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The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies., Competing Interests: Competing interests: R.A.I.B. holds equity and serves as a director for Centile Bioscience Inc. P.J.H. holds equity and serves as director for H2 Cognitive Designs LTD. R.U. was speaker at a promotional educational event for Otuska; and reports consultancy for Vitaris and Springer Healthcare in the past 3 years. T.A.P. reports consultancy for Arialys Therapeutics Inc. and speaker honoraria from Janssen. A.C. is President of the FND Society, Associate Editor of JNNP, and gives independent testimony in court on a range of neuropsychiatric topics. E.B. consults for GSK, SR One, Boehringer Ingelheim and Sosei Heptares. T.S. is Director of The Pandemic Institute, which has received funding from Innova and CSL Seqirus, and Aviva and DAM Health. T.S. was an advisor to the GSK Ebola Vaccine program and the Siemens Diagnostic Program. T.S. chaired the Siemens Healthineers Clinical Advisory Board. T.S. co-chaired the WHO Neuro-COVID task force and sat on the UK Government Advisory Committee on Dangerous Pathogens, and the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on COVID-19 vaccines. T.S. advised to the UK COVID-19 Therapeutics Advisory Panel. T.S. was a member of the COVID-19 Vaccines Benefit Risk Expert Working Group for the Commission on Human Medicines committee of the MHRA. T.S. has been a member of the Encephalitis Society since 1998 and President of the Encephalitis Society since 2019. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Reproducible and standardised neurological assessment scales are important in quantifying research outcomes. These scales are often performed by non-neurologists and/or non-clinicians and must be robust, quantifiable, reproducible and comparable to a neurologist's assessment. COVID-CNS is a multi-centre study which utilised the Neurological Impairment Scale (NIS) as a core assessment tool in studying neurological outcomes following COVID-19 infection. We investigated the strengths and weaknesses of the NIS when used by non-neurology clinicians and non-clinicians, and compared performance to a structured neurological examination performed by a neurology clinician. Through our findings, we provide practical advice on how non-clinicians can be readily trained in conducting reproducible and standardised neurological assessments in a multi-centre study, as well as illustrating potential pitfalls of these tools., Competing Interests: Declaration of competing interest T.S. is the Director of The Pandemic Institute which has received funding from Innova and CSL Seqirus and Aviva and DAM Health. T.S. was an advisor to the GSK Ebola Vaccine programme and the Siemens Diagnostic Programme. T.S. Chaired the Siemens Healthineers Clinical Advisory Board. T.S. Co-Chaired the WHO Neuro-COVID task force and sat on the UK Government Advisory Committee on Dangerous Pathogens, and the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on Covid-19 vaccines. T.S. Advised to the UK COVID-19 Therapeutics Advisory Panel (UK-TAP). T.S. was a Member of COVID-19 Vaccines Benefit Risk Expert Working Group for the Commission on Human Medicines (CHM) committee of the Medicines and Healthcare products Regulatory Agency (MHRA). T.S. has been a member of the Encephalitis Society since 1998 and President of the Encephalitis Society since 2019., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection., Methods: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment., Results: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups., Conclusions: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The symptomatic treatment of Parkinson's disease (PD) has been dominated by the use of dopaminergic medication, but significant unmet need remains, much of which is related to non-motor symptoms and the involvement of non-dopaminergic transmitter systems. As such, little has changed in the past decades that has led to milestone advances in therapy and significantly improved treatment paradigms and patient outcomes, particularly in relation to symptoms unresponsive to levodopa. This review has looked at how pharmacological approaches to treatment are likely to develop in the near and distant future and will focus on two areas: 1) novel non-dopaminergic pharmacological strategies to control motor symptoms; and 2) novel non-dopaminergic approaches for the treatment of non-motor symptoms. The overall objective of this review is to use a 'crystal ball' approach to the future of drug discovery in PD and move away from the more traditional dopamine-based treatments. Here, we discuss promising non-dopaminergic and 'dirty drugs' that have the potential to become new key players in the field of Parkinson's disease treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Given the growing evidence for an environmental contribution to the etiology of Parkinson's disease (PD), searching for local and regional differences in PD prevalence in multiple areas across the world may further clarify the role of environmental toxins., Objective: To provide local and regional prevalence estimates of PD in Poland., Methods: We analyzed the prevalence of PD and its trend over the last decade (2010 to 2019) based on data from the National Health Fund in Poland. We specifically examined sex differences in PD prevalence, as well as differences across Polish regions., Results: During the above period, the prevalence of PD in Poland increased from 226 per 100,000 to 269 per 100,000 inhabitants. Unexpectedly, we found that PD was 1.2-times more common in women than men. The increase in prevalence over the past decade was different between both sexes: an increase from 250 to 283 per 100,000 for women (13.3% increase), and from 200 to 254 per 100,000 for men (27.1% increase). In addition, we observed differences in prevalence across different Polish regions, with some regions having up to 51% lower prevalence rates than others., Conclusions: The prevalence of PD in Poland is in line with previously reported prevalence rates across Europe. However, unlike the situation in most of the world, PD was more prevalent in women than men. We discuss several possible explanations as well as potential measures that might help to reduce the growth of PD.

Objective: To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP)., Methods: A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span., Results: Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05)., Conclusions: Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up., (© 2023. The Author(s).)

Background: The circadian system and its dysfunction in persons with Parkinson's disease (PwP) has a clear impact on both motor and non-motor symptoms. Examples include circadian patterns in motor disability, with worsening of symptoms throughout the day, but also the existence of similar patterns in non-motor symptoms., Objective: In this narrative review, we discuss the role of the circadian system, we address the role of dopamine in this system, and we summarise the evidence that supports the use of circadian system treatments for motor and non-motor symptoms in PwP., Methods: A systematic search in PubMed and Web of Science database was performed and the final search was performed in November 2021. We included articles whose primary aim was to investigate the effect of melatonin, melatonin agonists, and light therapy in PwP., Results: In total 25 articles were retrieved. Of these, 12 were related to bright light therapy and 13 to melatonin or/and melatonin agonists. Most, but not all, studies showed that melatonin and melatonin agonists and light therapy induced improvements in measures of sleep, depression, motor function, and some also cognitive function and other non-motor symptoms. For some of these outcomes, including daytime sleepiness, depressive symptoms, and some motor symptoms, there is level 2 B evidence for the use of circadian treatments in PwP., Conclusions: Treatment with bright light therapy, exogenous melatonin and melatonin agonists seems to have not only positive effects on sleep quality and depression but also on motor function in PwP. Drawbacks in earlier work include the relatively small number of participants and the heterogeneity of outcome measures. Further large and well-designed trials are needed to address these shortcomings and to confirm or refute the possible merits of the circadian system as a treatment target in PwP., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD., (© 2022. The Author(s).)

