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Parkinson's disease (PD) is a chronic and progressive age-related neurodegenerative disease affecting up to 3% of the global population over 65 years of age. Currently, the underlying physiological aetiology of PD is unknown. However, the diagnosed disorder shares many common non-motor symptoms associated with ageing-related neurodegenerative disease progression, such as neuroinflammation, microglial activation, neuronal mitochondrial impairment, and chronic autonomic nervous system dysfunction. Clinical PD has been linked to many interrelated biological and molecular processes, such as escalating proinflammatory immune responses, mitochondrial impairment, lower adenosine triphosphate (ATP) availability, increasing release of neurotoxic reactive oxygen species (ROS), impaired blood brain barrier integrity, chronic activation of microglia, and damage to dopaminergic neurons consistently associated with motor and cognitive decline. Prodromal PD has also been associated with orthostatic hypotension and many other age-related impairments, such as sleep disruption, impaired gut microbiome, and constipation. Thus, this review aimed to present evidence linking mitochondrial dysfunction, including elevated oxidative stress, ROS, and impaired cellular energy production, with the overactivation and escalation of a microglial-mediated proinflammatory immune response as naturally occurring and damaging interlinked bidirectional and self-perpetuating cycles that share common pathological processes in ageing and PD. We propose that both chronic inflammation, microglial activation, and neuronal mitochondrial impairment should be considered as concurrently influencing each other along a continuum rather than as separate and isolated linear metabolic events that affect specific aspects of neural processing and brain function. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick type C (NPC) is an autosomal recessive progressive neurodegenerative disorder caused by mutations in the NPC1 or NPC2 genes. Patients with this disorder have variable phenotypic presentations that often include neuropsychiatric manifestations, cognitive decline, and movement disorders. There is considerable interpatient variation in movement disorders, with limited quantitative measurements describing the movements observed. Objective measurements using wearable sensors provide clinically applicable monitoring of patients with Parkinson's disease, and hence may be utilized in patients with NPC. Objective: To explore the relationship between objective measurements of movement obtained via the use of the Personal KinetiGraph (PKG) with the clinical information obtained via questionnaires and clinical rating tools of patients with Niemann-Pick type C. Methods: Twelve patients with Niemann-Pick type C were recruited who wore the PKG for 6 days during regular activities. A 6-day output was provided by the manufacturer, which provided bradykinesia (BK) and dyskinesia (DK) scores. BK and DK scores were further divided into their interquartile ranges. A fluctuation score (FDS), percentage time immobile (PTI), and percent time with tremors (PTT) were also provided. Clinical assessments included Abnormal Involuntary Movement Scale (AIMS), Epworth Sleepiness Score (ESS), Falls, Neuropsychiatric Unit Assessment Tool (NUCOG), Parkinson's disease questionnaire (PDQ), and modified Unified Parkinson's Disease Rating Scale (UPDRS) which were performed over telehealth within 2 weeks of PKG use. Pearson's correlation analyses were utilized to explore the relationship between DK and BK quartiles and clinical measures. Results: We found bradykinesia to be a feature among this cohort of patients, with a median BKS of 22.0 (7.4). Additionally, PTI scores were elevated at 4.9 (8.2) indicating elevated daytime sleepiness. Significant correlations were demonstrated between BK25 and Falls (r = − 0.74, 95% CI = [− 0.95, − 0.08]), BK50 and Falls (r = − 0.79, 95% CI = [− 0.96, − 0.19]), and BK75 and Falls (r = − 0.76, 95% CI = [− 0.95, − 0.11]). FDS correlated with PDQ (r = − 0.7, 95% CI = [− 0.92, − 0.18]), UPDRS IV (r = − 0.65, 95% CI = [− 0.90, − 0.09]), UPDRS (r = − 0.64, 95% CI = [− 0.9, − 0.06]), and AIMS (r = − 0.96, 95% CI = [− 0.99, − 0.49]). DK25 in comparison with NUCOG-A (r = 0.72, 95% CI = [0.17, 0.93]) and DK75 in comparison with NUCOG (r = 0.64, 95% CI = [0.02, 0.91]) and NUCOG-A (r = 0.63, 95% CI = [0.01, 0.90]) demonstrated significant correlations. Additionally, duration of illness in comparison with PTI (r = 0.72, 95% CI = [0.22, 0.92]) demonstrated significance. Conclusions: Utilization of PKG measures demonstrated that bradykinesia is under recognized among NPC patients, and the bradykinetic patients were less likely to report concerns regarding falls. Additionally, the FDS rather than the DKS is sensitive to the abnormal involuntary movements of NPC—reflecting a differing neurobiology of this chorea compared to levodopa-induced dyskinesias. Furthermore, dyskinetic individuals performed better in cognitive assessments of attention which may indicate an earlier timepoint within disease progression. [ABSTRACT FROM AUTHOR]

