Cannabis (in all the varied methods of delivery) continues to garner significant attention as a potential therapeutic intervention for neurodegenerative disorders, including Parkinson's disease (PD). The recent legalization of personal use of cannabis products in some parts of the world has increased this interest and with it, potential availability to many more people. However, such access has led to more questions than answers for both patients and health care professionals. These include what symptom(s) of PD will cannabis products treat; what dose; what type of cannabis product to use and what are the side effects?

Parkinson's disease (PD) is characterized by alpha-synuclein (α-Syn) pathology, neurodegeneration and neuroinflammation. Human leukocyte antigen (HLA) variants associated with PD and α-Syn specific CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) regulates major histocompatibility complex class II (MHCII) expression. Reduced Ciita levels significantly increase α-Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in α-Syn-induced rat PD models. Characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciita levels (DA.VRA4) compared to the background strain (DA). To model PD, we combined rAAV-mediated α-Syn overexpression in the substantia nigra with striatal injection of α-Syn preformed fibrils. Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naïve rats, 4- and 8 weeks post rAAV injection. Flow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response was highest at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells was highest at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to α-Syn and only subtle Ciita- and/or α-Syn-dependent changes in the T lymphocyte compartment. Lower Ciita levels were consistently associated with higher TNF levels in serum. Ciita regulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, indicating that mild immunomodulatory therapies could have therapeutic effects in PD.

Gait issues, including reduced speed, stride length and freezing of gait (FoG), are disabling in advanced phases of Parkinson's disease (PD), and their treatment is challenging. Levodopa/carbidopa intestinal gel (LCIG) can improve these symptoms in PD patients with suboptimal control of motor fluctuations, but it is unclear if continuous dopaminergic stimulation can further improve gait issues, independently from reducing Off-time. To analyze before (T0) and after 3 (T1) and 6 (T2) months of LCIG initiation: a) the objective improvement of gait and balance; b) the improvement of FoG severity; c) the improvement of motor complications and their correlation with changes in gait parameters and FoG severity. This prospective, longitudinal 6-months study analyzed quantitative gait parameters using wearable inertial sensors, FoG with the New Freezing of Gait Questionnaire (NFoG-Q), and motor complications, as per the MDS-UPDRS part IV scores. Gait speed and stride length increased and duration of Timed up and Go and of sit-to-stand transition was significantly reduced comparing T0 with T2, but not between T0-T1. NFoG-Q score decreased significantly from 19.3±4.6 (T0) to 11.8±7.9 (T1) and 8.4±7.6 (T2) (T1-T0 p = 0.018; T2-T0 p < 0.001). Improvement of MDS-UPDRS-IV (T0-T2, p = 0.002, T0-T1 p = 0.024) was not correlated with improvement of gait parameters and NFoG-Q from T0 to T2. LEDD did not change significantly after LCIG initiation. Continuous dopaminergic stimulation provided by LCIG infusion progressively ameliorates gait and alleviates FoG in PD patients over time, independently from improvement of motor fluctuations and without increase of daily dosage of dopaminergic therapy.

Previous studies have demonstrated the importance of the locus coeruleus (LC) in sleep-wake regulation. Both essential tremor (ET) and Parkinson's disease (PD) share common sleep disorders, such as poor quality of sleep (QoS). LC pathology is a feature of both diseases. A question arises regarding the contribution of LC degeneration to the occurrence of poor QoS. To evaluate the association between LC impairment and sleep disorders in ET and PD patients. A total of 83 patients with ET, 124 with PD, and 83 healthy individuals were recruited and divided into ET/PD with/without poor QoS (Sle/NorET and Sle/NorPD) subgroups according to individual Pittsburgh Sleep Quality Index (PSQI) score. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and free-water imaging derived from diffusion MRI were performed. Subsequently, we evaluated the association between contrast-to-noise ratio of LC (CNRLC) and free-water value of LC (FWLC) with PSQI scores in ET and PD groups. CNRLC was significantly lower in ET (p = 0.047) and PD (p = 0.018) than in healthy individuals, whereas no significant difference was found in FWLC among the groups. No significant differences were observed in CNR/FWLC between patients with/without sleep disorders after multiple comparison correction. No correlation was identified between CNR/FWLC and PSQI in ET and PD patients. LC degeneration was observed in both ET and PD patients, implicating its involvement in the pathophysiology of both diseases. Additionally, no significant association was observed between LC integrity and PSQI, suggesting that LC impairment might not directly relate to overall QoS.