Background: Non-motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied., Objective: To study NMF in PwP using both the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) NMF subscale and wearable sensors., Methods: We evaluated differences in overall burden of NMF and of specific NMF across disease durations: <2 years (n = 33), 2-5 years (n = 35), 5-10 years (n = 33), and > 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning "off" periods., Results: Significant between-group differences were observed for MDS-NMS NMF total scores ( P  < 0.001), and specifically for depression, anxiety, fatigue and cognition, with both NMF prevalence and burden increasing in those with longer disease duration. Whereas only 9.1% with a short disease duration had NMF (none of whom had dyskinesia), in PwP with a disease duration of >10 years this was 71.0% ( P  < 0.001). From a motor perspective, dyskinesia severity increased evenly with increasing disease duration, while NMF scores in affected individuals showed an initial increase with largest differences between 2-5 years disease duration ( P  < 0.001), with plateauing afterwards. Finally, we observed that the most common NMF symptoms in patients with sensor-confirmed early morning "off" periods were fluctuations in cognitive capabilities, restlessness, and excessive sweating., Conclusions: Non-motor fluctuations prevalence in PwP increases with disease duration, but in a pattern different from motor fluctuations. Moreover, NMF can occur in PwP without dyskinesia, and in those with NMF the severity of NMF increases most during years 2-5 after diagnosis., Competing Interests: The current data analyses were not supported by funding. There is no conflict of interest., (© 2022 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Unexplained weight changes that occur in Parkinson's disease (PD), are often neglected and remain a poorly understood non-motor feature in patients with PD. A specific 'Park-weight' phenotype with low body weight has been described, and our aim was to evaluate the clinical and prognostic trajectories and biomarkers of weight variability in PD. We evaluated body weight-related biomarkers in 405 de novo PD patients and 187 healthy controls (HC) over a 5-year follow-up period from the PPMI database. Body-weight variability was defined as intra-individual variability in body weight between visits. PD patients were categorized as weight losers, gainers, or patients with stable weight. The differential progression of motor and non-motor clinical variables between groups was explored using linear mixed-effects models. Finally, we estimated longitudinal changes in weight as a function of baseline and longitudinal striatal presynaptic dopaminergic transporter imaging. PD patients presented a greater weight variability compared to HC (p = 0.003). Patients who developed weight loss had lower CSF amyloid-beta 1-42 (p = 0.009) at baseline. In addition, patients with weight loss showed a faster cognitive decline (p = 0.001), whereas patients with weight gain showed a slower motor progression (p = 0.001), compared to patients with stable weight. Baseline right striatal denervation was a predictor of weight variability in both PD patients and HC (p < 0.001). Similarly, weight variability in PD patients was associated with the progression of right striatal denervation (p < 0.001). Weight variability and specifically weight loss are more frequent in PD compared to HC, and are associated with specific motor, non-motor and cognitive progression patterns. A greater CSF amyloid burden was present at baseline in patients with subsequent weight loss. Presynaptic dopaminergic imaging in the right striatum may serve as a predictor of future weight changes in PD and HC., (© 2022. The Author(s).)

Background: Postural Instability and Gait difficulties (PIGD) subtype has been associated with worse cognitive performance in Parkinson's disease (PD)., Objective: To investigate whether PIGD subtype classification or PIGD-related clinical features predict the development of cognitive decline in de novo PD patients., Methods: Data from 422 PD patients with de novo PD were obtained from the PPMI database. At follow-up (up to 6 years), patients were categorized as having cognitive impairment or not. Multivariate Cox survival analysis was carried out including motor subtype and individual MDS-UPDRS items defining PIGD phenotype as predictors. Previously validated clinical predictors of cognitive impairment were included in the model as covariates. Occurrence of cognitive impairment at follow-up was used as the time-to-event and Kaplan-Meier curve was generated., Results: At baseline, 76 patients were classified as PIGD, 299 tremor-dominant and 47 as indeterminate. Development of cognitive impairment was not associated with PIGD subtype (p = 0.252). When individual MDS-UPDRS items were interrogated in the model, postural instability proved to be an independent predictor of cognitive impairment (HR = 2.045; 95%CI: 1.068-3.918; p = 0.031), while gait difficulties were not associated with cognitive decline (p = 0.870)., Conclusions: Our findings suggest that postural instability, as assessed by MDS-UPDRS III, may serve as a possible indicator of the risk of developing cognitive impairment in de novo PD patients rather than the PIGD phenotype., (© 2021. The Author(s).)

The Coronavirus Disease 2019 (Covid-19) pandemic and the consequent restrictions imposed worldwide have posed an unprecedented challenge to research and training in Parkinson's disease (PD). The pandemic has caused loss of productivity, reduced access to funding, an oft-acute switch to digital platforms, and changes in daily work protocols, or even redeployment. Frequently, clinical and research appointments were suspended or changed as a solution to limit the risk of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spread and infection, but since the care and research in the field of movement disorders had traditionally been performed at in-person settings, the repercussions of the pandemic have even been more keenly felt in these areas. In this chapter, we review the implications of this impact on neurological research and training, with an emphasis on PD, as well as highlight lessons that can be learnt from how the Covid-19 pandemic has been managed in terms of restrictions in these crucial aspects of the neurosciences. One of the solutions brought to the fore has been to replace the traditional way of performing research and training with remote, and therefore socially distanced, alternatives. However, this has introduced fresh challenges in international collaboration, contingency planning, study prioritization, safety precautions, artificial intelligence, and various forms of digital technology. Nonetheless, in the long-term, these strategies will allow us to mitigate the adverse impact on PD research and training in future crises., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Coronavirus Disease 2019 (Covid-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to unprecedented challenges for the delivery of healthcare and has had a clear impact on people with chronic neurological conditions such as Parkinson's disease (PD). Acute worsening of motor and non-motor symptoms and long-term sequalae have been described during and after SARS-CoV-2 infections in people with Parkinson's (PwP), which are likely to be multifactorial in their origin. On the one hand, it is likely that worsening of symptoms has been related to the viral infection itself, whereas social restrictions imposed over the course of the Covid-19 pandemic might also have had such an effect. Twenty cases of post-Covid-19 para-infectious or post-infectious parkinsonism have been described so far where a variety of pathophysiological mechanisms seem to be involved; however, a Covid-19-induced wave of post-viral parkinsonism seems rather unlikely at the moment. Here, we describe the interaction between SARS-CoV-2 and PD in the short- and long-term and summarize the clinical features of post-Covid-19 cases of parkinsonism observed so far., (Copyright © 2022 Elsevier Inc. All rights reserved.)