Abstract Background The high incidence of falls associated with Parkinson’s disease (PD) increases the risk of injuries and immobility and compromises quality of life. Although falls education and strengthening programs have shown some benefit in healthy older people, the ability of physical therapy interventions in home settings to reduce falls and improve mobility in people with Parkinson’s has not been convincingly demonstrated. Methods/design 180 community living people with PD will be randomly allocated to receive either a home-based integrated rehabilitation program (progressive resistance strength training, movement strategy training and falls education) or a home-based life skills program (control intervention). Both programs comprise one hour of treatment and one hour of structured homework per week over six weeks of home therapy. Blinded assessments occurring before therapy commences, the week after completion of therapy and 12 months following intervention will establish both the immediate and long-term benefits of home-based rehabilitation. The number of falls, number of repeat falls, falls rate and time to first fall will be the primary measures used to quantify outcome. The economic costs associated with injurious falls, and the costs of running the integrated rehabilitation program from a health system perspective will be established. The effects of intervention on motor and global disability and on quality of life will also be examined. Discussion This study will provide new evidence on the outcomes and cost effectiveness of home-based movement rehabilitation programs for people living with PD. Trial registration The trial is registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12608000390381).

Since the initial reports of COVID-19 in December 2019, the world has been gripped by the disastrous acute respiratory disease caused by the SARS-CoV-2 virus. There are an ever-increasing number of reports of neurological symptoms in patients, from severe (encephalitis), to mild (hyposmia), suggesting the potential for neurotropism of SARS-CoV-2. This Perspective investigates the hypothesis that the reliance on self-reporting of hyposmia has resulted in an underestimation of neurological symptoms in COVID-19 patients. While the acute effect of the virus on the nervous system function is vastly overshadowed by the respiratory effects, we propose that it will be important to monitor convalescent individuals for potential long-term implications that may include neurodegenerative sequelae such as viral-associated parkinsonism. As it is possible to identify premorbid harbingers of Parkinson's disease, we propose long-term screening of SARS-CoV-2 cases post-recovery for these expressions of neurodegenerative disease. An accurate understanding of the incidence of neurological complications in COVID-19 requires long-term monitoring for sequelae after remission and a strategized health policy to ensure healthcare systems all over the world are prepared for a third wave of the virus in the form of parkinsonism. [ABSTRACT FROM AUTHOR]

The increasing global burden of Parkinson's disease (PD) poses a particular challenge for developing countries, such as Thailand, when delivering care to a geographically diverse populace with limited resources, often compounded by a lack of expertise in the use of certain PD medications, such as device-aided therapies (DAT). A panel of local, regional, and international PD experts convened to review the unmet needs of PD in Thailand and share insights into effective delivery of DAT, focusing on experience with apomorphine infusion. Despite its proven efficacy and safety, implementation of apomorphine infusion as a new option was not straightforward. This has prompted a range of health-care professional and patient-focused initiatives, led by the Chulalongkorn Center of Excellence for Parkinson's Disease and Related Disorders in Bangkok, to help establish a more coordinated approach to PD management throughout the country and ensure patients have access to suitable treatments. Overcoming the challenges of education, proficiency, resource capacity and standard of care for PD patients in developing countries requires a coordinated effort both nationally and beyond. The best practices identified in Thailand following the introduction of apomorphine infusion might be helpful for other countries when implementing similar programs. [ABSTRACT FROM AUTHOR]

Background: Although the COVID‐19 pandemic is affecting a relatively small proportion of the global population, its effects have already reached everyone. The pandemic has the potential to differentially disadvantage chronically ill patients, including those with Parkinson's disease (PD). The first health care reaction has been to limit access to clinics and neurology wards to preserve fragile patients with PD from being infected. In some regions, the shortage of medical staff has also forced movement disorders neurologists to provide care for patients with COVID‐19. Objective: To share the experience of various movement disorder neurologists operating in different world regions and provide a common approach to patients with PD, with a focus on those already on advanced therapies, which may serve as guidance in the current pandemic and for emergency situations that we may face in the future. Conclusion: Most of us were unprepared to deal with this condition given that in many health care systems, telemedicine has been only marginally available or only limited to email or telephone contacts. In addition, to ensure sufficient access to intensive care unit beds, most elective procedures (including deep brain stimulation or the initiation of infusion therapies) have been postponed. We all hope there will soon be a time when we will return to more regular hospital schedules. However, we should consider this crisis as an opportunity to change our approach and encourage our hospitals and health care systems to facilitate the remote management of chronic neurological patients, including those with advanced PD. [ABSTRACT FROM AUTHOR]

