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Abstract The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson’s disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Abstract Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy in advanced Parkinson’s disease (PD). Motor and non-motor outcomes, however, show considerable inter-individual variability. Preoperative morphometry-based metrics have recently received increasing attention to explain treatment effects. As evidence for the prediction of non-motor outcomes is limited, we sought to investigate the association between metrics of voxel-based morphometry and short-term non-motor outcomes following STN-DBS in this prospective open-label study. Forty-nine PD patients underwent structural MRI and a comprehensive clinical assessment at preoperative baseline and 6-month follow-up. Voxel-based morphometry was used to assess associations between cerebral volume and non-motor outcomes corrected for multiple comparisons using a permutation-based approach. We replicated existing results associating volume loss of the superior frontal cortex with subpar motor outcomes. Overall non-motor burden, however, was not significantly associated with morphometric features, limiting its use as a marker to inform patient selection and holistic preoperative counselling.

Abstract Objective A scoping review will be undertaken to examine and map the available evidence that has been produced in relation to pain management in Parkinson’s, with a focus on behavioural interventions, resources and/or how professionals support people with Parkinson’s self-management of pain. Methods This review will be based on the methodological framework given by Arksey and O’Malley’s (2005), including enhancements by Levac et al., Peters et al. and the Joanna Briggs Institute. We will include studies from PubMed, SCOPUS, CINAHL, MEDLINE Web of Science, APA PsycINFO and ASSIA from January, 2010 onwards. Both quantitative and qualitative data will be analysed separately to identify the characteristics of support for pain management available, orientation of the approach and any identifiable behaviour change components and their outcomes. The COM-B behaviour change model and Theoretical Domains Framework will provide a theoretical framework for synthesising evidence in this review. Conclusion This scoping review will help to explore studies focusing on the evidence supporting a range of interventions relating to the management of pain experienced by people living with Parkinson’s. The focus will be on describing what is available to support self-management, identify what behaviour change components have been used and their effectiveness, identify barriers and enablers to pain management and explore gaps in current provision of pain management. This review will identify implications and priorities for the follow-up phases to the larger ‘Pain in Parkinson’s’ Project which is designed to support clinicians and individuals living with Parkinson’s.

Abstract Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson’s disease (PD) in women compared to men raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal, prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of 316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015–09/2020) and 189 consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford’s Royal Hospital Manchester, and King’s College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose. Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD population (relative risk [RR], 0.72; 95%CI, 0.56–0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI, 1.03–1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48–1.12) compared to men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported worse mobility and bodily discomfort. At follow-up, all main outcomes improved equally in both genders. Our study provides evidence of a gender gap in DBS for PD. Women and men with PD have distinct preoperative nonmotor and motor profiles. We advocate that more focus should be directed toward the implementation of gender equity as both genders benefit from DBS with equal clinical efficacy. This study provides Class II evidence of beneficial effects of DBS in women with PD compared to male controls.

IntroductionParkinson's disease (PD) is an idiopathic disease of the central nervous system characterized by both motor and non-motor symptoms. It is the second most common neurodegenerative disease. Magnetic resonance imaging (MRI) can reveal underlying brain changes associated with PD.ObjectiveIn this study, structural connectivity and white matter networks were analyzed by diffusion MRI and graph theory in a cohort of patients with PD and a cohort of healthy controls (HC) obtained from the Parkinson's Progression Markers Initiative (PPMI) database in a cross-sectional analysis. Furthermore, we investigated longitudinal changes in the PD cohort over 36 months.ResultCompared with the control group, participants with PD showed lower structural connectivity in several brain areas, including the corpus callosum, fornix, and uncinate fasciculus, which were also confirmed by a large effect-size. Additionally, altered connectivity between baseline and after 36 months was found in different network paths inside the white matter with a medium effect-size. Network analysis showed trends toward lower network density in PD compared with HC at baseline and after 36 months, though not significant after correction. Significant differences were observed in nodal degree and strength in several nodes.ConclusionIn conclusion, altered structural and network metrics in several brain regions, such as corpus callosum, fornix, and cingulum were found in PD, compared to HC. We also report altered connectivity in the PD group after 36 months, reflecting the impact of both PD pathology and aging processes. These results indicate that structural and network metrics might yield insight into network reorganization that occurs in PD.

Abstract To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable “QoL responders”/“non-responders”. At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as “QoL non-responders”. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as ‘difficulties experiencing pleasure’ and ‘problems sustaining concentration’. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.

Studies of metabolites in neurodegeneration have not yet used sebum as a source fluid. Here the authors demonstrate the potential of metabolomics of sebum samples from individuals with Parkinson’s disease and controls.