As a result of the Coronavirus Disease 2019 (Covid-19) pandemic the use of telemedicine and remote assessments for patients has increased exponentially, enabling healthcare professionals to reduce the need for in-person clinical visits and, consequently, reduce the exposure to the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This development has been aided by increased guidance on digital health technologies and cybersecurity measures, as well as reimbursement options within healthcare systems. Having been able to continue to connect with people with Parkinson's Disease (PwP, PD) has been crucial, since many saw their symptoms worsen over the pandemic. Inspite of the success of telemedicine, sometimes even enabling delivery of treatment and research, further validation and a unified framework are necessary to measure the true benefit to both clinical outcomes and health economics. Moreover, the use of telemedicine seems to have been biased towards people from a white background, those with higher education, and reliable internet connections. As such, efforts should be pursued by being inclusive of all PwP, regardless of geographical area and ethnic background. In this chapter, we describe the effect he Covid-19 pandemic has had on the use of telemedicine for care and research in people with PD, the limiting factors for further rollout, and how telemedicine might develop further., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Device-aided therapies, including levodopa-carbidopa intestinal gel infusion, apomorphine subcutaneous infusion, and deep brain stimulation, are available in many countries for the management of the advanced stage of Parkinson's disease (PD). Currently, selection of device-aided therapies is mainly focused on patients' motor profile while non-motor symptoms play a role limited to being regarded as possible exclusion criteria in the decision-making process for the delivery and sustenance of a successful treatment. Differential beneficial effects on specific non-motor symptoms of the currently available device-aided therapies for PD are emerging and these could hold relevant clinical implications. In this viewpoint, we suggest that specific non-motor symptoms could be used as an additional anchor to motor symptoms and not merely as exclusion criteria to deliver bespoke and patient-specific personalised therapy for advanced PD.

Introduction: There is an ongoing digital revolution in the field of Parkinson's disease (PD) for the objective measurement of motor aspects, to be used in clinical trials and possibly support therapeutic choices. The focus of remote technologies is now also slowly shifting towards the broad but more "hidden" spectrum of non-motor symptoms (NMS)., Methods: A narrative review of digital health technologies for measuring NMS in people with PD was conducted. These digital technologies were defined as assessment tools for NMS offered remotely in the form of a wearable, downloadable as a mobile app, or any other objective measurement of NMS in PD that did not require a hospital visit and could be performed remotely. Searches were performed using peer-reviewed literature indexed databases (MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials), as well as Google and Google Scholar., Results: Eighteen studies deploying digital health technology in PD were identified, for example for the measurement of sleep disorders, cognitive dysfunction and orthostatic hypotension. In addition, we describe promising developments in other conditions that could be translated for use in PD., Conclusion: Unlike motor symptoms, non-motor features of PD are difficult to measure directly using remote digital technologies. Nonetheless, it is currently possible to reliably measure several NMS and further digital technology developments are underway to offer further capture of often under-reported and under-recognised NMS., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Growing evidence suggests that non-motor symptoms (NMS) in Parkinson's disease (PD) have differential progression patterns that have a different natural history from motor progression and may be geographically influenced. We conducted a cross-sectional analysis of 1607 PD patients of whom 1327 were from Europe, 208 from the Americas, and 72 from Asia. The primary objective was to assess baseline non-motor burden, defined by Non-Motor Symptoms Scale (NMSS) total scores. Other aims included identifying the factors predicting quality of life, differences in non-motor burden between drug-naïve and non-drug-naïve treated patients, and non-motor phenotypes across different geographical locations. Mean age was 65.9 ± 10.8 years, mean disease duration 6.3 ± 5.6 years, median Hoehn and Yahr stage was 2 (2-3), and 64.2% were male. In this cohort, mean NMSS scores were 46.7 ± 37.2. Differences in non-motor burden and patterns differed significantly between drug-naïve participants, those with a disease duration of less than five years, and those with a duration of five years or over (p ≤ 0.018). Significant differences were observed in geographical distribution (NMSS Europe: 46.4 ± 36.3; Americas: 55.3 ± 42.8; Asia: 26.6 ± 25.1; p < 0.001), with differences in sleep/fatigue, urinary, sexual, and miscellaneous domains (p ≤ 0.020). The best predictor of quality of life was the mood/apathy domain (β = 0.308, p < 0.001). This global study reveals that while non-motor symptoms are globally present with severe NMS burden impacting quality of life in PD, there appear to be differences depending on disease duration and geographical distribution.

