Objective: The aim of the present study was to test the hypothesis that central fatigue in Parkinson’s disease (PD) could be related to high levels of extracellular glutamate associated to neuroinflammation, by verifying the impact of safinamide, a drug that targets both dopaminergic and glutamatergic systems, in reducing this symptom.

Background: Central fatigue, defined as a failure in initiating and maintaining both attentional and physical tasks that require self-motivation, is a common and disabling non motor symptom of PD [1,2]. Even if dopamine loss is crucial in the development of PD clinical picture, other mechanisms may be implicated in the pathogenesis of central fatigue. Neuroinflammation, a pathological hallmark of PD which is associated with glutamate overactivity in basal ganglia, has been proposed as a crucial factor closely related to fatigue [3]. Safinamide is an orally administered alfa-aminoamide derivative, currently used in the treatment of fluctuating PD, given its dual mechanism of action: it selectively and reversibly inhibits MAOB and modulates glutamate release.

Method: The validated version of FSS and PFS-16 were administered to 35 fluctuating PD patients with central fatigue before and after a 24 weeks treatment period with safinamide100 mg as add-on therapy. An assessment of secondary variables such as depression, quality of life, motor and non-motor symptoms was conducted.

Results: A significant improvement was observed in FSS (pre: 5,2±1,1, post: 4,2±1,6; p<0,001), PFS16 (pre:3,6±0,7, post:3,1±0,9; p=0.01) and PDSI (pre:31,0±11,9, post: 22,7±15,5, p=0.01). No significant correlation emerged between fatigue and clinical characteristics of PD population.

Conclusion: Our data indicate that central fatigue is a primary manifestation of PD, rather than secondary to motor impairment, mood disorders or medications. Central fatigue improved in fluctuating PD patients as well as quality of life, possibly because fatigue was perceived as non-distressing, as the scores of FSS and PFS16 pointed out, after 24 weeks of treatment with safinamide. Rather than to be reflective of a single neurotransmitter deficiency, the pathogenesis of central fatigue appears to be multifactorial and a dysfunction in the glutamatergic system may contribute to its development. Drugs that interact with multiple neurotransmission systems, such as safinamide, could be useful in reducing this symptom.

References: [1] Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci. 2000 Oct 1;179(S 1-2):34-42
[2] Friedman JH, Brown RG, Comella C, Garber CE, Krupp LB, Lou JS, Marsh L, Nail L, Shulman L, Taylor CB; Working Group on Fatigue in Parkinson’s Disease. Fatigue in Parkinson’s disease: a review. Mov Disord. 2007 Feb 15;22(3):297-308
[3] Wang H, Liu Y, Zhao J, Guo X, Hu M, Chen Y. Possible inflammatory mechanisms and predictors of Parkinson’s disease patients with fatigue (Brief Review). Clin Neurol Neurosurg. 2021 Sep;208:106844.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/central-fatigue-and-glutamatergic-overactivity-in-parkinsons-disease-possible-impact-of-safinamide/