Background. While numerous validated questionnaires measuring psychiatric symptoms in Parkinson's disease (PD) are available, a quick multifaceted screening tool is lacking. Objective. To generate the Brief Psychiatric Questionnaire (BPQ) that quickly screens for depression, anxiety, and apathy and to evaluate its content validity against three reference scales. Methods. Forty-seven questions were drafted and measured against the Geriatric Depression Scale (GDS), State Trait Anxiety Inventory (Form Y2) (STAI-Y2), and Apathy Evaluation Scale (AES). Data were reduced by principal component analysis and linear regression. Content validity and repeatability were assessed in a second cohort. Results. Data from ninety-five patients were used for BPQ development. Variation explained by the final linear regression models was 52% for GDS (R2 = 0.521, F(2,94) = 49.97, p<0.0001), 65% for STAI-Y2 (R2 = 0.652, F(4,94) = 42.08, p<0.0001), and 14% for AES (R2 = 0.135, F(1,94) = 14.51, p<0.0001). From the initial pool, only five questions remained for further testing. BPQ questions correctly identified 88% in the second cohort of 33 patients scoring more than five on GDS and 91% who scored in the highest decile of STAI-Y2, but only 51% who scored in the highest decile of AES. Moderate to strong correlation (r = 0.464 − 0.733, p<0.004) between predicted scores based on BPQ questions and actual scores of three validated questionnaires was demonstrated. Good repeatability of BPQ questions was demonstrated by moderate to high intraclass correlation coefficients (0.47–0.772, p<0.01). Conclusions. BPQ questions were able to accurately identify patients at risk of depression and anxiety but not apathy. It is brief and multifaceted and can act as a preconsultation tool to prompt further psychiatric assessment. [ABSTRACT FROM AUTHOR]

Impulse control disorders (ICDs) and related impulsive and compulsive behaviors (together called ICBs) have been increasingly recognized in the context of Parkinson's disease (PD) and treatment. The International Parkinson's and Movement Disorder Society commissioned a task force to assess available clinical screening instruments and rating scales, including their clinimetric properties, make recommendations regarding their utility, and suggest future directions in scale development and validation. The literature was systematically searched for scales measuring a range of reported ICBs in PD. A scale was designated "recommended" if the scale had been employed in PD studies, been used beyond the group that developed it, and had adequate clinimetric data published for PD. Numerous diagnostic screening tools and severity rating scales were identified for a range of ICBs, including compulsive medication use, punding/hobbyism, walkabout, pathological gambling, hypersexuality, compulsive or binge eating, compulsive buying, reckless driving, compulsive exercise, pyromania, trichotillomania, hoarding, kleptomania, intermittent explosive disorder, and internet addiction. For screening across the range of ICBs (except compulsive medication use), the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP) and QUIP-Rating Scale (QUIP-RS) are recommended, and for severity rating across the range of ICBs the QUIP-RS and the Ardouin Scale of Behavior in Parkinson's Disease are recommended. The Scale for Outcomes in Parkinson's Disease-Psychiatric Complications is recommended for rating of hypersexuality and the compulsive behaviors gambling/shopping. Further testing of established scales against gold standard diagnostic criteria is urgently required for all other individual ICBs in PD. © 2019 International Parkinson and Movement Disorder Society © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Interference refers to learned associations and established behaviors “interfering” with response to new material. It forms a core pillar of executive functions, which are commonly affected in Parkinson’s disease (PD). Cognitive interference test (CIT) forms part of a smartphone application designed for ambulatory assessment in PD. Objective: The aims of this study were to establish that CIT could effectively demonstrate interference and would perform comparably to the Stroop Color-Word Test Victoria version (VST) despite PD-related motor impairment. Methods: Ninety-nine patients with PD were recruited. Initial evaluation included CIT, VST, Montreal cognitive assessment (MOCA), and Movement Disorders Society-sponsored revision of the ­Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-III). A group of patients underwent repeat assessment within 2 weeks. Thirty-four healthy controls were recruited for comparison. Results: Patients’ mean age was 66.2 years, disease duration was 8.7 years, on-state MDS-UPDRS-III was 22, and MOCA total score was 27. CIT effectively generated interference, whereby the total time taken to complete the incongruent task was 20% longer compared to that of the baseline task. CIT key test items demonstrated convergent validity to VST (r = 0.478–0.644, p < 0.0001) and satisfactory repeatability (intraclass correlation coefficient 0.46–0.808, p ≤ 0.0002). Performance on key CIT test parameters deteriorated with increasing age (r = 0.225–0.478, p < 0.01) and MDS-UPDRS-III total score (r = 0.354–0.481, p < 0.0001). When compared to controls and patients with less motor impairment, patients MDS-UPDRS-III > 30 took longer to complete CIT and VST and had lower MOCA-attention sub-score, implying that the degree of motor impairment could not be the sole explanation for reduced CIT performance. Conclusions: We established that despite motor impairment, the novel approach of using smartphone technology to test interference in PD patients is feasible. [ABSTRACT FROM AUTHOR]