Background: Identifying predictors of incident cognitive impairment (CI), one of the most problematic long-term outcomes, in Parkinson's disease (PD) is highly relevant for personalized medicine and prognostic counseling. The Nonmotor Symptoms Scale (NMSS) provides a global clinical assessment of a range of NMS, reflecting NMS burden (NMSB), and thus may assist in the identification of an "at-risk" CI group based on overall NMSB cutoff scores., Methods: To investigate whether specific patterns of PD NMS profiles predict incident CI, we performed a retrospective longitudinal study on a convenience sample of 541 nondemented PD patients taking part in the Nonmotor Longitudinal International Study (NILS) cohort, with Mini-Mental State Examination (MMSE), NMSS, and Scales for Outcomes in PD Motor Scale (SCOPA Motor) scores at baseline and last follow-up (mean 3.2 years) being available., Results: PD patients with incident CI (i.e., MMSE score ≤ 25) at last follow-up (n = 107) had severe overall NMSB level, significantly worse NMSS hallucinations/perceptual problems and higher NMSS attention/memory scores at baseline. Patients with CI also were older and with more advanced disease, but with no differences in disease duration, dopamine replacement therapy, sex, and comorbid depression, anxiety, and sleep disorders., Conclusions: Our findings suggest that a comprehensive baseline measure of NMS and in particular hallucinations and perceptual problems assessed with a validated single instrument can be used to predict incident CI in PD. This approach provides a simple, holistic strategy to predict future CI in this population., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Constipation is regarded as one of the prodromal features of Parkinson's disease (PD) and there is emerging evidence linking gastrointestinal dysfunction and cognitive impairment (CI) in PD., Objective: We explored whether constipation is associated with development of CI in two independent cohorts of de novo PD patients (n = 196 from the Non-motor International Longitudinal Study [NILS] and n = 423 from the Parkinson's Progression Markers Initiative [PPMI] study)., Methods: Constipation was clinically defined using the Non-Motor Symptoms Scale (NMSS) item-21 [NILS] and Scales for Outcomes in PD-Autonomic (SCOPA-AUT) item-5 [PPMI]. We assessed baseline group differences (PD with or without constipation) in CI, global non-motor symptoms burden, motor dysfunction, and striatal dopaminergic denervation. Kaplan-Meier method estimated group differences in cumulative proportion of patients with incident CI over three years. In PPMI, we subsequently performed univariate and multivariate Cox survival analyses to evaluate whether constipation predicts incident mild cognitive impairment or dementia over a 6-year period, including constipation and other known predictors of CI as covariates., Results: Patients with constipation had greater motor and global non-motor burden in both cohorts at baseline (p < 0.05). Kaplan-Meier plots showed faster conversion to CI in patients with constipation in both cohorts (p < 0.05). In PPMI, 37 subjects developed dementia during a mean follow-up of 4.9 years, and constipation was an independent predictor of dementia onset (hazard ratio = 2.311; p = 0.02)., Conclusion: Constipation in de novo PD patients is associated with development of cognitive decline and may serve as a clinical biomarker for identification of patients at risk for cognitive impairment.

Huntington's disease (HD), an autosomal dominant hereditary disorder associated with the accumulation of mutant huntingtin, is classically associated with cognitive decline and motor symptoms, notably chorea. However, growing evidence suggests that nonmotor symptoms are equally prevalent and debilitating. Some of these symptoms may be linked to hypothalamic pathology, demonstrated by findings in HD animal models and HD patients showing specific changes in hypothalamic neuropeptidergic populations and their associated functions. At least some of these alterations are likely due to local mutant huntingtin expression and toxicity, while others are likely caused by disturbed hypothalamic circuitry. Common problems include circadian rhythm disorders, including desynchronization of daily hormone excretion patterns, which could be targeted by novel therapeutic interventions, such as timed circadian interventions with light therapy or melatonin. However, translation of these findings from bench-to-bedside is hampered by differences in murine HD models and HD patients, including mutant huntingtin trinucleotide repeat length, which is highly heterogeneous across the various models. In this chapter, we summarize the current knowledge regarding hypothalamic alterations in HD patients and animal models, and the potential for these findings to be translated into clinical practice and management., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The Non-Motor Symptoms Scale (NMSS) was developed and validated in 2007 as the first instrument for the comprehensive assessment of a range of non-motor symptoms in Parkinson's disease (PD). Thirteen years have elapsed since its introduction and extensive international validation with good psychometric attributes has been carried out. Here, we review the validation data of the NMSS and its cross-validity with other scales, and describe the key evidence derived from use of the NMSS in clinical studies. To date, over 100 clinical studies and trials have made use of it as an outcome measure, showing consistent and strong correlations between NMSS burden and health-related quality of life measures. Moreover, the scale has shown to be capable of detecting longitudinal changes in non-motor symptoms, where studies have shown differential changes over time of several of the NMSS domains. The scale has become a key outcome in several randomized clinical trials. Highlighting the prevalence and importance of non-motor symptoms to quality of life in patients with PD, the development of NMSS has also been useful in signposting clinical and biomarker based research addressing non-motor symptoms in PD., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Background: Several small-scale studies have shown that motor performance in Parkinson's disease (PD) fluctuates throughout the day. Studies specifically focusing on de novo patients are, however, lacking., Objective: To evaluate the effect of clock time on motor performance in de novo drug-naïve patients with PD., Methods: We retrieved MDS-UPDRS III scores for 421 de novo PD patients from the PPMI cohort and stratified them into three groups based on time of assessment: group 1) 7:00-10:00; group 2) 10:00-13:00, and group 3) 13:00-18:00. Groups were compared using Kruskal-Wallis test and results corrected for multiple testing. In addition, we obtained 27 wearable sensor reports, objectively capturing bradykinesia scores in a home setting over a 6-day continuous period, in 12 drug-naïve patients from the Parkinson's Kinetigraph Registry held at King's College Hospital London. Time spent in severe bradykinesia scores were broken down into five daytime (06:00-21:00) three-hourly epochs and scores compared using the Friedman test., Results: There were no group differences in demographic or other clinical variables for the cross-sectional analysis. MDS-UPDRS III total scores worsened significantly during the course of the day (median 18 (group 1); 20 (group 2); and 23 (group 3); p = 0.001). In the longitudinal wearable sensor cohort, diurnal variations were present in percentage of time spent in severe bradykinesia (p < 0.001) with the lowest percentage during the 09:00-12:00 epoch (69.56±16.68%), when most patients are awake and start daily activity, and the highest percentage during the 18:00-21:00 epoch (73.58±16.35%)., Conclusion: This exploratory study shows the existence of a diurnal pattern of motor function in patients with de novo PD. The results obtained were corroborated by objective measurements in a small longitudinal cohort confirming a similar diurnal motor score variation.

Sialorrhoea in Parkinson's disease (PD) is an often neglected yet key non-motor symptom with impact on patient quality of life. However, previous studies have shown a broad range of prevalence figures. To assess prevalence of drooling in PD and its relationship to quality of life, we performed a retrospective analysis of 728 consecutive PD patients who had a baseline and follow-up assessment as part of the Non-motor International Longitudinal Study (NILS), and for whom drooling presence and severity were available, assessed through the Non-Motor Symptoms Scale (NMSS). In addition, we analysed the prevalence of associated dysphagia through self-reported outcomes. Quality of life was assessed through the PDQ-8 scale. Baseline (disease duration 5.6 years) prevalence of drooling was 37.2% (score ≥ 1 NMSS question 19), and after 3.27 ± 1.74 years follow-up, this was 40.1% (p = 0.17). The prevalence of drooling increased with age (p < 0.001). The severity of drooling, however, did not change (p = 0.12). While in 456 patients without drooling at baseline, only 16% (n = 73) had dysphagia (question 20 of the NMSS), in those with drooling this was 34.3% (p < 0.001). At follow-up, the number of patients with dysphagia had increased, 20.4% with no drooling had dysphagia, and 43.6% with drooling had dysphagia. Both at baseline and follow-up, drooling severity was significantly positively associated with quality of life (PDQ-8; r = 0.199; p < 0.001). In moderately advanced PD patients, subjective drooling occurs in over one-third of patients and was significantly associated with decreased quality of life. Dysphagia occurred significantly more often in patients with drooling.

