Cerebrospinal fluid neurofilament light and cerebral atrophy in younger-onset dementia and primary psychiatric disorders.

BACKGROUND AND AIMS: Neurodegeneration underpins the pathological processes of younger-onset dementia (YOD) and has been implicated in primary psychiatric disorders (PSYs). Cerebrospinal fluid (CSF) neurofilament light (NfL) has been used to investigate neurodegeneration severity through correlation with structural brain changes in various conditions, but has seldom been evaluated in YOD and PSYs. METHODS: This retrospective study included patients with YOD or PSYs with magnetic resonance imaging (MRI) of the brain and CSF NfL analysis. Findings from brain MRI were analysed using automated volumetry (volBrain) to measure white matter (WM), grey matter (GM) and whole brain (WB) volumes expressed as percentages of total intracranial volume. Correlations between NfL and brain volume measurements were computed whilst adjusting for age. RESULTS: Seventy patients (47 with YOD and 23 with PSY) were identified. YOD types included Alzheimer disease and behavioural variant frontotemporal dementia. PSY included schizophrenia and major depressive disorder. MRI brain sequences were either fast spoiler gradient-echo (FSPGR) or magnetization-prepared rapid acquisition gradient-echo (MPRAGE). In the total cohort, higher NfL was associated with reduced WB in the FSPGR and MPRAGE sequences (r = -0.402 [95% confidence interval (CI), -0.593 to -0.147], P = 0.008 and r = -0.625 [95% CI, -0.828 to -0.395], P < 0.001, respectively). Higher NfL was related to reduced GM in FSPGR (r = 0.385 [95% CI, -0.649 to -0.014], P = 0.017) and reduced WM in MPRAGE (r = -0.650 [95% CI, -0.777 to -0.307], P < 0.001). Similar relationships were seen in YOD, but not in PSY. CONCLUSION: Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity.

Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: protocol for a phase 2, randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).

Odor Identification Testing Can Assist in the Clinical Distinction Between Psychiatric Disorders and Neurological/Neurodegenerative Disorders.

BACKGROUND/OBJECTIVES: The aim was to identify whether performance on olfactory identification can distinguish neurological/neurodegenerative disorders (NNDs) from primary psychiatric disorders (PPDs). METHODS: This is a cross-sectional retrospective study of inpatients assessed in Neuropsychiatry, Royal Melbourne Hospital. Data extracted from the admission records included: demographics, tobacco use, medical comorbidities, cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), and odor identification using the Sniffin' Sticks Screening 12 test. The final diagnosis for patients was informed by established diagnostic criteria. RESULTS: A total 121 patients were included. Eighty-eight patients (73%) were diagnosed with neurological or neurodegenerative disease, including Alzheimers dementia, frontotemporal dementia, Lewy body parkinsonian-related dementias (Parkinson disease, multiple system atrophy, dementia with Lewy bodies) and other neurological causes of dementia; 33 patients (27%) were diagnosed with PPDs (including mood and psychotic disorders). Patients who scored ≤8 on the Sniffin' Sticks Screening 12 test were more likely to have NND than PPD, even after adjustment for age, sex and tobacco use (P=0.009, adjusted odds ratios=3.85, 95% confidence interval=1.40-10.62). Receiver operating characteristic curve analyses demonstrated that a score of ≤8 differentiated NND from PPD with sensitivity of 57% and specificity of 73% (receiver operating characteristic area under the curve of 0.67, P=0.004). CONCLUSIONS: Patients with neuropsychiatric difficulties who score 8 or less on Sniffin' Sticks are more likely to have a neurodegenerative illness. A cut-off score of 8 is potentially a "red flag" for clinicians faced with the diagnostic question of PPD versus NND.

Parkinsonism as a Third Wave of the COVID-19 Pandemic?

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.

Pain and dyskinesia in Parkinson's disease may share common pathophysiological mechanisms - An fMRI study.

BACKGROUND: 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. OBJECTIVE: Establish if centrally sensitized nociceptive pathways are altered and dopaminergically driven in dyskinetic patients. METHODS: 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. RESULTS: 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. CONCLUSION: Dyskinetic PD patients experience increased pain sensitivity and centrally sensitized nociceptive pathways resembling levodopa induced sensitization though this is not directly influenced by dopamine.

Management of Advanced Therapies in Parkinson's Disease Patients in Times of Humanitarian Crisis: The COVID-19 Experience.