Background: Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson’s disease (PD). However, few studies have compared their nonmotor effects. Objective: To compare nonmotor effects of STN-DBS and GPi-DBS. Methods: In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, –III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size. Results: In both groups, PDQ, UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains. Conclusions: To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients’ individual motor and nonmotor profiles.

Neuropathic pain has multiple etiologies, but a major feature is small fiber dysfunction or damage. Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that can image small nerve fibers in the cornea and has been utilized to show small nerve fiber loss in patients with diabetic and other neuropathies. CCM has comparable diagnostic utility to intraepidermal nerve fiber density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fiber loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease and dementia. We conclude that corneal confocal microscopy has good diagnostic and prognostic capability and fulfills the FDA criteria as a surrogate end point for clinical trials in peripheral and central neurodegenerative diseases.

Introduction Parkinson’s disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure.Methods and analysis This is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences.Ethics and dissemination This trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format.Trial registration numbers NCT04232969, ISRCTN14552789.

Pathological hyperphosphorylated tau is a key feature of Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Using transgenic mice overexpressing human non-mutated tau (htau mice), we assessed the contribution of tau to peripheral and central neurodegeneration. Indices of peripheral small and large fiber neuropathy and learning and memory performances were assessed at 3 and 6 months of age. Overexpression of human tau is associated with peripheral neuropathy at 6 months of age. Our study also provides evidence that non-mutated tau hyperphosphorylation plays a critical role in memory deficits. In addition, htau mice had reduced stromal corneal nerve length with preservation of sub-basal corneal nerves, consistent with a somatofugal degeneration. Corneal nerve degeneration occurred prior to any cognitive deficits and peripheral neuropathy. Stromal corneal nerve loss was observed in patients with FTD but not AD. Corneal confocal microscopy may be used to identify early neurodegeneration and differentiate FTD from AD.

Abstract. Introduction:. Several studies have reported that some types of orofacial pain are more common in patients with Parkinson disease (PD) than the general population. Objectives:. In this study, we aimed to investigate the prevalence of self-reported orofacial pain in a larger group of patients with PD than has been previously studied. Methods:. We analysed data from 1916 participants with PD in a cross-sectional study recruited to the UK Parkinson's Pain Study who had detailed assessments of pain, motor, and nonmotor symptoms. The King's Parkinson's Pain scale was used to quantify different subtypes of pain. Results:. A total of 139 (7.3%) patients reported the presence of some form of orofacial pain. Burning mouth syndrome was reported in 32 (1.7%), whereas chewing pain was found in 38 (2.0%) and grinding pain in 78 (4.0%). Orofacial pain was significantly more common in females (10.4%) than males (5.9%). Multiple logistic regression analysis showed a significant association between orofacial pain and pain severity, neuropathic pain, and oral motor and nonmotor dysfunction. Conclusion:. In our study, population cohort of early patients with PD found prevalence of orofacial pain conditions similar to that in the general population.

Background: Previous studies have shown cutaneous small fiber pathology in patients with Parkinson's disease (PD). These studies have focused on nerve degeneration, but recent reports suggest that nerve regeneration may also be important in PD pathology.Objective: To establish the extent of intraepidermal nerve fiber (IENF) degeneration and regeneration and its relationship to clinical and neurological deficits in Parkinson's disease (PD).Methods: Twenty-three PD patients and 10 age-matched controls underwent skin biopsy and assessment of somatic and autonomic symptoms and deficits. We have assessed Intraepidermal Nerve Fiber Density (IENFD) using standard PGP9.5 staining and GAP-43 to assess Mean Axonal Length (MAL) and Intraepidermal Total Nerve Fiber Length (IETNFL).Results: IENFD (p < 0.0001), MAL (p < 0.0001), IETNFL/Area (p = 0.009), and IETNFL/Length (p = 0.04) were significantly reduced in patients with PD compared to controls. IENFD correlated significantly with disease duration (p = 0.03), cumulative levodopa dose (p = 0.02), Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III) (p = 0.01), Schwab and England Activities of Daily Living (ADL) (p = 0.03), NSP (p = 0.03), and 30:15 ratio (p = 0.03). IETNFL/Area correlated with the Autonomic Scale for Outcomes in Parkinson's Disease (SCOPA-AUT) (p = 0.03) and Diabetic Neuropathy Symptom score (DNS) (p = 0.04) and IETNFL/Length correlated with DNS (p = 0.03). MAL correlated with SCOPA-AUT (p = 0.01), DNS (p = 0.02), and DB-HRV (p = 0.02).Conclusion: Increased IENF degeneration and impaired regeneration correlates with somatic and autonomic symptoms and deficits in patients with PD.