Introduction : Fatigue and apathy are two key non-motor symptoms in Parkinson's disease (PD), with documented negative impact on Quality of life (QoL) and a frequent burden for caregivers. Areas covered : In this review, the authors comment on the latest pathophysiology, clinical phenomenology, the most frequently used scales for fatigue and apathy in PD with a focus on available therapeutic strategies. Expert opinion :The identification of fatigue and apathy in PD is mainly hampered by the lack of a clear consensus on these subjective symptoms. The pathophysiological processes remain unclear, and the large variation in prevalence is likely due to the heterogeneous PD populations and the lack of an enriched cohort of people with fatigue and/or apathy as main symptoms. Treatment strategies, and especially level 1 evidence for specific treatments for fatigue and apathy in PD, remain scarce. The best evidence to date is doxepin, rasagiline and levodopa infusion therapy (for fatigue), and rivastigmine (for apathy). Further efforts should be made to properly identify these two major symptoms in PD, to correctly detect those who may benefit most from tailored personalized interventions.

Background: Previous studies have identified low serum uric acid (SUA) levels as a risk factor for the development of Parkinson's disease (PD). Prodromal PD mainly manifests as a complex of non-motor features, but the association between SUA levels and nonmotor symptoms (NMS) burden level in advanced PD patients is poorly studied., Objective: To determine the association between SUA levels and NMS in PD patients., Methods: Data were gathered from an open label, cross sectional, study with analysis of SUA levels in 87 PD patients and were correlated to NMS through the NMS scale (NMSS). In addition, we examined the possible relation between SUA and NMS burden levels and motor scores., Results: There was a moderate negative association between SUA levels and NMSS total score (ρ= -0.379, p < 0.001). In line with this, we observed that higher NMS burden was associated with lower SUA levels (p < 0.001). Within individual NMSS domains, a moderate negative correlation was observed between SUA levels and the cardiovascular/falls (ρ= -0.285, p = 0.008), sleep/fatigue (ρ= -0.299, p = 0.005), and miscellaneous domains (ρ= -0.318, p = 0.003)., Conclusion: In this observational study we observed that SUA levels were negatively associated to NMS burden in PD patients with a specific link to miscellaneous, sleep/fatigue and cardiovascular domains of the NMSS. Interestingly, we did not find a clear relation between SUA and motor scores. Future large-scale prospective studies in de novo and advanced PD are needed to evaluate and establish these associations.

Stress is ubiquitous with many factors contributing to its effects, including psychological responses and associated biological factors, including cortisol related physiological responses, and inflammation. Also in Parkinson's disease there is growing evidence for the role of stress in some key symptoms, even stretching to the prodromal stage. Here we discuss the possible contributions of the range and nature of stress in PD and we aim to summarize the current knowledge about the role of stress-related responses on motor and non-motor symptoms, the underlying pathophysiology, and the potential implications for treatment., (© 2020 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is the second commonest neurodegenerative disorder in the world with a rising prevalence. The pathophysiology is multifactorial but aggregation of misfolded α-synuclein is considered to be a key underpinning mechanism. Amyloid-β (Aβ) and tau deposition are also comorbid associations and especially Aβ deposition is associated with cognitive decline in PD. Some existing evidence suggests that low cerebrospinal fluid (CSF) Aβ 42 is predictive of future cognitive impairment in PD. Recent studies also show that CSF Aβ is associated with the postural instability and gait difficulties (PIGD) or the newly proposed cholinergic subtype of PD, a possible risk factor for cognitive decline in PD. The glial-lymphatic system, responsible for convective solute clearance driven by active fluid transport through aquaporin-4 water channels, may be implicated in brain amyloid deposition. A better understanding of the role of this system and more specifically the role of Aβ in PD symptomatology, could introduce new treatment and repurposing drug-based strategies. For instance, apomorphine infusion has been shown to promote the degradation of Aβ in rodent models. This is further supported in a post-mortem study in PD patients although clinical implications are unclear. In this review, we address the clinical implication of cerebral Aβ deposition in PD and elaborate on its metabolism, its role in cognition and motor function/gait, and finally assess the potential effect of apomorphine on Aβ deposition in PD.

Wearable sensors are becoming increasingly more available in Parkinson's disease and are used to measure motor function. Whether non-motor symptoms (NMS) can also be measured with these wearable sensors remains unclear. We therefore performed a retrospective, exploratory, analysis of 108 patients with a diagnosis of idiopathic Parkinson's disease enroled in the Non-motor Longitudinal International Study (UKCRN No. 10084) at King's College Hospital, London, to determine the association between the range and nature of NMS and an accelerometer-based outcome measure of bradykinesia (BKS) and dyskinesia (DKS). NMS were assessed by the validated NMS Scale, and included, e.g., cognition, mood and sleep, and gastrointestinal, urinary and sexual problems. Multiple linear regression modelling was used to identify NMS associated with BKS and DKS. We found that BKS was associated with domains 6 (gastrointestinal tract; p  = 0.006) and 8 (sexual function; p  = 0.003) of the NMS scale. DKS was associated with domains 3 (mood/cognition; p  = 0.016), 4 (perceptual problems; p  = 0.025), 6 (gastrointestinal tract; p  = 0.029) and 9 (miscellaneous, p  = 0.003). In the separate domains, constipation was significantly associated with BKS. Delusions, dysphagia, hyposmia, weight change and hyperhidrosis were identified as significantly associated with DKS. None of the NMSS domains were associated with disease duration ( p  ≥ 0.08). In conclusion, measures of BKS and DKS were mainly associated with gastrointestinal problems, independent of disease duration, showing the potential for wearable devices to pick up on these symptoms. These exploratory results deserve further exploration, and more research on this topic in the form of comprehensive large-scale studies is needed., Competing Interests: Competing interestsK.R. Chaudhuri reports personal fees from Global Kinetics, outside the submitted work. The remaining authors declare no competing interests., (© The Author(s) 2019.)

