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Metabolomics in Neurodegenerative Diseases, 2nd Edition
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Metabolomics in Neurodegenerative Diseases, 2nd Edition

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Cell Metabolism".

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 6275

Special Issue Editors

Dr. Stewart Francis Graham

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Guest Editor
Metabolomics Department, Corewell Health Research Institute, 3811 W. 13 Mile Road, Royal Oak, MI 49546, USA
Interests: Alzheimer’s disease; mild cognitive impairment; Parkinson’s disease; delirium; neurodegeneration; metabolomics; biomarkers; biochemistry; etiology; pathophysiology
Special Issues, Collections and Topics in MDPI journals
Dr. Nazia M. Saiyed

E-Mail Website
Guest Editor
Metabolomics Division, Beaumont Research Institute, 3811 W. 13 Mile Road, Royal Oak, MI 48073, USA
Interests: delirium; Alzheimer’s disease; Parkinson’s disease; metabolomics; biomarkers; biochemistry; etiology; pathophysiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The application of metabolomics in neurodegenerative diseases could provide molecular insights into conditions such as Alzheimer's disease and Parkinson's disease. This promising discipline scrutinizes the intricate metabolic profiles of biological systems, aiding in the identification of biomarkers, unraveling disease mechanisms, and enhancing diagnostic precision. By employing advanced analytical techniques, such as mass spectrometry and nuclear magnetic resonance spectroscopy, researchers can evaluate the alterations in metabolite patterns associated with neurodegeneration. These alterations encompass a disrupted energy metabolism, aberrant lipid processing, and amino acid imbalances, offering valuable information regarding the intricate pathophysiology of these diseases. Metabolomics also offers opportunities for the development of novel therapeutic targets and personalized interventions. However, challenges related to standardization, data integration, and understanding the causative relationships remain. This Special Issue of Metabolites underscores the role of metabolomics in enhancing our comprehension of neurodegenerative disorders, fostering innovative diagnostic avenues and treatment strategies.

Dr. Stewart Francis Graham
Dr. Nazia M. Saiyed
Guest Editors

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Keywords

  • neurodegenerative disease
  • Alzheimer’s
  • Parkinson’s
  • Huntington’s
  • ALS
  • neurodegeneration
  • bi-omarkers
  • metabolism
  • etiology
  • pathophysiology
  • biochemistry

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Published Papers (4 papers)

