Parkinson’s disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies (LB). During the course of disease, misfolded α-synuclein, the major constituent of LB, spreads to different regions of the brain in a prion-like fashion, giving rise to successive non-motor and motor symptoms. Etiology is likely multifactorial, and involves interplay among aging, genetic susceptibility and environmental factors. The prevalence of PD rises exponentially with age, and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death. However, the majority of those over the age of 80 do not have PD, thus other factors in addition to aging are needed to cause disease. Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk. Nevertheless, the causality of most environmental factors is not conclusively established, and alternative explanations such as reverse causality and recall bias cannot be excluded. The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD. Rare mutations as well as common variants in genes such as SNCA, LRRK2 and GBA are associated with risk of PD, but Mendelian causes collectively only account for 5% of PD and common polymorphisms are associated with small increase in PD risk. Heritability of PD has been estimated to be around 30%. Thus, aging, genetics and environmental factors each alone is rarely sufficient to cause PD for most patients. PD is a multifactorial disorder involving interplay of aging, genetics and environmental factors. This has implications on the development of appropriate animal models of PD which take all these factors into account. Common converging pathways likely include mitochondrial dysfunction, impaired autophagy, oxidative stress and neuroinflammation, which are associated with the accumulation and spread of misfolded α-synuclein and neurodegeneration. Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted. It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). The observation of pleiotropy has emerged, with mutations in the same gene giving rise to diverse phenotypes, which further increases the complexity of phenotype-genotype correlation. Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene, presence of modifier genes, and oligogenic inheritance. Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms, translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies, and ultimately finding disease-modifying therapies for neurodegenerative disorders.

Synaptogyrin-3 (SYNGR3) is a synaptic vesicular membrane protein. Amongst four homologues (SYNGR1 to 4), SYNGR1 and 3 are especially abundant in the brain. SYNGR3 interacts with the dopamine transporter (DAT) to facilitate dopamine (DA) uptake and synaptic DA turnover in dopaminergic transmission. Perturbed SYNGR3 expression is observed in Parkinson’s disease (PD). The regulatory elements which affect SYNGR3 expression are unknown. Nuclear-receptor-related-1 protein (NURR1) can regulate dopaminergic neuronal differentiation and maintenance via binding to NGFI-B response elements (NBRE). We explored whether NURR1 can regulate SYNGR3 expression using an in silico analysis of the 5′-flanking region of the human SYNGR3 gene, reporter gene activity and an electrophoretic mobility shift assay (EMSA) of potential cis-acting sites. In silico analysis of two genomic DNA segments (1870 bp 5′-flanking region and 1870 + 159 bp of first exon) revealed one X Core Promoter Element 1 (XCPE1), two SP1, and three potential non-canonical NBRE response elements (ncNBRE) but no CAAT or TATA box. The longer segment exhibited gene promoter activity in luciferase reporter assays. Site-directed mutagenesis of XCPE1 decreased promoter activity in human neuroblastoma SH-SY5Y (↓43.2%) and human embryonic kidney HEK293 cells (↓39.7%). EMSA demonstrated NURR1 binding to these three ncNBRE. Site-directed mutagenesis of these ncNBRE reduced promoter activity by 11–17% in SH-SY5Y (neuronal) but not in HEK293 (non-neuronal) cells. C-DIM12 (Nurr1 activator) increased SYNGR3 protein expression in SH-SY5Y cells and its promoter activity using a real-time luciferase assay. As perturbed vesicular function is a feature of major neurodegenerative diseases, inducing SYNGR3 expression by NURR1 activators may be a potential therapeutic target to attenuate synaptic dysfunction in PD.