Video-oculography constitutes a highly-sensitive method of characterizing ocular movements, which could detect subtle premotor changes and contribute to the early diagnosis of Parkinson's disease (PD). To investigate potential oculomotor differences between idiopathic PD (iPD) and PD associated with the G2019S variant of LRRK2 (L2PD), as well as to evaluate oculomotor function in asymptomatic carriers of the G2019S variant of LRRK2. The study enrolled 129 subjects: 30 PD (16 iPD, 14 L2PD), 23 asymptomatic carriers, 13 non-carrier relatives of L2PD patients, and 63 unrelated HCs. The video-oculographic evaluation included fixation, prosaccade, antisaccade, and memory saccade tests. We did not find significant differences between iPD and L2PD. Compared to controls, PD patients displayed widespread oculomotor deficits including larger microsaccades, hypometric vertical prosaccades, increased latencies in all tests, and lower percentages of successful antisaccades and memory saccades. Non-carrier relatives showed oculomotor changes with parkinsonian features, such as fixation instability and hypometric vertical saccades. Asymptomatic carriers shared multiple similarities with PD, including signs of unstable fixation and hypometric vertical prosaccades; however, they were able to reach percentages of successful antisaccade and memory saccades similar to controls, although at the expense of longer latencies. Classification accuracy of significant oculomotor parameters to differentiate asymptomatic carriers from HCs ranged from 0.68 to 0.74, with BCEA, a marker of global fixation instability, being the parameter with the greatest classification accuracy. iPD and LRRK2-G2019S PD patients do not seem to display a differential oculomotor profile. Several oculomotor changes in asymptomatic carriers of LRRK2 mutations could be considered premotor biomarkers.

Parkinson's disease (PD) is a common neurodegenerative disorder that is predominantly known for its motor symptoms but is also accompanied by non-motor symptoms, including anxiety. The underlying neurobiological substrates and brain network changes associated with comorbid anxiety in PD require further exploration. An analysis of oscillation-specific nodal properties in patients with and without anxiety was conducted using resting-state functional magnetic resonance imaging (rs-fMRI) and graph theory. We used a band-pass filtering approach to differentiate oscillatory frequency bands for subsequent functional connectivity (FC) and graph analyses. The study included 68 non-anxiety PD (naPD) patients, 62 anxiety PD (aPD) patients, and 64 healthy controls (NC). Analyses of nodal betweenness centrality (BC), degree centrality (DC), and efficiency were conducted across multiple frequency bands. The findings indicated no significant differences in BC among naPD, aPD, and NC within the 0.01-0.08 Hz frequency range. However, we observed a specific reduction in BC at narrower frequency ranges in aPD patients, as well as differing patterns of change in DC and efficiency, which are believed to reflect the neurophysiological bases of anxiety symptoms in PD. Differential oscillation-specific nodal characteristics have been identified in PD patients with anxiety, suggesting potential dysregulations in brain network dynamics. These findings emphasize the complexity of brain network alterations in anxiety-associated PD and identify oscillatory frequencies as potential biomarkers. The study highlights the importance of considering oscillatory frequency bands in the analysis of brain network changes.

Patient and public involvement and engagement (PPIE) in the design of trials is important, as participant experience critically impacts delivery. The Edmond J Safra Accelerating Clinical Trials in PD (EJS ACT-PD) initiative is a UK consortium designing a platform trial for disease modifying therapies in PD. The integration of PPIE in all aspects of trial design and its evaluation throughout the project. PwP and care partners were recruited to a PPIE working group (WG) via UK Parkinson's charities, investigator patient groups and participants of a Delphi study on trial design. They are supported by charity representatives, trial delivery experts, researchers and core project team members. PPIE is fully embedded within the consortium's five other WGs and steering group. The group's terms of reference, processes for effective working and PPIE evaluation were co-developed with PPIE contributors. 11 PwP and 4 care partners have supported the PPIE WG and contributed to the development of processes for effective working. A mixed methods research-in-action study is ongoing to evaluate PPIE within the consortium. This includes the Patient Engagement in Research Scale -a quantitative PPIE quality measure; semi-structured interviews -identifying areas for improvement and overall impressions of involvement; process fidelity- recording adherence; project documentation review - identifying impact of PPIE on project outputs. We provide a practical example of PPIE in complex projects. Evaluating feasibility, experiences and impact of PPIE involvement in EJS ACT-PD will inform similar programs on effective strategies. This will help enable future patient-centered research.

