Abstract Background. Parkinson's disease (PD) is frequently accompanied by mood and chronic fatigue syndrome (CFS) symptoms. It is unknown whether immune activation and insulin resistance (IR) or brain injuries impacts the severity of affective and CFS symptoms due to PD. Aims. To examine whether immune, IR, and/or brain injury biomarkers determine affective and CFS symptoms due to PD. Methods. 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). Results. 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, interleukin-10 (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. Discussion. 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.

The authors have declared no competing interest.

There was no funding for this study.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

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.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The database created during this investigation will be provided by the corresponding author (MM) upon a reasonable request once the authors have thoroughly used the data set.