Introduction: The phenomenon of sleep benefit (SB) in Parkinson's disease (PD), whereby waking motor function is improved despite no dopaminergic treatment overnight, is controversial. Previous studies suggested a significant discrepancy between subjective functional and objective motor improvement. The aim of this study was to determine how well subjective reporting of SB correlates with objective measures and if true motor improvement can be predicted by a standardized questionnaire.Methods: Ninety-two patients with PD participated. A structured questionnaire was developed to assess subjective SB. Quantitative motor assessment was performed using a validated smartphone application. Objective motor SB was considered to be present when the waking motor function was similar or superior to the daytime on-state.Results: Twenty (22%) patients showed objective motor improvement on waking compared to end-of-dose. Most patients (77%) reported subjective SB without corresponding objective motor benefit. Our structured questionnaire could not predict Motor SB. The ability to delay morning medications and a perception of indifference or paradoxical worsening following the morning levodopa dose may suggest Motor SB.Conclusions: Most patients experience subjective SB with no measureable motor improvement. This perceived benefit could be related to non-motor improvement that is distinctly different to objective motor benefit. [ABSTRACT FROM AUTHOR]

Background Sleep benefit ( SB) in Parkinson's disease refers to improved motor symptoms upon waking despite an entire night without medications. Although it was first proposed 30 years ago, this phenomenon proved difficult to investigate, and its true prevalence and underlying mechanisms remain unclear. Objective This study aimed to identify and quantify SB through measurement of motor function using a validated smartphone application and to identify disease characteristics that predicted SB. Methods Ninety-two patients recruited from 2 Movement Disorder Services were clinically assessed at home using a validated smartphone application. Each patient was tested in the on-state, at the end of dose, and on waking (before medications) 3 times. Differences between the 3 states were used to determine the impact of sleep and levodopa on motor function. SB was considered to be a 'measurable improvement in parkinsonism from the end of dose.' Results The morning waking motor function of 20 patients (22%) improved compared with the end-of-dose function, with 9 patients demonstrating superior function compared with their on-state. No clinical features predicted SB. Although all participants subjectively reported motor fluctuations, only 35 patients (38%) demonstrated an objective improvement with levodopa. Patients who had SB more often demonstrated objective motor fluctuations compared with those who did not (65% vs. 31%; P = 0.008). Conclusions SB is a genuine motor phenomenon: 1 in 5 patients have a measurable improvement in motor function on waking. It remains questionable whether this improvement is a direct effect of sleep. Until its underlying mechanism is better understood, it is more appropriate to refer to this phenomenon as simply morning improvement or diurnal fluctuation of motor symptoms. [ABSTRACT FROM AUTHOR]

Questions For people with idiopathic Parkinson’s disease, does a 6-week, comprehensive, home exercise program reduce falls and disability and improve health-related quality of life? Is the program cost-effective? Design Randomised, controlled trial with concealed allocation and assessor blinding. Participants One hundred and thirty-three community-dwelling adults with Parkinson’s disease. Intervention The experimental group completed a 6-week home program comprising progressive resistance strength training, movement strategy training and falls education. The control group completed 6 weeks of non-specific life skills training. Participants in both groups received weekly therapist-guided sessions for 6 consecutive weeks and a weekly self-directed home program. Outcome measures The primary outcome was the rate of falls, documented for the 12-month period immediately after therapy. Secondary outcomes were disability and health-related quality of life, assessed before and after intervention and at a 12-month follow-up. Results A total of 2255 falls were reported by the 12-month follow-up. The proportion of fallers in the experimental and control groups was 61 and 72%, respectively, which was not statistically significantly different (RR = 0.85, 95% CI 0.66 to 1.09). There was no significant between-group difference in the rate of falls (incidence rate ratio = 1.58, 95% CI 0.73 to 3.43). A survival analysis of participant time to first fall did not show a significant between-group difference (log-rank test χ 2 = 0.79, p = 0.37). No significant between-group differences occurred for mobility, disability or quality of life. The mean cost of delivering the experimental intervention was AUD1596. Conclusion A home program of strength and movement strategy training and falls education does not prevent falls when applied at the dose used in this study. Arguably, the dosage of therapy was insufficient. Future trials need to explore further therapy content, repetitions and duration, in order to optimise outcomes and cost-effectiveness. [Morris ME, Taylor NF, Watts JJ, Evans A, Horne M, Kempster P, Danoudis M, McGinley J, Martin C, Menz HB (2017) A home program of strength training, movement strategy training and education did not prevent falls in people with Parkinson’s disease: a randomised trial. Journal of Physiotherapy 63: 94–100] [ABSTRACT FROM AUTHOR]