Objective: To identify associated (non-)motor profiles of Parkinson's disease (PD) patients with hyperhidrosis as a dominant problem., Methods: This is a cross-sectional, exploratory, analysis of participants enrolled in the Non-motor Longitudinal International Study (NILS; UKCRN No: 10084) at the Parkinson's Centre at King's College Hospital (London, UK). Hyperhidrosis scores (yes/no) on question 28 of the Non-Motor Symptom Questionnaire were used to classify patients with normal sweat function (n = 172) and excessive sweating (n = 56) (Analysis 1; n = 228). NMS scale (NMSS) question 30 scores were used to stratify participants based on hyperhidrosis severity (Analysis 2; n = 352) using an arbitrary severity grading: absent score 0 (n = 267), mild 1-4 (n = 49), moderate 5-8 (n = 17), and severe 9-12 (n = 19). NMS burden, as well as PD sleep scale (PDSS) scores were then analysed along with other correlates., Results: No differences were observed in baseline demographics between groups in either analysis. Patients with hyperhidrosis exhibited significantly higher total NMSS burden compared to those without (p < 0.001). Secondary analyses revealed higher dyskinesia scores, worse quality of life and PDSS scores, and higher anxiety and depression levels in hyperhidrosis patients (p < 0.001). Tertiary analyses revealed higher NMSS item scores for fatigue, sleep initiation, restless legs, urinary urgency, and unexplained pain (p < 0.001)., Conclusions: Chronic hyperhidrosis appears to be associated with a dysautonomia dominant subtype in PD patients, which is also associated with sleep disorders and a higher rate of dyskinesia (fluctuation-related hyperhidrosis). These data should prompt the concept of hyperhidrosis being used as a simple clinical screening tool to identify PD patients with autonomic symptoms.

Background: Blue light glasses have been introduced as a possible new treatment option to treat sleep disturbances in patients with Parkinson disease (PD). Assessing patient attitudes represents a key step in the road towards formal testing and introduction into clinical practice. Specifically, we aimed to assess how patients experience the use of blue light glasses, aiming to optimise compliance in upcoming clinical trials where these glasses will be tested for efficacy., Methods: We invited 58 PD patients who had used the blue light glasses for at least one week on a daily basis to complete an online survey about their experiences and self-reported impact. For this purpose, the System Usability Scale was used, supplemented with additional questions about (side)effects. A total of 31 patients (53%) replied., Results: 74% of respondents reported subjective improvements in night-time sleep, daytime sleepiness, depressive symptoms, motor functioning, or a combination thereof. The median score for the System Usability Scale (SUS; 0-100 range, higher scores indicating better performance) was 70.0. A total of 26 patients (84%) had an overall positive attitude towards the technique, with patients rating the glasses with an average score of 6.9 ± 2.0 (SD) out of 10. Except for one patient, all responders would like to continue using the glasses, mostly because they considered it a useful aid., Conclusion: Blue light therapy appears to have a positive effect on sleep, mood, and motor symptoms in PD. PD patients had an overall positive attitude towards blue light glasses as treatment for sleep disorders.

Introduction: Although circadian variation of (motor) symptoms in Parkinson disease (PD) patients has been described, it remains unclear what effect seasonal variation may have on non-motor symptoms (NMS)., Methods: Cross-sectional retrospective study on 372 consecutive PD patients taking part in the Non-motor Longitudinal International Study at King's College Hospital London between November 2011 and July 2018. Patients were divided into three groups based on their date of assessment, using a simplified seasonal model: group 1: November-February (n = 107); group 2: March-15 June (n = 107); and group 3: 16 June-October (n = 158). Primary outcome was a seasonal difference in NMS scale (NMSS) total scores (higher scores reflecting greater disability). We hypothesized that PD patients exhibit circannual NMS burden patterns., Results: All groups were identical concerning disease onset and duration, HY stage, Levodopa equivalent dose, and gender. There was a seasonal difference in NMSS total scores (p = 0.040), with the highest scores (57.1 ± 42.5) in season 1 (winter months) and the lowest (45.1 ± 34.4) in season 3 (summer months) (p = 0.037). Seasonal differences were observed in NMSS domain 1 (cardiovascular symptoms) (p = 0.011), domain 4 (perceptual problems) (p = 0.017) and domain 9 (miscellaneous symptoms) (p = 0.009). A trend was observed for domain 2 (sleep) (p = 0.057)., Conclusion: NMS in PD fluctuate throughout the year, with worsening of symptoms in the winter months compared to the summer months suggestive of dysfunction of the body's master clock, the suprachiasmatic nuclei. Such variations must be accommodated in daily care to ascertain appropriate changes in medication regimes and in clinical trials for the interpretation of outcomes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We report the first videotaped case of focal and task-specific dystonia of the upper limb that occurred exclusively while using a cue during billiard playing. The repetitive movements in conjunction with a highly skilled performance likely contributed to the development of this focal dystonia., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: To determine if autonomic dysfunction, cognitive disorders or axial disability are associated with white matter lesions (WML) in Parkinson disease (PD)., Methods: We performed a retrospective cross-sectional review study on 204 consecutive PD patients who underwent cerebral MRI in our center between January 2012 and July 2016. For each patient, we scored the severity of WML and PV (periventricular) WML using the Fazekas score and using the ARWMC scale for WML and BG (basal ganglia) and clinical characteristics such as neurogenic orthostatic hypotension and cognitive function., Results: 204 PD patients were included of whom n = 53 (26.0%) had neurogenic orthostatic hypotension (nOH). The presence of nOH was significantly associated with the severity of WML as defined by the Fazekas score and the ARWMC scale. An ordinal regression model confirmed this association with an OR of 0.41 (95% CI 0.18-0.92: p = .03) and an OR of 0.39 (95% CI 0.17-0.88: p = .02). There were no significant associations between WML and other co-variables, including hypertension, dopaminergic medication use, Hoehn and Yahr stage, gender and cognitive decline., Conclusion: The presence of nOH is associated with WML severity in PD patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Continuous dopaminergic stimulation in Parkinson's disease (PD) has several advantages over pulsatile, non-continuous, stimulation. These therapies currently consist of pump-based and transcutaneous therapies and are based on a more constant delivery of the dopaminergic drug resulting in continuous dopaminergic stimulation and a more stable treatment effect. Several clinical and experimental observations have shown that continuous stimulation of dopaminergic receptors induces fewer complications, such as dyskinesia, compared to pulsatile stimulation. Currently available non-oral pharmacological continuous therapies in PD include the transdermal Rotigotine (RTG) patch, infusion therapies with Apomorphine and Intrajejunal Levodopa (IJLI) and the Rivastigmine patch. Here we aim to provide a concise review of these current therapies and discuss ongoing and future developments of continuous non-oral pharmacological dopaminergic therapies in PD.

