Cognitive Impairment in Parkinson’s Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches

Abstract

Cognitive impairment in patients with Parkinson’s disease (PD) is one of the commonest and most disabling non-motor manifestations during the course of the disease. The clinical spectrum of PD-related cognitive impairment includes subjective cognitive decline (SCD), mild cognitive impairment (MCI) and PD dementia (PDD). As the disease progresses, cognitive decline creates a significant burden for the family members and/or caregivers of patients with PD, and has a great impact on quality of life. Current pharmacological treatments have demonstrated partial efficacy and failed to halt disease progression, and novel, effective, and safe therapeutic strategies are required. Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. Potential underlying mechanisms include the inhibition of a-synuclein aggregation, the improvement of mitochondrial function, the regulation of synaptic plasticity, an impact on the gut–brain axis, the modulation of neuroinflammation and the upregulation of neurotrophic factors, as well as cholinergic, dopaminergic, serotoninergic and norepinephrine neurotransmission. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment.

Glucosamine Enhancement of Learning and Memory Functions by Promoting Fibroblast Growth Factor 21 Production

“…Additionally, employing combined knockdown and overexpression strategies to manipulate individual signaling molecules will be pursued to validate the findings obtained from inhibitor usage. As FGF21 has been proposed as a potential therapeutic agent for AD and Parkinson's disease (PD) [12,70], investigating whether GLN-mediated FGF21 production exerts beneficial effects in animal models of AD and PD could inform potential therapeutic strategies for neurodegenerative diseases or cognitive impairment in the future. Furthermore, GLN, which has been identified as either a food additive or a nutraceutical, is typically taken orally.…”

Progress of Ginsenoside Rb1 in neurological disorders

“…Dyskinesia and non-motor symptoms are the hallmarks of PD—a chronic, progressive neurodegenerative condition ( Mahoney-Sánchez et al, 2021 ). From a pathophysiological perspective, PD is primarily characterized by neurodegeneration coupled with misfolding and aggregation of the neuronal inclusions α-synuclein (α-Syn), which accumulate into protein inclusions within the cell and lead to the formation of Lewy bodies, as well as the loss or degeneration of nigrostriatal dopaminergic neurons ( Beitz, 2014 ; Bridi and Hirth, 2018 ; Dickson, 2018 ; Degirmenci et al, 2023 ). A key etiology of PD is an imbalance between the excitatory Glu and inhibitory γ-aminobutyric acid (GABA) systems, which results in neuro excitotoxicity and dopaminergic cell death in the substantia nigra compacta ( Rose, 2016 ).…”

The janus face of oxidative stress in health and disease: The cause or the cure?

“…It is characterized by the degeneration of dopaminergic neurons located within the substantia nigra (98). Many therapeutic approaches targeting mitochondrial abnormalities and oxidative stress are still being studied to counteract AD and PD (98,102). Antioxidants are a very powerful tool in combating oxidative stress and improving the effects of age on the brain (103).…”