Autonomic dysfunction precedes endothelial dysfunction in Parkinson's disease (PD) and causes blood pressure and circulation abnormalities that are highly disruptive to one's quality of life. While exercise interventions have proven helpful for motor symptoms of PD, improving associated non-motor symptoms is limited. Low-intensity resistance training with blood flow restriction (LIRT-BFR) improves autonomic dysfunction in non-PD patients and high-intensity resistance training (HIRT) is recommended for motor symptom improvements for people with PD (PwPD). To determine the effects of LIRT-BFR and HIRT on homocysteine and autonomic and endothelial function in PwPD and to determine the hemodynamic loads during LIRT-BFR and HIRT in PwPD using a novel exercise protocol. Thirty-eight PwPD were assigned LIRT-BFR, HIRT or to a control (CNTRL) group. The LIRT-BFR and HIRT groups exercised three days per week for four weeks. The LIRT-BFR protocol used 60% limb occlusion pressure (LOP) and performed three sets of 20 repetitions at 20% of the one-repetition maximum (1RM). The HIRT group performed three sets of eight repetitions at 80% 1RM. The CNTRL group was asked to continue their normal daily routines. LIRT-BFR significantly improved orthostatic hypotension (p = 0.026), homocysteine levels (p < 0.001), peripheral circulation (p = 0.003), supine blood pressure (p = 0.028) and heart rate variability (p = 0.041); LIRT-BFR improved homocysteine levels (p < 0.018), peripheral circulation (p = 0.005), supine blood pressure (p = 0.007) and heart rate variability (p = 0.047) more than HIRT; and hemodynamic loads for LIRT-BFR and HIRT were similar. LIRT-BFR may be more effective than HIRT for autonomic and endothelial function improvements in PwPD and hemodynamic loads may be lessened in LIRT-BFR protocols using single-joint exercises with intermittent blood flow restriction. Further research is needed to determine if non-motor symptoms improve over time and if results are sustainable.

Parkinson's disease (PD) is caused by the misfolding and aggregation of α-synuclein in neurons into toxic oligomers and fibrils that have prion-like properties allowing them to infect healthy neurons and to be transmitted to animal models of PD by injection or oral exposure. Given α-synuclein fibrils' potential transmission on the gut-brain axis, α-synuclein may be transmitted through colonoscopy procedures. This study examines a possible association between colonoscopy and PD. Longitudinal health insurance data of 250,000 individuals aged 50+ from 2004-2019 was analyzed. Cox proportional hazard and competing risk models with death as a competing event were estimated to calculate the risk of PD. Colonoscopy was categorized as never receiving colonoscopy, colorectal cancer (CRC) screening without or with biopsy, destruction or excision (BDE), and diagnostic colonoscopy without or with BDE. We identified 6,422 new cases of PD among 221,582 individuals. The Cox model revealed a significantly increased risk of PD for patients who ever had a diagnostic colonoscopy without or with BDE (HR = 1.31; 95% CI: [1.23-1.40]; HR = 1.32 [1.22-1.42]) after adjustment for age and sex. After controlling for covariates and death, persons who ever underwent CRC screening had a 40% reduced risk of PD (CRHR = 0.60 [0.54-0.67]), while persons who underwent diagnostic colonoscopy had a 20% reduced risk of PD (CRHR = 0.81 [0.75-0.88]). Colonoscopy does not increase the risk of PD, after adjusting for death and covariates. Individuals who underwent only CRC screening had the lowest risk of PD, which may be a result of a more health-conscious lifestyle.

Misfolded α-synuclein can be detected in blood samples of Parkinson's disease (PD) patients by a seed amplification assay (SAA), but the association with disease duration is not clear, yet. In the present study we aimed to elucidate whether seeding activity of misfolded α-synuclein derived from neuronal exosomes in blood is associated with PD diagnosis and disease duration. Cross-sectional samples of PD patients were analyzed and compared to samples of age- and gender-matched healthy controls using a blood-based SAA. Presence of α-synuclein seeding activity and differences in seeding parameters, including fluorescence response (in arbitrary units) at the end of the amplification assay (F60) were analyzed. Additionally, available PD samples collected longitudinally over 5-9 years were included. In the cross-sectional dataset, 79 of 80 PD patients (mean age 69 years, SD = 8; 56% male) and none of the healthy controls (n = 20, mean age 70 years, SD = 10; 55% male) showed seeding activity (sensitivity 98.8%). When comparing subgroups divided by disease duration, longer disease duration was associated with lower α-synuclein seeding activity (F60: p < 0.001). In the longitudinal analysis 10/11 patients showed a gradual decrease of α-synuclein seeding activity over time. This study confirms the high sensitivity of the blood-based α-synuclein SAA applied here. The negative association of α-synuclein seeding activity in blood with disease duration makes this parameter potentially interesting as biomarker for future studies on the pathophysiology of disease progression in PD, and for biologically oriented trials in this field.