decline.
Methods
Twenty-six consecutive subjects who complained of memory problems participated in this study. We applied transcranial quadripuse stimulation with an interstimulus interval of 5ms (QPS5) to induce LTP-like plasticity. Motor-evoked potentials were recorded from the right first-dorsal interosseous muscle before and after QPS5. Cognitive functions, Aβ42 and tau levels in the cerebrospinal fluid (CSF) were measured. Amyloid positron-emission tomography (PET) with 11C-Pittsburg compound-B was also conducted. We studied correlations of QPS5-induced plasticity with cognitive functions or AD-related biomarkers.
Results
QPS5-induced LTP-like plasticity positively correlated with cognitive scores. The degree of LTP-like plasticity negatively correlated with levels of CSF-tau, and the amount of amyloid-PET accumulation at the precuneus, and correlated with the CSF-Aβ42 level positively. In the amyloid-PET positive subjects, non-responder rate of QPS5 was higher than the CSF-tau positive rate.
Conclusions
Findings suggest that QPS5-induced LTP-like plasticity is a functional biomarker of AD. QPS5 could detect abnormality at earlier stages than CSF-tau in the amyloid-PET positive subjects.
Significance
Assessing motor-cortical plasticity could be a useful neurophysiological biomarker for AD pathology.
Access this article: https://doi.org/10.1016/j.clinph.2023.12.131
Title:Systematic identification of key basement membrane related genes as potential new biomarkers in Alzheimer's disease
Authors: Jia'xing Lin, Jing Chen, Cheng Huang
Type: Research Article
Abstract:
Objective
The study aimed to identify biomarkers associated with basement membranes (BMs)-related genes (BMGs) in Alzheimer's disease (AD) and investigate their potential role in the progression of AD pathology.
Methods
Gene expression profiles were retrieved from Gene Expression Omnibus database. 222 human BMGs were collected from the relevant literature. Subsequently, the differentially expressed BMGs (DE-BMGs) were filtered, and the key DE-BMGs were identified using weighted gene correlation network analysis (WGCNA) and two machine learning algorithms. The expression levels, diagnostic values, clinical significances, enrichment analyses and regulatory networks of these candidate biomarkers were further examined.
Results
A total of 44 DE-BMGs were acquired by comparing AD temporal cortex with nondemented controls. Using WGCNA and machine learning, versiscan (VCAN), tissue inhibitor of metalloproteinase 1 (TIMP1), structural maintenance of chromosome 3 (SMC3), and laminin β2 (LAMB2) were ultimately identified as candidate biomarkers, and they were verified in a murine model. These biomarkers had high diagnostic value (area under the curve (AUC)＞0.8). The diagnostic value of the four gene combination was then evaluated in multiple databases, yielding AUCs ranging from 0.688 to 1. Furthermore, a meaningful correlation between these biomarkers and AD pathology progression was observed. Finally, comprehensive analyses involving Hallmark pathway enrichment, immune cell infiltration analysis, transcriptional regulatory, and competitive endogenous RNA networks indicated that key DE-BMGs closely correlated with oxidative stress and immune dysfunction.
Conclusion
Our study comprehensively identified four candidate BMGs and their combination model that play a crucial part in the diagnosis and pathogenesis of AD.
Access this article: https://doi.org/10.1016/j.clineuro.2023.108094
Title:A multiclass extreme gradient boosting model for evaluation of transcriptomic biomarkers in Alzheimer’s disease prediction
Authors: Yi Zhang, Shasha Shen, Xiaokai Li, Songlin Wang, Zongni Xiao, Jun Cheng, Ruifeng Li
Type: Research Article
Abstract:
Background
Patients with young-onset Alzheimer's disease (AD) (before the age of 50 years old) often lack obvious imaging changes and amyloid protein deposition, which can lead to misdiagnosis with other cognitive impairments. Considering the association between immunological dysfunction and progression of neurodegenerative disease, recent research has focused on identifying blood transcriptomic signatures for precise prediction of AD.
Methods
In this study, we extracted blood biomarkers from large-scale transcriptomics to construct multiclass eXtreme Gradient Boosting models (XGBoost), and evaluated their performance in distinguishing AD from cognitive normal (CN) and mild cognitive impairment (MCI).
Results
Independent testing with external dataset revealed that the combination of blood transcriptomic signatures achieved an area under the receiver operating characteristic curve (AUC of ROC) of 0.81 for multiclass classification (sensitivity = 0.81; specificity = 0.63), 0.83 for classification of AD vs. CN (sensitivity = 0.72; specificity = 0.73), and 0.85 for classification of AD vs. MCI (sensitivity = 0.77; specificity = 0.73). These candidate signatures were significantly enriched in 62 chromosome regions, such as Chr.19p12-19p13.3, Chr.1p22.1-1p31.1, and Chr.1q21.2-1p23.1 (adjusted p < 0.05), and significantly overrepresented by 26 transcription factors, including E2F2, FOXO3, and GATA1 (adjusted p < 0.05). Biological analysis of these signatures pointed to systemic dysregulation of immune responses, hematopoiesis, exocytosis, and neuronal support in neurodegenerative disease (adjusted p < 0.05).