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Research

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21 pages, 2263 KB  
Article
Longitudinal, Intra-Individual Stability of Untargeted Plasma and Cerebrospinal Fluid Metabolites
by Briana Rocha, Erin M. Jonaitis, Alana Hamwi and Corinne D. Engelman
Metabolites 2026, 16(1), 35; https://doi.org/10.3390/metabo16010035 - 30 Dec 2025
Viewed by 840
Abstract
Background/Objectives: Longitudinal metabolomics analysis offers valuable insights into how metabolic pathways change according to age and health status. However, metabolite levels can fluctuate due to biological factors (e.g., age, diet, and health status) and technical factors (e.g., sample handling, storage times, and instrument [...] Read more.
Background/Objectives: Longitudinal metabolomics analysis offers valuable insights into how metabolic pathways change according to age and health status. However, metabolite levels can fluctuate due to biological factors (e.g., age, diet, and health status) and technical factors (e.g., sample handling, storage times, and instrument performance), with some metabolites exhibiting greater sensitivity to these sources of variability than others. This study aimed to characterize the longitudinal and technical stability of untargeted plasma and cerebrospinal fluid (CSF) metabolites and to identify a subset that remains reliable over the extended time scales required for epidemiological research. Methods: Untargeted ultrahigh-performance liquid chromatography–mass spectrometry (LC-MS) metabolomic profiles were available from multiple visits in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Research Center (ADRC) studies. For this analysis, we constructed a subset of generally healthy participants with samples drawn at four time points (~2.5 years apart): two visits analyzed in 2017 and two visits analyzed in 2023, corresponding to two distinct analytical waves. We computed Rothery’s intraclass correlation coefficients (ICCs) to quantify intra-wave and inter-wave stability, evaluated pooled quality-control (QC) variation, classified metabolite stability by established thresholds, and developed a composite score integrating longitudinal stability and susceptibility to technical variance. Results: Across all metabolites, median stability was classified as ‘fair’ (Rothery’s ρ > 0.40 to ≤0.75) for both plasma and CSF. Although analytical batches were bridged using pooled QC samples, inter-wave stability was significantly lower than intra-wave stability, reflecting increased technical variability across waves. Using the composite score, we identified subsets of metabolites with ‘excellent’ stability and low susceptibility to batch effects in plasma and CSF. Stability patterns varied across biochemical super pathways. Conclusions: This work highlights metabolites suitable for long-term epidemiological studies and informs experimental design and analytical strategies for combining data across cohorts and analytical batches. Full article
(This article belongs to the Special Issue Metabolomics in Neurodegenerative Diseases, 2nd Edition)
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20 pages, 8620 KB  
Article
Multi-Omics Analysis Reveals Distinct Lipid Remodelling and Mitochondrial Stress in SH-SY5Y Cells Modelling Parkinson’s Disease
by Shu Wang, Zhen Ni, Gaoge Wang, Jingzheng Zhang, Yunfu Tan, Enliang Hong, Yunting Wang, Huan Chen, Hongwei Hou and Qingyuan Hu
Metabolites 2025, 15(12), 781; https://doi.org/10.3390/metabo15120781 - 4 Dec 2025
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Abstract
Background: Neurotoxin-based in vitro models are commonly used to replicate the mitochondrial dysfunction and oxidative stress associated with Parkinson’s disease (PD). While these models reproduce similar hallmark features of PD pathology, their capacity to capture lipid dysregulation remains less well defined. In [...] Read more.
Background: Neurotoxin-based in vitro models are commonly used to replicate the mitochondrial dysfunction and oxidative stress associated with Parkinson’s disease (PD). While these models reproduce similar hallmark features of PD pathology, their capacity to capture lipid dysregulation remains less well defined. In particular, it is unclear whether different neurotoxins induce distinct glycerophospholipid (GPL) alterations that reflect upstream mechanisms driving mitochondrial impairment. Methods: We conducted a comparative multi-omics analysis in SH-SY5Y cells treated with either 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+). Lipidomic profiling focused on GPL composition, while transcriptomic changes and organelle stress responses were assessed in parallel, including mitochondrial morphology and lipid droplet accumulation. Results: A total of 389 GPL species were identified. MPP+ suppressed the expression of mitochondrial genome-encoded respiratory genes and increased polyunsaturated 20:4 GPL species, while selectively depleting odd-chain lipids. In contrast, 6-OHDA activated pathways related to ferroptosis and endoplasmic reticulum stress, along with an accumulation of 20:3 enriched GPLs. In addition, GPL profiles in MPP+-treated cells showed a stronger similarity to previously reported alterations in PD patient brain tissue. Despite inducing some shared phenotypes such as lipid droplet accumulation and mitochondrial fragmentation, the two models displayed divergent molecular responses. Conclusions: Our findings reveal that MPP+ and 6-OHDA drive fundamentally different patterns of GPL remodelling and cellular stress. These results highlight lipid remodelling as a mechanistic indicator of neurotoxin-induced mitochondrial dysfunction and suggest that the MPP+ model may provide greater relevance for investigating GPL-related processes in PD. Full article
(This article belongs to the Special Issue Metabolomics in Neurodegenerative Diseases, 2nd Edition)
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24 pages, 4582 KB  
Article
Multiple Hits on Cerebral Folate, Tetrahydrobiopterin and Dopamine Metabolism in the Pathophysiology of Parkinson’s Disorder: A Limited Study of Post-Mortem Human Brain Tissues
by Dhruti Balakrishna Doddaballapur, Derren J. Heyes and Jaleel A. Miyan
Metabolites 2025, 15(5), 307; https://doi.org/10.3390/metabo15050307 - 5 May 2025
Cited by 3 | Viewed by 3151
Abstract
Background: Parkinson’s disorder (PD) affects around 1:500 individuals and is associated with enlarged ventricles and symptoms of normal pressure hydrocephalus (NPH). These features suggest disrupted cerebrospinal fluid (CSF) dynamics and folate metabolism. With L-DOPA treatment showing diminishing benefits over time, there is [...] Read more.
Background: Parkinson’s disorder (PD) affects around 1:500 individuals and is associated with enlarged ventricles and symptoms of normal pressure hydrocephalus (NPH). These features suggest disrupted cerebrospinal fluid (CSF) dynamics and folate metabolism. With L-DOPA treatment showing diminishing benefits over time, there is an urgent need to investigate upstream metabolic disruptions, including folate and tetrahydrobiopterin (BH4) pathways, in post-mortem CSF and brain tissue to understand their roles in PD pathogenesis. Methods: CSF and brain tissue from 20 PD patients (mean age 84 years; 55% male; disease duration 10–30 years) and 20 controls (mean age 82 years; 50% male) were analysed. Western and Dot Blots measured proteins and metabolites, spectroscopic assays assessed enzyme activities, BH4 and Neopterin levels were measured using ELISA, and levels of hydrogen peroxide, used as a proxy for reactive oxygen species, and calcium were quantified using horseradish peroxidase and flame photometry assays, respectively. ClinVar genetic data were analysed for variants in genes encoding key enzymes. Statistical significance was assessed using unpaired t-tests (p < 0.05). Results: All enzymes were significantly reduced in PD compared to controls (p < 0.01) except for methyltetrahydrofolate reductase (MTHFR), which was elevated (p < 0.0001). Enzymes were functional in control but undetectable in PD CSF except tyrosine hydroxylase (TH). BH4 and Neopterin were elevated in PD CSF (p < 0.0001, p < 0.001) but significantly reduced (p < 0.001) or unchanged in tissue. Peroxide was increased in both PD CSF (p < 0.001) and tissue (p < 0.0001) selectively inhibiting TH. Calcium was 40% higher in PD than controls (p < 0.05). No pathogenic variants in enzyme genes were found in ClinVar data searches, suggesting the observed deficiencies are physiological. Conclusions: We identified significant disruptions in folate and BH4 pathways in PD, with enzyme deficiencies, oxidative stress and calcium dysregulation pointing to choroid plexus dysfunction. These findings highlight the choroid plexus and CSF as key players in cerebral metabolism and promote further exploration of these as therapeutic targets to address dopaminergic dysfunction and ventricular enlargement in PD. Full article
(This article belongs to the Special Issue Metabolomics in Neurodegenerative Diseases, 2nd Edition)
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Review