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.

Establishing apomorphine treatment in Thailand: understanding the challenges and opportunities of Parkinson's disease management in developing countries.

INTRODUCTION: 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). AREAS COVERED: 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. EXPERT OPINION: 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.

Parkinson's disease in the Western Pacific Region.

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.

Scales to assess impulsive and compulsive behaviors in Parkinson's disease: Critique and recommendations.

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.

Parkinson disease: A systemic review of pain sensitivities and its association with clinical pain and response to dopaminergic stimulation.

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.

Novel Functional MRI Task for Studying the Neural Correlates of Upper Limb Tremor.

Introduction: Tremor of the upper limbs is a disabling symptom that is present during several neurological disorders and is currently without treatment. Functional MRI (fMRI) is an essential tool to investigate the pathophysiology of tremor and aid the development of treatment options. However, no adequately or standardized protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the in vivo pathology of tremor. Objective: This study aims to validate the tremor-evoking potential of the fMRI task in a small group of tremor patients outside the scanner and assess the reproducibility of the fMRI task related activation in healthy controls. Methods: Twelve HCs were scanned at two time points (baseline and after 6-weeks). There were two runs of multi-band fMRI and the tasks included a "brick-breaker" joystick game. The game consisted of three conditions designed to control for most of the activation related to performing the task by contrasting the conditions: WATCH (look at the game without moving joystick), MOVE (rhythmic left/right movement of joystick without game), and PLAY (playing the game). Task fMRI was analyzed using FSL FEAT to determine clusters of activation during the different conditions. Maximum activation within the clusters was used to assess the ability to control for task related activation and reproducibility. Four tremor patients have been included to test ecological and construct validity of the joystick task by assessing tremor frequencies captured by the joystick. Results: In HCs the game activated areas corresponding to motor, attention and visual areas. Most areas of activation by our game showed moderate to good reproducibility (intraclass correlation coefficient (ICC) 0.531-0.906) with only inferior parietal lobe activation showing poor reproducibility (ICC 0.446). Furthermore, the joystick captured significantly more tremulous movement in tremor patients compared to HCs (p = 0.01) during PLAY, but not during MOVE. Conclusion: Validation of our novel task confirmed tremor-evoking potential and reproducibility analyses yielded acceptable results to continue further investigations into the pathophysiology of tremor. The use of this technique in studies with tremor patient will no doubt provide significant insights into the treatment options.

Pain sensitivity in Parkinson's disease: Systematic review and meta-analysis.

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.

Deep brain stimulation for severe treatment-resistant obsessive-compulsive disorder: An open-label case series.

OBJECTIVE: Deep brain stimulation can be of benefit in carefully selected patients with severe intractable obsessive-compulsive disorder. The aim of this paper is to describe the outcomes of the first seven deep brain stimulation procedures for obsessive-compulsive disorder undertaken at the Neuropsychiatry Unit, Royal Melbourne Hospital. The primary objective was to assess the response to deep brain stimulation treatment utilising the Yale-Brown Obsessive Compulsive Scale as a measure of symptom severity. Secondary objectives include assessment of depression and anxiety, as well as socio-occupational functioning. METHODS: Patients with severe obsessive-compulsive disorder were referred by their treating psychiatrist for assessment of their suitability for deep brain stimulation. Following successful application to the Psychosurgery Review Board, patients proceeded to have deep brain stimulation electrodes implanted in either bilateral nucleus accumbens or bed nucleus of stria terminalis. Clinical assessment and symptom rating scales were undertaken pre- and post-operatively at 6- to 8-week intervals. Rating scales used included the Yale-Brown Obsessive Compulsive Scale, Obsessive Compulsive Inventory, Depression Anxiety Stress Scale and Social and Occupational Functioning Assessment Scale. RESULTS: Seven patients referred from four states across Australia underwent deep brain stimulation surgery and were followed for a mean of 31 months (range, 8-54 months). The sample included four females and three males, with a mean age of 46 years (range, 37-59 years) and mean duration of obsessive-compulsive disorder of 25 years (range, 15-38 years) at the time of surgery. The time from first assessment to surgery was on average 18 months. All patients showed improvement on symptom severity rating scales. Three patients showed a full response, defined as greater than 35% improvement in Yale-Brown Obsessive Compulsive Scale score, with the remaining showing responses between 7% and 20%. CONCLUSION: Deep brain stimulation was an effective treatment for obsessive-compulsive disorder in these highly selected patients. The extent of the response to deep brain stimulation varied between patients, as well as during the course of treatment for each patient. The results of this series are comparable with the literature, as well as having similar efficacy to ablative psychosurgery techniques such as capsulotomy and cingulotomy. Deep brain stimulation provides advantages over lesional psychosurgery but is more expensive and requires significant multidisciplinary input at all stages, pre- and post-operatively, ideally within a specialised tertiary clinical and/or academic centre. Ongoing research is required to better understand the neurobiological basis for obsessive-compulsive disorder and how this can be manipulated with deep brain stimulation to further improve the efficacy of this emerging treatment.