Patients with progressive neurologic diseases (PNDs) face a prolonged and fluctuating course of illness marked by increasing disability and a range of nonmotor symptoms. However, the impacts of nonmotor symptoms and unmet care needs remain underexplored. Palliative care needs arise from the multifaceted sufferings associated with PNDs, encompassing not only physical pain but also psychological, social, and spiritual distress. Despite recommendations for early palliative care for PNDs to address these multidimensional sufferings, access to such supportive care is often restricted to advanced stages of the disease. This cross-sectional study aimed to examine palliative care needs, psychological distress, health-related quality of life, and the mediating effects of psychological distress on palliative care needs and health-related quality of life among patients with PNDs. 210 patients with PNDs (Parkinson's disease or multiple sclerosis) were recruited using convenience sampling from regional neurology outpatient clinics and patient support groups in Hong Kong. Participants responded to Palliative Care Outcome Scale (POS), Hospital Anxiety and Depression Scale (HADS), and EQ-5D-5L surveys. Most respondents (59.0%) walked without aid, whereas 26.2% required assistance and 14.8% were wheelchair-restricted. The most prevalent palliative care needs were physical symptoms other than pain, psychosocial support, and spiritual burden. A significant portion of participants exhibited possible anxiety (41.1%) or depression (48.6%). Hierarchical regression analysis indicated that mobility, palliative care needs, anxiety, and depression were significantly associated with the health-related quality of life. Anxiety and depression partially mediated the relationship between palliative care needs and quality of life. Given the chronic, fluctuating illness trajectory, early recognition and management of emerging palliative care needs, particularly psychospiritual distress, is crucial for enhancing health-related quality of life for patients with PNDs.

Background: Between 40 and 50% of patients with Parkinson’s disease (PD) experience anxiety and depression, associated with impaired physical function, high care dependency and mortality. Recently, the United States National Institutes of Health has urged the implementation of mindfulness practices in chronic illness care. Most research to date has examined the effects on chronically ill patients of complex interventions using a combination of mindfulness techniques. In PD patients, however, such complex modalities appear to hinder the technique mastery. Hence, the aim of this trial is to investigate the effects and underlying mechanism of individual mindfulness techniques among PD patients, as well as exploring participants’ experience in using individual mindfulness techniques as a lifestyle intervention for stress and symptom management. Methods: We will conduct an assessor-blind three-arm randomized waitlist-controlled trial with a descriptive qualitative evaluation. Up to 168 PD patients will be recruited from community settings and out-patient clinics, and randomized to meditation, yoga, or usual care group. Meditation and yoga sessions of 90-minute are held weekly for 8 weeks. Primary outcomes include anxiety and depression. Secondary outcomes include PD-related motor and non-motor symptoms and quality-of-life; and level of mindfulness and biomarkers of stress and inflammatory responses will be measured as mediating variables. All outcome evaluations will be assessed at baseline, 8 weeks, and 24 weeks. Following the intention-to-treat principle, generalized estimating equation models and path analysis will be used to identify the treatment effects and the mediating mechanisms. A subsample of 30 participants from each intervention group will be invited for qualitative interviews. Discussion: The study would also generate important insights to enhance the patients’ adaptation to debilitating disease. More specifically, symptom management and stress adaptation are highly prioritized healthcare agenda in managing PD. The research evidence will further inform the development of community-based, nurse-led compassionate care models for neurodegenerative conditions, which is complementary to existing health services. Trial registration: WHO Primary Registry – Chinese Clinical Trials Registry number: ChiCTR2100045939; registered on 2021/04/29 (https://www.chictr.org.cn/showproj.html?proj=125878).

Objectives: Mindfulness has emerged as a promising mental health and wellness practice, but perceptions and experiences regarding its use for chronic illness care have not been well elucidated. This study explored the perceptions and experiences of people living with Parkinson’s disease on using mindfulness techniques for rehabilitation. Method: This is a qualitative descriptive study with thematic analysis. Sixty-one Chinese people with Parkinson’s disease, participating in a community-based mindfulness rehabilitation program, completed individual semi-structured interviews. Results: Three themes emerged: (1) reshaping illness experience through embodiment, (2) cultivating a sense of community through mindful engagement, and (3) fostering lasting mindfulness impact. Participants viewed mindfulness as transformative, offering psychosocial and spiritual benefits beyond physical relief. Group dynamics, mindful interactions, and culturally relevant affirmations were crucial factors in motivating participants in mindful engagement. Challenges in experiential learning highlighted the need for tailored support and resources for sustained mindfulness practice. Conclusions: The findings emphasize the transformative potential of mindfulness in empowering self-care practices through a whole-person approach. Integrating mindfulness into gerontological care is crucial to optimize holistic wellness, particularly for people with Parkinson’s disease. Efforts should focus on personalizing disease-specific mindfulness techniques, expanding mind–body experiences beyond goal-driven practice, and fostering a supportive environment for routine integration.