Physical Activity Since Childhood and its Association with Changes in Midlife Cognitive Functions: A Longitudinal Prospective Cohort Study.

Since the 1960s, the gold standard treatment for Parkinson's disease (PD) has remained levodopa therapy. Although highly effective for managing motor symptoms, the emergence of motor fluctuations and levodopa related complications due to the degenerative nature of PD limit its effectiveness as the disease progresses. In order to slow or stop disease progression, interventions must target the pathogenic steps that ultimately drive dopaminergic neuronal loss within the substantia nigra pars compacta of the basal ganglia, as well as the more widespread loss of neurons in the brainstem and cortical regions. PD is characterised by several core pathophysiological hallmarks including -synuclein misfolding and aggregation, impaired protein clearance, mitochondrial dysfunction, and neuroinflammation and oxidative stress. For example, circulating inflammatory biomarkers, including tumour necrosis factor- (TNF-), interferon-y (IFN-y) and various interleukins are elevated in PD relative to control patients. More recently, additional pathophysiological hallmarks, such as gut microbiome dysbiosis, endoplasmic reticulum impairment and neuronal excitotoxicity have been proposed. All of these hallmarks are closely interlinked and correlate positively with nigral neurodegeneration. Multiple phase II and III trials have examined pharmacological agents aimed at modulating these pathophysiological hallmarks; however, all have failed to demonstrate significant disease-modifying effects. Therefore, due to challenges in determining disease-modifying pharmacological therapies, research focus has increasingly shifted towards lifestyle, including diet and exercise. Whilst the positive effect of exercise is now well-established, with strong evidence supporting its neuroprotective and disease-modifying potential, evidence from trials of diet, including dietary supplements, remains limited. Mechanistically, diet offers plausible benefits for neuroprotection and disease modification due to potential antioxidant and anti-inflammatory properties, as well as potential positive effects on the gut microbiome. Dietary supplements are of particular interest in PD, as their primary function is to add to or supplement the diet, making them convenient to administer and well suited for clinical trials, where participants can be effectively blinded. Furthermore, in the studies that have investigated supplement use in PD, up to two thirds of participants reported using dietary supplements. In addition, similar to dietary interventions, several studies suggest that certain dietary supplements possess relevant mechanisms of action thought to be able to decelerate or even stop the pathophysiological processes driving PD, including neurodegeneration, -synuclein pathology, oxidative stress, inflammation, mitochondrial dysfunction and gut microbiome dysbiosis. Examples of dietary supplements include vitamins, minerals, botanicals, herbs, amino acids, biotics and other such products. While both and studies have established the therapeutic potential of dietary supplements, human clinical trials are required to determine causality between a particular dietary supplement and PD modification. Primary mechanisms by which omega-3 fatty acids (-3), nicotinamide riboside, and biotics influence key pathophysiological hallmarks of Parkinson’s disease. Inflammation, oxidative stress, and mitochondrial dysfunction are core, interconnected hallmarks that interact bidirectionally with α-synuclein aggregation. -3 and NR may attenuate inflammation, oxidative stress, and mitochondrial dysfunction, whereas biotics modulate the gut microbiome, influencing α-synuclein aggregation and downstream pathways. Pathophysiological hallmarks: A, Neuroinflammation and oxidative stress; B, Mitochondrial dysfunction; C, α-synuclein aggregation; D, Gut dysbiosis. Interventions: 1, -3; 2, NR; 3, Biotics.