A pathological feature of Parkinson’s disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. DA is the neurotransmitter of dopaminergic neurons. Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products, including reactive oxygen species, DA quinones, and 3,4-dihydroxyphenylacetaldehyde. Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways, and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.

Parkinson’s disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson’s disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson’s disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson’s disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson’s disease.

Cerebral small vessel disease (CSVD) is a generic term used for intracranial vascular disorders caused by the structural changes of cerebral microvessels, including the small arteries, arterioles, capillaries and venules. CSVD exhibits various neuroimaging features and is associated clinical characteristics. Although CSVD is recognized as the leading cause of vascular cognitive impairment (VCI), the underlying mechanism(s) remains elusive. Growing evidence indicates a significant association between altered neurovascular unit (NVU) functioning and the pathophysiology of evolving CSVD-induced VCI. Therefore, research is required to understand how NVU dysregulation contributes to cognitive impairment due to CSVD. In this review, we describe the link between the neuroimaging focal lesions and cognitive alterations. We also discuss the potential pathological role of NVU dysregulation in the entry of pathogens from the blood into the parenchyma by altering the blood-brain barrier (BBB), affecting the cerebral microvascular and consequently cause VCI. Next, we review the coupling of neural activity with cerebral blood flow to control the microvascular perfusion; and the disrupted clearance of metabolic byproducts with CSF-ISF exchange via perivascular pathways and glymphatic system. Finally, we discussed the possible therapeutic interventions in CSVD.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive form of brain stimulation that positively regulates the motor and non-motor symptoms of Parkinson's disease (PD). Although, most reviews and meta-analysis have shown that rTMS intervention is effective in treating motor symptoms and depression, very few have used randomised controlled trials (RCTs) to analyse the efficacy of this intervention in PD. We aimed to review RCTs of rTMS in patients with PD to assess the efficacy of rTMS on motor and non-motor function in patients with PD. In this systematic review and meta-analysis, we searched PubMed, MEDLINE and Web of Science databases for RCTs on rTMS in PD published between January 1, 1988 to January 1, 2022. Eligible studies included sham-controlled RCTs that used rTMS stimulation for motor or non-motor symptoms in PD. RCTs not focusing on the efficacy of rTMS in PD were excluded. Summary data were extracting from those RCTs by two investigators independently. We then calculated standardised mean difference with random-effect models. The main outcome included motor and non-motor examination of scales that were used in PD motor or non-motor assessment. This study was registered with PROSPERO, CRD42022329633. Fourteen studies with 469 patients met the criteria for our meta-analysis. Twelve eligible studies with 381 patients were pooled to analyse the efficacy of rTMS on motor function improvement. The effect size on motor scale scores was 0.51 (P < 0.0001) and were not distinctly heterogeneous (I² = 29%). Five eligible studies with 202 patients were collected to evaluate antidepressant-like effects. The effect size on depression scale scores was 0.42 (P = 0.004), and were not distinctly heterogeneous (I² = 25%), indicating a significant anti-depressive effect (P = 0.004). The results suggest that high-frequency of rTMS on primary motor cortex (M1) is effective in improving motor symptoms; while the dorsolateral prefrontal cortex (DLPFC) may be a potentially effective area in alleviating depressive symptom. The findings suggest that rTMS could be used as a possible adjuvant therapy for PD mainly to improve motor symptoms, but could have potential efficacy on depressive symptoms of PD. However, further investigation is needed. The National Natural Science Foundation of China (NO: 81873777, 82071414), Initiated Foundation of Zhujiang Hospital (NO: 02020318005), Scientific Research Foundation of Guangzhou (NO: 202206010005), and Science and Technology Program of Guangdong of China (NO: 2020A0505100037).