Objective: This clinical update review focuses on treatment approaches of neuropsychiatric manifestations in Parkinson's disease.Methods: We conducted a systematic search of the literature using Pubmed and selected recent and relevant papers for this review.Results: Neuropsychiatric symptoms in Parkinson's disease usually require optimization of levodopa therapy as a first step. Most psychotropic drugs can be used in Parkinson's disease, however there is still lack of an evidence base due to limited studies and difficulties in diagnosis of neuropsychiatric disorders. Non-pharmacological treatments have also proved effective in Parkinson's disease. Cognitive impairment requires special consideration.Conclusions: Management of neuropsychiatric manifestations in Parkinson's disease is complicated by the lack of evidence. Treatment should be individualized and benefits and risks must be balanced. [ABSTRACT FROM AUTHOR]

Objective: This clinical update review focuses on the classification and description of common neuropsychiatric manifestations in Parkinson's disease (PD).Method: We conducted a systematic search of the literature using Pubmed and selected the most recent and relevant papers for this review.Results: Neuropsychiatric manifestations in PD are are very frequent and may arise from an abnormal psychopathological response to the disease, neurobiological changes related to the disease itself, complications of treatments or a combination of all of these.Conclusions: Neuropsychiatric symptoms may precede the motor clinical presentation of PD. Early recognition is essential. [ABSTRACT FROM AUTHOR]

Background: Measurement of motor function is critical to the assessment and management of Parkinson's disease. Ambulatory motor assessment has the potential to provide a glimpse of the patient's clinical state beyond the consultation. We custom-designed a smartphone application that quantitatively measures hand dexterity and hypothesized that this can give an indication of a patient's overall motor function. Objective: The aims of this study were to (i) validate this smartphone application against MDS-UPDRS motor assessment (MDS-UPDRS-III) and the two-target tapping test; (ii) generate a prediction model for MDS-UPDRS-III; (iii) assess repeatability of our smartphone application and (iv) examine compliance and user-satisfaction of this application. Methods: 103 patients with Parkinson's disease were recruited from twomovement disorders clinics. After initial assessment, a group of patients underwent repeat assessment within two weeks. Patients were invited to use the smartphone application at home over three days, followed by a survey to assess their experience. Results: Significant correlation between key smartphone application test parameters and MDS-UPDRS-III (r = 0.281-0.608, p < 0.0001) was demonstrated. A prediction model based on these parameters accounted for 52.3% of variation in MDSUPDRS- III (R2 = 0.523, F(4,93) = 25.48, p < 0.0001). Forty-eight patients underwent repeat assessment under identical clinical conditions. Repeatability of key smartphone application tests parameters and predicted MDS-UPDRS-III was moderate to strong (intraclass correlation coefficient 0.584-0.763, p < 0.0001). The follow-up survey identified that our patients were very comfortable with the smartphone application and mobile technology. Conclusions: Our smartphone application demonstrated satisfactory repeatability and validity when measured against MDS-UPDRS-III. Its performance is acceptable considering our smartphone application measures hand dexterity only. [ABSTRACT FROM AUTHOR]

Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson's disease (PD). Other impulsive-compulsive behaviors (ICBs) have been described in PD, including punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive PD medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Possible risk factors for ICDs include male sex, younger age and younger age at PD onset, a pre-PD history of ICDs, and a personal or family history of substance abuse, bipolar disorder, or gambling problems. Given the paucity of treatment options and potentially serious consequences, it is critical for PD patients to be monitored closely for development of ICDs as part of routine clinical care. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objectives: Parkinson's Disease patients wore a device on the wrist that gave reminders to take levodopa and also measured bradykinesia and dyskinesia. Consumption of medications was acknowledged by placing the thumb on the device. Some patients performed this acknowledgement repeatedly and unconsciously. This study examines whether this behaviour reflected increased impulsivity. Methods and Results: Twenty five participants were selected because they had i) excess acknowledgements described above or ii) Impulsive-Compulsive Behaviours or iii) neither of these. A blinded assessor applied clinical scales to measure Impulsive-Compulsive Behaviours, cognition, depression, anxiety and apathy. A Response Ratio, representing the number of acknowledgements/number of doses (expressed as a percentage) was tightly correlated with ratings of Impulsive-Compulsive Behaviours (r2 = 0.79) in 19/25 subjects. Some of these patients had dyskinesia, which was higher with extraneous responses than with response indicating medication consumption. Six of the 25 subjects had high Impulsive-Compulsive Behaviour Scores, higher apathy scores, low levels of dyskinesia and normal Response Ratios. Patients without ICB (low RR) also had low dyskinesia levels regardless of the relevance of the response. Conclusion: An elevated Response Ratio is a specific measure of a type of ICB where increased incentive salience is attributed to cues by the presence of high striatal dopamine levels, manifested by high levels of dyskinesia. This study also points to a second form of ICBs which occur in the absence of dyskinesia, has normal Response Ratios and higher apathy scores, and may represent prefrontal pathology. [ABSTRACT FROM AUTHOR]