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18 pages, 1490 KB  
Review
Physiological Functions of Side-Chain-Retaining Sterols in the Brain and Their Roles in Neurodegenerative Diseases
by Yoshimitsu Kiriyama, Akira Nakatsuma, Hiroshi Tokumaru, Hisayo Sadamoto and Hiromi Nochi
Metabolites 2026, 16(3), 189; https://doi.org/10.3390/metabo16030189 - 11 Mar 2026
Viewed by 700
Abstract
Although the brain comprises only 2% of total body weight, it contains approximately 23% of the total cholesterol of the body. In the brain, cholesterol plays a critical role as a structural component of cell membranes and myelin sheaths. However, the blood–brain barrier [...] Read more.
Although the brain comprises only 2% of total body weight, it contains approximately 23% of the total cholesterol of the body. In the brain, cholesterol plays a critical role as a structural component of cell membranes and myelin sheaths. However, the blood–brain barrier restricts cholesterol influx from the systemic circulation into the brain. As a result, the brain synthesizes cholesterol de novo and regulates its metabolism independently. Desmosterol, a cholesterol precursor produced during cholesterol biosynthesis, and cholesterol metabolites, 24S-hydroxycholesterol and chenodeoxycholic acid, are sterols with structurally retained side chains. These side-chain-retaining sterols have traditionally been regarded as intermediates in the cholesterol synthesis process or as metabolites for cholesterol excretion, but accumulating evidence indicates that they also function as physiologically active signaling molecules that influence brain function via nuclear receptors, such as liver X receptors, and membrane receptors, such as NMDA receptors. Through nuclear receptors, these side-chain-retaining sterols regulate the transcription of genes involved in lipid transport, inflammation control, and amyloid clearance, while their membrane receptor action enables rapid synaptic effects. These side-chain-retaining sterols mediate metabolic crosstalk between neurons and glial cells and contribute to maintaining cholesterol balance in the developing brain. Furthermore, these side-chain-retaining sterols have been shown to affect amyloid-β clearance, α-synuclein aggregation, neuroinflammation, mitochondrial function, and remyelination. Dysregulation of these side-chain-retaining sterols is associated with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Overall, side-chain-retaining sterols are important regulators of brain physiology. This review focuses on the current knowledge regarding the physiological functions of side-chain-retaining sterols in the brain and their roles in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Metabolomics in Neurodegenerative Diseases, 2nd Edition)
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