There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neuronal/glial glutamate transporters was determined by qPCR in postmortem prefrontal cortex. The anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) were selected from young MDD patients who had committed suicide (MDD-S; n = 17), from MDD patients who died of non-suicide related causes (MDD-NS; n = 7) and from matched control subjects (n = 12). We also compared elderly depressed patients who had not committed suicide (n = 14) with matched control subjects (n = 22). We found that neuronal located components (EAAT3, EAAT4, ASCT1, SNAT1, SNAT2) of the glutamate-glutamine cycle were increased in the ACC while the astroglia located components (EAAT1, EAAT2, GLUL) were decreased in the DLPFC of MDD-S patients. In contrast, most of the components in the cycle were increased in the DLPFC of MDD-NS patients. In conclusion, the glutamate-glutamine cycle - and thus glutamine transmission - is differentially affected in depressed suicide patients and depressed non-suicide patients in an area specific way., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted.

Objective: Suicide occurs in some, but not all depressed patients. So far, it remains unknown whether the studied stress-related candidate genes change in depression, suicide or both. The prefrontal cortex (PFC) is involved in, among other things, impulse control and inhibitory behavior and plays an important role in both suicide and depression., Methods: We have employed qPCR to study 124 anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) brain samples, obtained from two brain banks, from: i) young depressed patients (average age 43 years) who committed suicide (MDD-S) and depressed patients who died from causes other than suicide (MDD-NS) and from ii) elderly depressed patients (average age 75 years) who did not commit suicide (DEP). Both cohorts were individually matched with non-psychiatric non-suicide control subjects. We determined the transcript levels of hypothalamic-pituitary-adrenal axis-regulating molecules (corticotropin-releasing hormone (CRH), CRH receptors, CRH binding protein, mineralocorticoid receptor/glucocorticoid receptor), transcription factors that regulate CRH expression, CRH-stimulating cytokines, chaperone proteins, retinoid signaling, brain-derived neurotrophic factor and tropomyosin-related kinase B, cytochrome proteins, nitric oxide synthase (NOS) and monoamines., Results: In the MDD-S group, expression levels of CRH and neuronal NOS-interacting DHHC domain-containing protein with dendritic mRNA (NIDD) were increased. Other changes were only present in the DEP group, i.e. decreased NIDD, and increased and 5-hydroxytryptamine receptor 1A (5-HT1A) expression levels. Changes were found to be more pronounced in the anterior cingulate cortex than in the dorsolateral PFC., Conclusion: Depressed patients who committed suicide have different gene expression patterns than depressed patients who died of causes other than suicide., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unintended weight loss, sleep and circadian disturbances and autonomic dysfunction are prevalent features of Huntington's disease (HD), an autosomal dominantly inherited neurodegenerative disorder caused by an expanded CAG repeat sequence in the HTT gene. These features form a substantial contribution to disease burden in HD patients and appear to be accompanied by a number of neuroendocrine and metabolic changes, pointing towards hypothalamic pathology as a likely underlying mechanism. Neuronal inclusion bodies of mutant huntingtin, which are hallmarks of the disease, occur throughout the hypothalamus, and indicate local mutant huntingtin expression that could interfere with hypothalamic neuropeptide production. Also, several genetic rodent models of HD show features that could be related to hypothalamic pathology, such as weight loss and circadian rhythm disturbances. In these rodents, several hypothalamic neuropeptide populations are affected. In the present review, we summarise the changes in genetic rodent models of HD for individual hypothalamic nuclei, compare these observations to the hypothalamic changes that occur in HD patients, and make an inventory of the work that still needs to be done. Surprisingly, there is only limited overlap in the hypothalamic changes reported in HD patients and genetic rodent models. At present, the only similarity between the hypothalamic alterations in HD patients and genetic rodent models is a decrease in the number of orexin-expressing neurones in the lateral hypothalamus. Possible reasons for these discrepancies, as well as potential consequences for the development of novel therapeutic strategies, are discussed., (© 2014 British Society for Neuroendocrinology.)

In Huntington disease (HD), hypothalamic neuropeptidergic systems are not equally affected at the peptide and mRNA levels. Because prohormone convertases (PCs) are critically involved in the conversion of propeptides into their active forms, we postulated that a decrease in PC expression may underlie these discrepancies. Therefore, we assessed the expression of PC1/3 and PC2 in the hypothalamic infundibular, suprachiasmatic, and paraventricular nuclei in postmortem tissues of HD patients and controls (n = 9, each) using immunocytochemistry and quantitative reverse transcription polymerase chain reaction. We also assessed PC1/3 and PC2 mRNA expression in the inferior frontal gyrus and colocalization of both PCs with corticotropin-releasing hormone and α-melanocyte-stimulating hormone. In HD patients, PC1/3 and PC2 expression was decreased in the hypothalamic infundibular (both p = 0.046) and paraventricular nuclei (p = 0.031 and p = 0.019). In the suprachiasmatic nucleus, PC1/3 and PC2 expressions were not different between HD and control cases; PC1/3 and PC2 mRNA levels in the inferior frontal gyrus were also not different. None of the PCs was colocalized with corticotropin-releasing hormone, whereas α-melanocyte-stimulating hormone showed colocalization with PC1/3 and PC2. These data suggest that defects in the processing of hypothalamic neuropeptides in HD may partially arise from decreased PC1/3 and PC2 expressions. These changes might contribute to selective neuropathology underlying various clinical manifestations and may provide novel therapeutic targets in HD patients.