Abstract: Background: Motor response complications that arise with repeated L-dopa administration for the treatment of Parkinson’s disease are well understood but the relationship between motor response complications and affect are not. We proposed that patients with dyskinesias would report rebound worsening in affect during wearing-off of L-dopa effect. Methods: Fifty Parkinson’s disease patients with were assessed with the Purdue Pegboard test and rated Positive Affect and Negative Affect after overnight withdrawal of dopaminergic medications and half hourly for 6 h after a standard L-dopa challenge. Patients were carefully classified into stable responder (n = 12), fluctuator (n = 15), and dyskinetic (n = 23) groups. Results: Positive Affect was improved by L-dopa in dyskinetics and to a lesser degree in fluctuators but not in stable responders. At T = 4–6 h, Positive Affect rebounded below baseline in dyskinetics only. On regression analysis, rebound worsening positively correlated with ratings of dyskinesia severity. Negative Affect improved with L-dopa in all groups and tended to remain below baseline for 6 h after L-dopa challenge. Peak effects of L-dopa on Positive Affect and Negative Affect occurred significantly earlier than effects on Purdue Pegboard test and were positively correlated with L-dopa equivalent daily dose. Conclusion: There is a clinical dissociation between L-dopa effects on motor function, Positive Affect and Negative Affect. Rebound worsening in Positive Affect occurred only in dyskinetic patients and the onset of rebound worsening occurred before the end of the motor benefit phase. These observations could explain why some Parkinson patients report wearing-off symptoms despite the external impression of good motor control. [Copyright &y& Elsevier]

Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinson’s disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using 11C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and l-dopa challenge in patients with Parkinson’s disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three 11C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinson’s disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinson’s disease groups following l-dopa challenge with neutral cues. The group with Parkinson’s disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum 11C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following l-dopa challenge (16.3% compared with 5.8% in Parkinson’s disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive-compulsive behaviours and addictions and may have important implications with regards to advertisement legislation in an effort to prevent the onset of behavioural addictions. [ABSTRACT FROM AUTHOR]

Abstract: Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinson’s disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance. [Copyright &y& Elsevier]

In the past decade, impulse control disorders, punding, and dopamine dysregulation syndrome (which we refer to collectively as disinhibitory psychopathologies) have been increasingly recognized in treated patients with Parkinson's disease. Practicing neurologists must understand these problems to limit potential harm. In this article, we summarize current knowledge regarding these behavioral disorders, including phenomenology, epidemiology, pathophysiology, and treatment. [ABSTRACT FROM AUTHOR]

Abstract: Patients with Parkinson''s disease may use Dopamine Replacement Therapy (DRT) in excess of therapeutic need. We investigate whether a group of 10 patients with Parkinson''s disease, provisionally diagnosed with “Hedonistic Homeostatic Dysregulation” because of their excessive use of DRT, met established operational psychiatric criteria for substance dependence, compared with 10 patients with Parkinson''s disease compliant with prescribed DRT. Using a semi-structured questionnaire designed to distinguish between adaptive therapeutic dependence on DRT and a maladaptive pathological pattern of DRT use, in conjunction with the SCID-1, we found that seven of the patients deemed by their treating physicians to be misusing DRT fulfilled operational criteria for maladaptive dependence in contrast to none of the compliant group. The majority experienced dysphoric “withdrawal” symptoms in the “off” state and increased their dose of DRT in an effort to control their mood. They also continued to use high doses of DRT despite disabling dyskinesias and social difficulties. This study provides preliminary evidence that some patients with Parkinson''s disease may become maladaptively dependent on DRT. This finding has both clinical relevance for the treatment of PD and further implicates dopaminergic pathways in the genesis of substance dependence. [Copyright &y& Elsevier]

Dopamine replacement therapy (DRT) is the most effective treatment for Parkinson''s disease (PD); it provides substantial benefit for most patients, extends independence, and increases survival. A few patients with PD, however, take increasing quantities of medication far beyond those required to treat their motor disabilities. These patients demand rapid drug escalation and continue to request more DRT despite the emergence of increasingly severe drug-induced motor complications and harmful behavioural consequences. In this article we detail the features of compulsive DRT-seeking and intake in PD, in relation to theories of compulsive drug use. [Copyright &y& Elsevier]

The article presents the case of a 42-year-old man with Parkinson's disease that demonstrates the phenomenon of punding, which is characterized by pointless repetitive behaviors that are performed for long periods of time. He developed a tendency of spending up to 10 hours doing housework. This tendency disrupted his sleep pattern.

