Numerous challenges hinder the development of neuroprotective treatments for Parkinson\'s disease, with a regularly identified issue being the lack of clinically relevant animal models. Viral vector overexpression of α-synuclein is widely considered the most relevant model; however, this has been limited by high variability and inconsistency. One potential method of optimisation is pairing it with a secondary insult such as FN075, a synthetic molecule demonstrated to accelerate α-synucleinopathy. Thus, the aim of this study was to investigate if sequential infusion of adeno-associated virus (AAV)-α-synuclein and FN075 into the rat brain can replicate α-synucleinopathy, nigrostriatal pathology and motor dysfunction associated with Parkinson\'s disease. Rats received a unilateral injection of AAV-α-synuclein (or AAV-green fluorescent protein) into two sites in the substantia nigra, followed 4 weeks later by unilateral injection of FN075 (or vehicle) into the striatum. Animals underwent behavioural testing every 4 weeks until sacrifice at 20 weeks, followed by immunohistochemistry assessment post-mortem. As anticipated, AAV-α-synuclein led to extensive overexpression of human α-synuclein throughout the nigrostriatal pathway, as well as elevated levels of phosphorylated and aggregated forms of the protein. However, the sequential administration of FN075 into the striatum did not exacerbate any of the α-synuclein pathology. Furthermore, despite the extensive α-synuclein pathology, neither administration of AAV-α-synuclein nor FN075, alone or in combination, was sufficient to induce dopaminergic degeneration or motor deficits. In conclusion, this approach did not replicate the key characteristics of Parkinson\'s disease, and further studies are required to create more representational models for testing of novel compounds and treatments for Parkinson\'s disease.

BACKGROUND: Up to 10 % of Parkinson\'s disease (PD) populations carry a genetic risk variant, which may not only increase one\'s chance of developing PD but also affect disease presentation and progression. We hypothesize motor impairment in genetic carriers of PD correlate to different patterns of microstructural changes over time.
METHODS: Data were accessed from the Parkinson\'s Progression Markers Initiative (PPMI) project. Connectometry analyses were performed for GBA1+ PD, LRRK2+ PD, and sporadic PD correlating white matter structural changes, as measured by quantitative anisotropy (QA), with motor impairment, as measured by MDS-UPDRS III.
RESULTS: There was a negative correlation between QA and MDS-UPDRS III in all 3 cohorts at 48 months. In GBA1+ PD (n = 12), the white matter tracts identified were cortical and subcortical, while in the LRRK2+ PD (n = 18) and sporadic PD (n = 45) cohorts white tracts identified were primarily subcortical and within the brainstem.
CONCLUSIONS: Our findings highlight the association between motor symptom progrerssion and structural connectivity in individuals with GBA1+ PD, LRRK2+ PD, and sporadic PD. Due to the small sample size, larger studies are needed in the future to confirm the findings.

Parkinson\'s disease is one of the vital neurodegenerative ailments attributed to a rise in Alpha-synuclein proteins leading to the advancement of motor and cognitive deterioration. Interestingly, in PD lncRNAs, miRNAs and siRNAs are also key regulators of SNCA and alpha-synuclein aggregation. This review will focus on the roles of these three types of small RNAs in trebling the development of PD through regulating SNCA expression or alpha-synuclein protein mediating the RNA from acting. Parkinson\'s disease is defined by the build-up of alpha-synuclein protein resulting predominantly from the elevated expression level of the SNCA gene. Non-coding RNAs have gained broad appeal as fundamental modulators of gene expression and protein aggregation dynamics, with significant implications on the aetiology of PD. LncRNAs modulate SNCA transcription and edit epigenetic modifications, while miRNA target mRNA is involved in the stability and translation of count alpha-synuclein. Considering all these data, siRNAs can achieve the precise gene silencing effect that directly induces the downregulation of SNCA mRNA. This review also summarizes some recent reports about the interaction between these ncRNAs with the SNCA gene and alpha-synuclein protein, each through its independent in addition to synergistic mechanisms. This review highlights the possibility of therapeutic interventions to perturb SNCA expression to prevent alpha-synuclein aggregation via targeting ncRNAs that might be spun off novel drug development for PD.

Sake may potentially halt the progression of Parkinson\'s disease due to its properties, yet no studies have explored its effects. This preliminary study aimed to assess the impact of sake supplementation on Parkinson\'s disease using a zebrafish model. Sixty fish were divided into six groups: control, rotenone (ROT), and groups administered rotenone along with sake at concentrations of 25, 50, 75, and 100 mg/L (25S, 50S, 75S, and 100S). After 28 days of treatment, behavioral responses and the activities of catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and glutathione-S-transferase (GST), as well as the expressions of TNF-α, IL-1β, and COX-2, were evaluated. The results indicated that rotenone administration significantly reduced crossing number (P = 0.001), entries in the top area (P = 0.001), and time spent in the top area (P = 0.001). It also markedly increased levels of TBARS and SH compared to the control group (P = 0.001). Rotenone significantly decreased CAT, SOD, and GSH activities while increasing GST levels. Furthermore, it upregulated the expressions of TNF-α (P = 0.001), IL-1β (P = 0.001), and COX-2 (P = 0.001). Supplementation with sake, particularly at higher doses, reversed the adverse effects of rotenone on behavioral, oxidative, and inflammatory responses. In conclusion, sake shows promise for preventing Parkinson\'s disease pending further clinical studies.