Data from transgenic mouse models of Huntington's disease (HD) suggest that dysfunction of the hypothalamic infundibular nucleus (INF) (in rodents, the arcuate nucleus) may contribute to unintended weight loss and insatiable appetite among HD patients. Using post-mortem paraffin-embedded tissue, we assessed the total number of INF neurones by thionin staining and four major regulatory neuropeptides in the INF of HD patients by immunocytochemistry and in situ hybridisation. In HD patients, the total number of neurones in the INF was unchanged compared to control subjects (P = 0.92), whereas it contained over 30% less neuropeptide Y-immunoreactive (IR) neurones (P = 0.016), as well as reduced peptide levels, in fibres to the paraventricular and ventromedial nucleus (P = 0.003, P = 0.005, respectively). Conversely, neuropeptide Y mRNA expression levels were increased three-fold (P = 0.047). No changes were observed in the number of neurones immunoreactive for α-melanocyte-stimulating hormone, agouti-related peptide, and cocaine- and amphetamine-regulated transcript (P ≥ 0.17). Our findings suggest changes in the pathology of the INF neuropeptide Y-expressing neurones in HD patients without changes in other (an)orexigenic neuropeptides and without neuronal cell loss. These findings indicate that unintended weight loss in patients suffering from this disease may be partly a result of neuropeptidergic alterations in the hypothalamic infundibular nucleus., (© 2012 British Society for Neuroendocrinology.)

Study Objective: To study whether sleep and circadian rhythm disturbances in patients with Huntington's disease (HD) arise from dysfunction of the body's master clock, the hypothalamic suprachiasmatic nucleus., Design: Postmortem cohort study., Patients: Eight patients with HD and eight control subjects matched for sex, age, clock time and month of death, postmortem delay, and fixation time of paraffin-embedded hypothalamic tissue., Measurements and Results: Using postmortem paraffin-embedded tissue, we assessed the functional integrity of the suprachiasmatic nucleus in patients with HD and control subjects by determining the expression of two major regulatory neuropeptides, vasoactive intestinal polypeptide and arginine vasopressin. Additionally, we studied melatonin 1 and 2 receptor expression. Compared with control subjects, the suprachiasmatic nucleus contained 85% fewer neurons immunoreactive for vasoactive intestinal polypeptide and 33% fewer neurons for arginine vasopressin in patients with HD (P = 0.002 and P = 0.027). The total amount of vasoactive intestinal polypeptide and arginine vasopressin messenger RNA was unchanged. No change was observed in the number of melatonin 1 or 2 receptor immunoreactive neurons., Conclusions: These findings indicate posttranscriptional neuropeptide changes in the suprachiasmatic nucleus of patients with HD, and suggest that sleep and circadian rhythm disorders in these patients may at least partly arise from suprachiasmatic nucleus dysfunction.

Neuroendocrine, metabolic and autonomic nervous system dysfunctions are prevalent among patients with Huntington's disease (HD) and may underlie symptoms such as depression, weight loss and autonomic failure. Using post-mortem paraffin-embedded tissue, we assessed the integrity of the major neuropeptide populations in the paraventricular nucleus (PVN)-the hypothalamic neuroendocrine and autonomic integration center-in HD patients. The number corticotropin-releasing hormone, cocaine- and amphetamine-regulated transcript, arginine vasopressin and oxytocin immunoreactive (ir) neurons did not differ between HD patients and control subjects. However, the significant positive correlation between arginine vasopressin and oxytocin ir neurons in control subjects (P = 0.036) was absent in patients. Corticotropin-releasing hormone mRNA levels were 68% higher in HD patients (P = 0.046). Thyrotropin-releasing hormone mRNA levels did not differ between HD patients and control subjects, although a negative correlation with disease duration was present in the former (P = 0.036). These findings indicate that the PVN is largely unaffected in HD patients. However, our findings suggest that hypothalamic-pituitary-thyroid axis activity may alter during the course of the disease and that autonomic nervous system dysfunction might partly arise from an imbalance between arginine vasopressin and oxytocin neurons in the PVN., (© 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.)

Study Objectives: Neuronal histamine shows diurnal rhythms in rodents and plays a major role in the maintenance of vigilance. No data are available on its diurnal fluctuation in humans, either in health or in neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD), or Huntington disease (HD), all of which are characterized by sleep-wake disturbances., Design: Quantitative in situ hybridization was used to study the mRNA expression of histidine decarboxylase (HDC), the key enzyme of histamine production in the tuberomammillary nucleus (TMN) in postmortem human hypothalamic tissue, obtained from 33 controls and 31 patients with a neurodegenerative disease-PD (n = 15), AD (n = 9), and HD (n = 8)-and covering the full 24-h cycle with respect to clock time of death., Results: HDC-mRNA levels in controls were found to be significantly higher during the daytime than at night (e.g., 08:01-20:00 versus 20:01-08:00, P = 0.004). This day-night fluctuation was markedly different in patients with neurodegenerative diseases., Conclusion: The diurnal fluctuation of HDC-mRNA expression in human TMN supports a role for neuronal histamine in regulating day-night rhythms. Future studies should investigate histamine rhythm abnormalities in neurodegenerative disorders., Citation: Shan L; Hofman MA; van Wamelen DJ; Van Someren EJW; Bao AM; Swaab DF. Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases.

To evaluate whether central histaminergic signaling in Huntington's disease (HD) patients is affected, we assessed mRNA levels of histidine decarboxylase (HDC), volume of and neuron number in the hypothalamic tuberomamillary nucleus (TMN) (HD n = 8, controls n = 8). In addition, we assessed histamine N-methyltransferase (HMT) and histamine receptor (H(1) R, H(2) R and H(3) R) mRNA levels in the inferior frontal gyrus (IFG) (n = 9 and 9) and caudate nucleus (CN) (n = 6 and 6) by real-time polymerase chain reaction. In HD patients, TMN volume and neuronal number was unaltered (P = 0.72, P = 0.25). The levels of HDC mRNA (P = 0.046), IFG HMT (P < 0.001), H(1) R (P < 0.001) and H(3) R mRNA levels (P = 0.011) were increased, while CN H(2) R and H(3) R mRNA levels were decreased (P = 0.041, P = 0.009). In HD patients, we observed a positive correlation between IFG H(3) R mRNA levels and CAG repeat length (P = 0.024) and negative correlations between age at onset of disease and IFG HMT (P = 0.015) and H(1) R (P = 0.021) mRNA levels. These findings indicate a functional increase in brain histaminergic signaling in HD, and provide a rationale for the use of histamine receptor antagonists., (© 2010 The Authors. Brain Pathology © 2010 International Society of Neuropathology.)