Abstract: We report postoperative unresponsiveness in a 79-year-old woman who underwent excision of a posterior fossa meningioma with a past history of Parkinson’s disease. This report highlights the development of a post-surgical akinetic or Parkinsonian crisis that presents with unresponsiveness. We discuss the condition briefly and emphasise the need for early recognition and prompt treatment. [Copyright &y& Elsevier]

Dopaminergic medication can induce severe addictive behaviours (e.g., pathological gambling) in susceptible Parkinson's disease (PD) patients. It is still unknown which particular neurocognitive processes become exacerbated or dysfunctional in PD patients with addictive behaviours. We sought to systematically review the relevant literature to identity potential neurocognitive correlates of medication-induced addictive behaviours in PD. We framed our review around neurocognitive processes central to four dominant accounts of substance addiction: ‘aberrant learning’, ‘incentive sensitization’, ‘impulsivity to compulsivity’ and ‘impaired response inhibition and salience attribution’. Searches of the PubMed and Scopus databases were completed on June 23, 2017. To be included, studies were required to involve: (a) medicated PD patients, without a history of deep brain stimulation, with and without addictive behaviours; (b) a reward-related or decision-making task; and (c) statistical comparison of addictive and non-addictive groups’ ‘on’ medication performance on the task(s). Studies were summarised qualitatively with statistically significant ( p <.05) group differences and effect sizes (Cohen's d ) highlighted. 35 studies were included. Findings showed that the extant literature is highly heterogeneous. The domains of reward and punishment learning, reflection impulsivity and disadvantageous decision-making exemplify this. More homogeneity exists in domains in which (a) neurocognitive dysfunction is not apparent (motor control, cognitive/attentional flexibility and cognitive control) or (b) typical neurocognitive processes appear exacerbated by medication (reward motivation and choice impulsivity). Future large-scale neurocognitive studies are still required to develop our scientific understanding of addictive behaviours in PD and aid their clinical treatment and prediction. [ABSTRACT FROM AUTHOR]

1·8 billion people of diverse ethnicities and cultures live in the Western Pacific Region. The increasing longevity of populations in this region is a major contributor to the exponential increase in Parkinson's disease prevalence worldwide. Differences exist between Parkinson's disease in the Western Pacific Region and in Europe and North America that might provide important insights into our understanding of the disease and approaches to management. For example, some genetic factors (such as LRRK2 mutations or variants) differ, environmental exposures might play differential roles in modulating the risk of Parkinson's disease, and fewer dyskinesias are reported, with some differences in the profile of non-motor symptoms and comorbidities. Gaps in awareness of the disease and inequitable access to treatments pose challenges. Further improvements in infrastructure, clinical governance, and services, and concerted collaborative efforts in training and research, including greater representation of the Western Pacific Region in clinical trials, will improve care of patients with Parkinson's disease in this region and beyond. [ABSTRACT FROM AUTHOR]

Abstract Patients with Parkinson disease (PD) experience hyperalgesia on evoked pain sensitivity testing, although the relationship of this with persistent pain in PD is less certain. Studies examining this have generated contradictory findings. Further, the role of dopaminergic deficiency as an underlying substrate for hyperalgesia is controversial. We report the results of meta-analyses of the PD pain sensitivity literature in an attempt to answer these questions. We identified 429 records, of which ten articles compared pain sensitivity between PD patients that experienced clinical pain (PDP) to those who did not (PDNP), and twenty studies that examined the effect of dopaminergic medications on pain sensitivity in PD patients. PDP patients experienced a moderate increase in pain sensitivity, had more severe disease, required higher dosages of medication, and were more likely to be female when compared to those PDNP patients. PD patients also had reduced pain sensitivity when tested on dopaminergic medications compared to when they were not on medications. Overall, the results of this systematic review and meta-analysis supports the hypothesis that hyperalgesia contributes to clinical pain in PD, and that the underlying mechanism may be dopaminergically driven. Highlights • PD patients experiencing clinical pain have an increase in pain sensitivity • PD patients also have reduced pain sensitivity when tested on dopaminergic medications • Hyperalgesia likely contributes to clinical pain and this is likely dopaminergically driven [ABSTRACT FROM AUTHOR]

In this commentary we discuss International Stem Cell Corporation's (ISCO's) approach to developing a pluripotent stem cell based treatment for Parkinson's disease (PD). In 2016, ISCO received approval to conduct the world's first clinical study of a pluripotent stem cell based therapy for PD. The Australian regulatory agency Therapeutic Goods Administration (TGA) and the Melbourne Health's Human Research Ethics Committee (HREC) independently reviewed ISCO's extensive preclinical data and granted approval for the evaluation of a novel human parthenogenetic derived neural stem cell (NSC) line, ISC-hpNSC, in a PD phase 1 clinical trial ( ClinicalTrials.gov NCT02452723). This is a single-center, open label, dose escalating 12-month study with a 5-year follow-up evaluating a number of objective and patient-reported safety and efficacy measures. A total of 6 years of safety and efficacy data will be collected from each patient. Twelve participants are recruited in this study with four participants per single dose cohort of 30, 50, and 70 million ISC-hpNSC. The grafts are placed bilaterally in the caudate nucleus, putamen, and substantia nigra by magnetic resonance imaging-guided stereotactic surgery. Participants are 30–70 years old with idiopathic PD ≤13 years duration and unified PD rating scale motor score (Part III) in the “OFF” state ≤49. This trial is fully funded by ISCO with no economic involvement from the patients. It is worth noting that ISCO underwent an exhaustive review process and successfully answered the very comprehensive, detailed, and specific questions posed by the TGA and HREC. The regulatory/ethic review process is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines or novel therapies. [ABSTRACT FROM AUTHOR]