Practical approaches to commencing device-assisted therapies for Parkinson disease in Australia.

In Australia 1% of individuals aged over 50 years have Parkinson disease (PD). Guidance for commencing device-assisted therapies (DAT) for PD in Australia was developed based on a review of European recommendations and their relevance to the local clinical setting. An online survey and teleconference discussions were held by a group of eight local movement disorder experts to develop consensus. Referral to a movement disorder specialist and consideration of DAT is appropriate when motor fluctuations cause disability or reduced quality of life, response to treatment is inconsistent or motor fluctuations and dyskinesias require frequent treatment adjustment without apparent benefit and levodopa is required four or more times daily. Three types of DAT are available in Australia for patients with PD: continuous subcutaneous apomorphine; continuous levodopa-carbidopa intestinal gel infusion; and deep brain stimulation. All improve consistency of motor response. The most important aspects when considering which DAT to use are the preferences of the patient and their carers, patient comorbidities, age, cognitive function and neuropsychiatric status. Patients and their families need to be provided with treatment options that are suitable to them, with adequate explanations regarding the recommendations and comparison of potential device-related complications. DAT are best managed, where possible, in a specialist centre with experience in all three types of therapy. Proactive and early management of symptoms during disease progression is essential to maintain optimally motor responses and quality of life in patients with PD.

Integrating Patient Concerns into Parkinson's Disease Management.

Parkinson's disease (PD) is a complex motor and non-motor disorder and management is often challenging. In this review, we explore emerging approaches to improve the care of patients, drawing from the literature regarding patient-centred care, patient and caregiver perspectives and priorities, gaps in knowledge among patients and caregivers and the need for accurate information, individual variability in disease manifestations, prognostication of disease course, new developments in health technologies and personalized medicine, specialty care, pharmacological and non-pharmacological management, financial burden, lifestyle and work-related issues, support groups and palliative care.

Objective Measurement and Characterization of Sleep Benefit in Parkinson's Disease.

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.

Clinical validation of a precision electromagnetic tremor measurement system in participants receiving deep brain stimulation for essential tremor.

Tremor is characterized commonly through subjective clinical rating scales. Accelerometer-based techniques for objective tremor measurement have been developed in the past, yet these measures are usually presented as an unintuitive dimensionless index without measurement units. Here we have developed a tool (TREMBAL) to provide quantifiable and objective measures of tremor severity using electromagnetic motion tracking. We aimed to compare TREMBAL's objective measures with clinical tremor ratings and determine the test-retest reliability of our technique. Eight participants with ET receiving deep brain stimulation (DBS) therapy were consented. Tremor was simultaneously recorded using TREMBAL and video during DBS adjustment. After each adjustment, participants performed a hands-outstretched task (for postural tremor) and a finger-nose task (for kinetic tremor). Video recordings were de-identified, randomized, and shown to a panel of movement disorder specialists to obtain their ratings. Regression analysis and Pearson's correlations were used to determine agreement between datasets. Subsets of the trial were repeated to assess test-retest reliability. Tremor amplitude and velocity measures were in close agreement with mean clinical ratings (r > 0.90) for both postural and kinetic tremors. Test-retest reliability for both translational and rotational components of tremor showed intra-class correlations >0.80. TREMBAL assessments showed that tremor gradually improved with increasing DBS therapy-this was also supported by clinical observation. TREMBAL measurements are a sensitive, objective and reliable assessment of tremor severity. This tool may have application in clinical trials and in aiding automated optimization of deep brain stimulation.

Neuropsychiatric manifestations of Parkinson's disease.

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.