BACKGROUND: Poor postural control has been reported in people with Parkinson\'s disease, which could be explained by the changes in muscular activation patterns related to antigravitational muscles. This study aims to measure the muscle activation of antigravitational muscles during balance tasks in individuals, with and without Parkinson\'s.
METHODS: Sixteen (16) participants (9 with Parkinson\'s), aged ≥65 yrs., performed 2 × 30-s trials of 4 balance tasks (bipodal and semi-tandem opened eyes and closed eyes) on a force platform (center of pressure measurement); while surface electromyography measurements were obtained bilaterally on the multifidus at L5, biceps femoris and medialis gastrocnemius. Electromyography amplitude analysis was processed by the Root Mean Square (250 ms window epochs) and normalized by the peak of activation during the balance task, to determine each muscle\'s activity level.
RESULTS: The Parkinson\'s group reported lower muscle activation than control across tasks (in mean for multifidus = 8%, biceps femoris = 16%, gastrocnemius = 7%), although not statistically significant. Parkinson\'s reported significantly poorer postural control than control, mainly for the center of pressure sway ellipse area (p = 0.016) from challenge balance tasks such as semi-tandem.
CONCLUSIONS: Poor postural control was confirmed in the Parkinson\'s group, but not significantly associated by the changes from muscle activation of trunk and lower limbs, during balance performance.

BACKGROUND: Of the neurodegenerative diseases, Parkinson\'s disease is recognised to have the fastest growing prevalence. It is unclear whether this is due to the ageing global population alone, with several environmental factors increasingly implicated in changing prevalence rates. Large data sets have been used nationally and globally to help predict future disease burden. However, the reliability of such sources is yet unknown for Parkinson\'s disease.
CONCLUSIONS: This review discusses the methods used in all published UK prevalence studies conducted to date. Direct comparison between prevalence figures obtained from the 10 to discussed prevalence studies is precluded due to differences in methodology for case ascertainment and diagnosis. Age adjusted estimates vary from 105/100,000 to 168/100,000.
CONCLUSIONS: These studies demonstrate no overall trend in changing prevalence figures between 1961 and 2007. No difference in prevalence trends were seen for those living in rural or urban areas. Differences between ethnic groups, for example, remains an under explored area.

BACKGROUND: Iron overload is observed in neurodegenerative diseases, especially Alzheimer\'s disease (AD) and Parkinson\'s disease (PD). Homozygotes for the iron-overload (haemochromatosis) causing HFE p.C282Y variant have increased risk of dementia and PD. Whether brain iron deposition is causal or secondary to the neurodegenerative processes in the general population is unclear.
METHODS: We analysed 39,533 UK Biobank participants of European genetic ancestry with brain MRI data. We studied brain iron estimated by R2* and quantitative susceptibility mapping (QSM) in 8 subcortical regions: accumbens, amygdala, caudate, hippocampus, pallidum, putamen, substantia nigra, and thalamus. We performed genome-wide associations studies (GWAS) and used Mendelian Randomization (MR) methods to estimate the causal effect of brain iron on grey matter volume, and risk of AD, non-AD and PD. We also used MR to test whether genetic liability to AD or PD causally increased brain iron (R2* and QSM).
RESULTS: In GWAS of R2* and QSM we replicated 83% of previously reported genetic loci and identified 174 further loci across all eight brain regions. Higher genetically predicted brain iron, using both R2* and QSM, was associated with lower grey matter volumes in the caudate, putamen and thalamus (e.g., Beta-putamenQSM: -0.37, p = 2*10-46). Higher genetically predicted thalamus R2* was associated with increased risk of non-AD dementia (OR 1.36(1.16;1.60), p = 2*10-4) but not AD (p > 0.05). In males, genetically predicted putamen R2* increased non-AD dementia risk, but not in females. Higher genetically predicted iron in the caudate, putamen, and substantia nigra was associated with an increased risk of PD (Odds Ratio QSM ∼ substantia-nigra 1.21(1.07;1.37), p = 0.003). Genetic liability to AD or PD was not associated with R2* or QSM in the dementia or PD-associated regions.
CONCLUSIONS: Our genetic analysis supports a causal effect of higher iron deposition in specific subcortical brain regions for Parkinson\'s disease, grey matter volume, and non-Alzheimer\'s dementia.

BACKGROUND: People with Parkinson\'s disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that \"nothing can be done about it\". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia.
OBJECTIVE: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia.
METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources.
RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals.
CONCLUSIONS: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Neurons in the substantia nigra reticulata (SNr) transmit information about basal ganglia output to dozens of brain regions in thalamocortical and brainstem motor networks. Activity of SNr neurons is regulated by convergent input from upstream basal ganglia nuclei, including GABAergic inputs from the striatum and the external globus pallidus (GPe). GABAergic inputs from the striatum convey information from the direct pathway, while GABAergic inputs from the GPe convey information from the indirect pathway. Chronic loss of dopamine, as occurs in Parkinson\'s disease, disrupts the balance of direct and indirect pathway neurons at the level of the striatum, but the question of how dopamine loss affects information propagation along these pathways outside of the striatum is less well understood. Using a combination of in vivo and slice electrophysiology, we find that dopamine depletion selectively weakens the direct pathway\'s influence over neural activity in the SNr due to changes in the decay kinetics of GABA-mediated synaptic currents. GABAergic signaling from GPe neurons in the indirect pathway was not affected, resulting in an inversion of the normal balance of inhibitory control over basal ganglia output through the SNr. These results highlight the contribution of cellular mechanisms outside of the striatum that impact the responses of basal ganglia output neurons to the direct and indirect pathways in disease.

[This corrects the article DOI: 10.3389/fnhum.2023.1325215.].