Conclusions
Blood transcriptomic biomarkers hold great promise in clinical use for the accurate assessment and prediction of AD.
Access this article: https://doi.org/10.1016/j.neulet.2023.137609
Title: Neuropsychiatric symptoms in Alzheimer's continuum and their association with plasma biomarkers
Authors: Lin Huang, Qi Huang, Fang Xie, Qihao Guo
Type: Research Article
Abstract:
Background
Little is known about association between neuropsychiatric symptoms and plasma biomarkers across the entire Alzheimer's continuum.
Methods
A total of 305 individuals with amyloid-β (Aβ) deposition (determined by 18F-florbetapir PET) participated in this study, including cognitively normal controls (n = 53), subjective cognitive decline (SCD, n = 75), mild cognitive impairment (MCI, n = 74), and dementia (n = 103). Plasma biomarkers (Aβ1-42, Aβ1-40, total tau [t-tau], phosphorylated tau 181 [p-tau181], and neurofilament light [NfL]), apolipoprotein E (APOE) genotyping and Neuropsychiatric Inventory Questionnaire (NPI-Q) were completed. Neuropsychiatric symptoms were classified into four subsymdromes (hyperactivity, psychosis, affective, and apathy). Logistic regression analysis was conducted to investigate relationships between neuropsychiatric symptoms and plasma biomarkers.
Results
About one-third of cognitively unimpaired individuals (normal controls: 34.0 %, SCD: 28.0 %) reported one or more neuropsychiatric symptoms, and more in symptomatic stages such as MCI (40.5 %) and dementia (81.0 %). Plasma NfL significantly increased in dementia group compared to SCD and healthy controls, relating to a higher risk of aberrant motor behavior, anxiety, sleep disturbance, disinhibition, and euphoria. Older age (odds ratio [OR] = 1.079, 95 % confidence interval [CI] = 1.022–1.140, p = 0.006), lower cognitive score (OR = 0.846, 95%CI = 0.791–0.905, p < 0.001) and increased plasma NfL (OR = 1.021, 95%CI = 1.00–1.042, p = 0.041) could predict psychosis. No significant differences were found in plasma Aβ1-42/Aβ1-40, t-tau or p-tau181 across all groups, and none correlated with neuropsychiatric symptoms.
Limitations
The cross-sectional design, small sample size and use of NPI-Q.
Conclusions
This study supported neuropsychiatric symptoms as early manifestations of preclinical Alzheimer's disease, and suggested plasma NfL to be a potential biomarker for detecting neuropsychiatric symptoms in Alzheimer's continuum.
Access this article: https://doi.org/10.1016/j.jad.2023.12.062
Title: Probable chronic pain, brain structure, and Alzheimer’s plasma biomarkers in older men
Authors: Tyler R. Bell PhD., Carol E. Franz PhD., Lisa T. Eyler PhD., Christine Fennema-Notestine PhD., Olivia K. Puckett BS., Stephen M. Dorros MD., Matthew S. Panizzon PhD., Rahul C. Pearce BS., Donald J. Hagler Jr., PhD., Michael J. Lyons PhD., Asad Beck BA., Jeremy A. Elman PhD., William S. Kremen PhD
Type: Research Article
Abstract:
Chronic pain leads to tau accumulation and hippocampal atrophy in mice. In this study, we provide one of the first assessments in humans, examining the associations of probable chronic pain with hippocampal volume, integrity of the locus coeruleus (LC)—an upstream site of tau deposition—and Alzheimer’s Disease (AD)-related plasma biomarkers. Participants were mostly cognitively unimpaired men. Probable chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, 424 participants underwent structural MRI of hippocampal volume and LC-sensitive MRI providing an index of LC integrity (LC contrast-to-noise ratio [LCCNR]). Analyses adjusted for confounders including major health conditions, depressive symptoms, and opioid use. Models showed that men with probable chronic pain had smaller hippocampal volume and lower rostral-middle—but not caudal—LCCNR compared to men without probable chronic pain. Men with probable chronic pain also had higher levels of plasma total tau, beta-amyloid-42, and beta-amyloid-40 compared to men without probable chronic pain. These findings suggest that probable chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected early in the development of AD.
Access this article: https://doi.org/10.1016/j.jpain.2024.01.006
