Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 1;15(1):20647.
doi: 10.1038/s41598-025-07735-7.

Affective and chronic fatigue symptoms are associated with serum neuronal damage markers in Parkinson's disease

Hussein Kadhem Al-Hakeim  1   2   3 , Hayder Naji Khudhair  3 , Sayed-Omid Ranaei-Siadat  4 , Fataneh Fatemi  4 , Fateme Mirzajani  4 , Mengqi Niu  1   2 , Michael Maes  5   6   7   8   9   10   11   12   13
Affiliations

Affective and chronic fatigue symptoms are associated with serum neuronal damage markers in Parkinson's disease

Hussein Kadhem Al-Hakeim et al. Sci Rep. .

Abstract

Parkinson's disease (PD) is frequently accompanied by mood and chronic fatigue syndrome (CFS) symptoms. The aim of this study is to examine whether the affective and CFS symptoms due to PD are associated with serum biomarkers of neuronal injury in association with immune activation and insulin resistance. Using a case (70 PD patients) control (60 healthy controls) study design, we assessed affective and CFS symptoms, measured the peripheral immune-inflammatory response system (IRS) using interleukin-6 (IL-6), IL-10, zinc, and calcium levels, the Homeostasis Model Assessment 2 insulin resistance (HOMA2IR) index, and serum brain injury markers including S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), phosphorylated tau217 (pTau217), and glial fibrillary acidic protein (GFAP). The aim is to examine whether immune, IR, and/or brain injury biomarkers determine affective and CFS symptoms due to PD. PD patients showed increased affective and CFS scores, IRS activation, HOMA2IR, NSE, GFAP, pTau217, and S100B levels as compared to controls. A large part (52.5%) of the variance in the mood + CFS score was explained by the regression on NSE, S100B, HOMA2IR index, IL-10 (all positively), and calcium (inversely). The HOMA2IR and IRS indices were significantly associated with all 4 brain injury biomarkers. A large part of the variance in the latter markers (37.0%) was explained by the cumulative effects of the IRS and HOMA2IR indices. IRS activation and IR in patients with PD contribute to damage to glial cell projections and type III intermediate filament, which in turn contribute to affective and CFS symptoms.

Keywords: Biomarkers; Chronic fatigue syndrome; Depression; Inflammation; Mood disorders; Neuroimmune.

PubMed Disclaimer

Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study has been approved by the institutional ethics committee of the University of Kufa (2109/2023). The study adhered to both Iraqi and international ethical and privacy laws, including the International Conference on Harmonization of Good Clinical Practice, the Belmont Report, the CIOMS Guidelines, and the World Medical Association’s Declaration of Helsinki. Before participating in this study, each subject provided written informed consent.

Figures

Fig. 1
Fig. 1
Flow chart showing the flow of the healthy controls (HC) and patients with Parkinson’s disease (PD) through the study. PD patients were divided using affective (MOOD) and chronic fatigue syndrome (CFS) symptoms into those with low versus high MOOD + CFS scores. The latter were based on part I or non-motor Experiences of Daily Living. Mg: magnesium, Ca: calcium, Cu: copper, Zn zinc.
Fig. 2
Fig. 2
Partial regression of neuron-specific enolase (NSE) on a composite reflecting the immune-inflammatory response system (Comp_IRS) after adjusting for age and sex (p < 0.001).
Fig. 3
Fig. 3
Partial regression of a composite score reflecting glial cell projection damage (Comp_GPT) on a composite score reflecting the immune-inflammatory response system (Comp_IRS) (p < 0.001).
Fig. 4
Fig. 4
Partial regression of a composite score reflecting glial cell projection damage (Comp_GPT) on the Homeostasis Model Assessment 2 of insulin resistance (HOMA2IR) (p < 0.001).
Fig. 5
Fig. 5
Results of gene network analysis performed on 4 genes, namely MAPT (tau), S100 calcium-binding protein B (S100B), ENO2 (neuron-specific enolase or NSE), and glial fibrillary acidic protein (GFAP). Left figure: the gene network; right figure: results of subcellular localization compartments enrichment (terms are sorted by strength).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Uwishema, O. et al. The Understanding of parkinson’s disease through genetics and new therapies. Brain Behav.12, e2577. 10.1002/brb3.2577 (2022). - PMC - PubMed
    1. Saini, N. et al. Motor and non-motor symptoms, drugs, and their mode of action in parkinson’s disease (PD): a review. Med. Chem. Res., 1–20 (2024).
    1. Silva, A. B. R. L. et al. Premotor, nonmotor and motor symptoms of parkinson’s disease: a new clinical state of the Art. Ageing Res. Rev.84, 101834 (2023). - PubMed
    1. Hirsch, E. C. & Hunot, S. Neuroinflammation in parkinson’s disease: a target for neuroprotection? Lancet Neurol.8, 382–397 (2009). - PubMed
    1. Butkovich, L. M., Houser, M. C. & Tansey, M. G. α-synuclein and noradrenergic modulation of immune cells in parkinson’s disease pathogenesis. Front. NeuroSci.12, 626 (2018). - PMC - PubMed