Introduction: Pain is a common and disabling non-motor symptom of Idiopathic Parkinson's disease (PD) but its underlying pathophysiological mechanisms are not well understood. There is evidence to suggest that altered pain sensitivity may contribute to the experience of pain in PD patients, but clinical studies investigating this have yielded inconsistent results.Objectives: To examine whether pain thresholds are altered in PD patients compared to normal healthy controls (HC), via the use of systematic review and meta-analysis.Data Sources: A systematic search of the MEDLINE and EMBASE library from 1966 to April 2015.Study Selection: Studies that compared pain thresholds in PD patients versus HC were included in the systematic review. Additionally, data comparing PD patients off dopaminergic medications (PDMoff) to HC off medications (HCMoff) were pooled for meta-analysis by pain modality.Main Outcomes: Heat pain threshold, cold pain threshold, electrical pain threshold, nociceptive withdrawal reflex threshold, pressure pain threshold, and pain ratings.Results: 22 studies were reviewed, comprising of 616 PD and 451 HC. In the comparison of PDMoff versus HCMoff, a large majority of trials (15/19) found reduced pain thresholds (increased pain sensitivity) in PD patients. Meta-analysis of these trials revealed significantly reduced pain thresholds, of moderate to large effect size, in PD patients across all pain modalities. Results were much more heterogenous when PD patients on medications were compared with HC off medications, with most trials reporting no significant difference in pain thresholds between groups. No significant differences were found in pain thresholds for trials that compared PD patients on medications and HC on medications.Conclusion: PD patients are more sensitive to noxious stimuli compared to HC when tested in the off medication state. This increase in pain sensitivity is observed across all modalities, but is not as apparent when PD patients are administered Levodopa, suggesting that dopamine deficient states may contribute to hyperalgesia. However, it remains to be seen whether or not increased pain sensitivity translates clinically into increased prevalence of pain. Similarly, it is unclear if dopaminergic medications influence pain sensitivity. Performing a meta-analysis on studies comparing pain thresholds in PD patients with and without pain, and on and off dopaminergic medications, may draw more definitive conclusions in this regard. [ABSTRACT FROM AUTHOR]

Non-motor features have a great impact on progression and quality of life in individuals with Parkinson's disease. Current treatments for PD are limited and apomorphine is one of the advanced therapies available with advantageous effects on motor complications. Several studies have suggested that apomorphine has potential benefits in PD patients beyond its established role in the treatment of motor fluctuations and levodopa-induced dyskinesia. This review examines the efficacy of apomorphine in the treatment of non-motor symptoms (NMS), describing recent studies that highlight its possible effect on cognition. Despite a limited number of studies, the available evidence shows that apomorphine has an overall beneficial effect on NMS of PD patients, including neuropsychiatric symptoms, sleep disturbances, pain, urinary dysfunction, and impulse control disorders. If the effects of apomorphine on amyloid deposition are confirmed in the future, its place in the armamentarium of PD treatment could see a shift towards younger and non-demented PD patients. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) patients develop levodopa induced dyskinesia with disease progression from sensitization of central pathways. Pain pathways are also impacted with suggestions dyskinetic patients may process pain differently. Establish if centrally sensitized nociceptive pathways are altered and dopaminergically driven in dyskinetic patients. Clinical characteristics, affect, pain thresholds and sensitivity to pressure stimulation in the ON and OFF medication states as well as distribution of pain related activation of cortical regions on BOLD fMRI were assessed and compared between groups of patients suffering from dyskinesia and not. Dyskinetic PD participants experienced increased pressure pain sensitivity. This was associated with increased pressure induced pain>innocuous BOLD activity in areas associated with encoding pain intensity, pain spatial orientation, descending pain mediation, sensorimotor integration, and motor control. Levodopa reduced pressure pain ratings and improved negative affect, though did not impact BOLD activity differently between the groups. Dyskinetic PD patients experience increased pain sensitivity and centrally sensitized nociceptive pathways resembling levodopa induced sensitization though this is not directly influenced by dopamine. • Dyskinetic PD patients experience increased pain sensitivity. • Centrally sensitized nociceptive pathways resembling levodopa induced sensitization are implicated. • This is not directly influenced by dopamine. [ABSTRACT FROM AUTHOR]