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INTRODUCTION: Predictive biomarkers of Parkinson’s Disease progression are needed to expedite neuroprotective treatment development and facilitate prognoses for patients. This work uses measures derived from resting-state functional magnetic resonance imaging, including regional homogeneity (ReHo) and fractional amplitude of low frequency fluctuations (fALFF), to predict an individual’s current and future severity over up to 4 years and to elucidate the most prognostic brain regions. METHODS: ReHo and fALFF are measured for 82 Parkinson’s Disease subjects and used to train machine learning predictors of baseline clinical and future severity at 1 year, 2 years, and 4 years follow-up as measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Predictive performance is measured with nested cross-validation, validated on an external dataset, and again validated through leave-one-site-out cross-validation. Important predictive features are identified. RESULTS: The models explain up to 30.4% of the variance in current MDS-UPDRS scores, 55.8% of the variance in year 1 scores, and 47.1% of the variance in year 2 scores (p < 0.0001). For distinguishing high and low-severity individuals at each timepoint (MDS-UPDRS score above or below the median, respectively), the models achieve positive predictive values up to 79% and negative predictive values up to 80%. Higher ReHo and fALFF in several regions, including components of the default motor network, predicted lower severity across current and future timepoints. CONCLUSION: These results identify an accurate prognostic neuroimaging biomarker which may be used to better inform enrollment in trials of neuroprotective treatments and enable physicians to counsel their patients.

Objective Motor fluctuations develop in most patients treated with carbidopa/levodopa for Parkinson disease. The continuous dopamine stimulation hypothesis suggests that longer-acting forms of levodopa might improve outcomes, but this has been inadequately tested in humans. We undertook to determine if there is any difference in symptom progression rate among patients taking immediate-release carbidopa/levodopa (IR), controlled-release carbidopa/levodopa (CR), or carbidopa/levodopa/entacapone (CLE) using standard outcome measures in a naturalistic study. Methods We evaluated Parkinson disease subjects prospectively followed for up to 48 months in the Parkinson's Disease Biomarker Project. Bayesian linear or generalized linear mixed-effects models were developed to determine if oral levodopa formulation influenced the rate of symptom progression as measured by 8 outcome measures. Results At baseline, the IR, CR, and CLE groups were similar except that the CR group had milder disease and was represented at only 1 site, and the CLE group had a longer disease duration. In the primary analysis, there was no difference in rate of symptom progression as measured by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale Part II, Part IV, or total score. In the secondary exploratory analysis, there was no difference in progression rate as measured by change in levodopa equivalent daily dose, Montreal Cognitive Assessment, Parkinson's Disease Questionnaire mobility subscore, Schwab and England Activities of Daily Living Scale, or a global composite outcome. Conclusions We found no difference in symptom progression rate in patients taking IR, CR, or CLE. This clinical observation supports pharmacokinetic studies demonstrating that none of these oral levodopa formulations achieve continuous dopamine stimulation.

Using a multi-cohort, discovery-replication-validation design, we sought new plasma biomarkers that predict which individuals with Parkinson's disease (PD) will experience cognitive decline.In 108 discovery cohort PD individuals and 83 replication cohort PD individuals, we measured 940 plasma proteins on an aptamer-based platform. Using proteins associated with subsequent cognitive decline in both cohorts, we trained a logistic regression model to predict which patients with PD showed fast ( = 1 point drop/year on Montreal Cognitive Assessment [MoCA]) versus slow ( 1 point drop/year on MoCA) cognitive decline in the discovery cohort, testing it in the replication cohort. We developed alternate assays for the top 3 proteins and confirmed their ability to predict cognitive decline - defined by change in MoCA or development of incident mild cognitive impairment (MCI) or dementia - in a validation cohort of 118 individuals with PD. We investigated the top plasma biomarker for causal influence by Mendelian randomization (MR).A model with only 3 proteins (melanoma inhibitory activity protein [MIA], C-reactive protein [CRP], and albumin) separated fast versus slow cognitive decline subgroups with an area under the curve (AUC) of 0.80 in the validation cohort. The individuals with PD in the validation cohort in the top quartile of risk for cognitive decline based on this model were 4.4 times more likely to develop incident MCI or dementia than those in the lowest quartile. Genotypes at MIA single nucleotide polymorphism (SNP) rs2233154 associated with MIA levels and cognitive decline, providing evidence for MIA's causal influence.An easily obtained plasma-based predictor identifies individuals with PD at risk for cognitive decline. MIA may participate causally in development of cognitive decline. ANN NEUROL 2022;92:255-269.

In resting-state functional magnetic resonance imaging (rs-fMRI), artefactual signals arising from subject motion can dwarf and obfuscate the neuronal activity signal. Typical motion correction approaches involve the generation of nuisance regressors, which are timeseries of non-brain signals regressed out of the fMRI timeseries to yield putatively artifact-free data. Recent work suggests that concatenating all regressors into a single regression model is more effective than the sequential application of individual regressors, which may reintroduce previously removed artifacts. This work compares 18 motion correction pipelines consisting of head motion, independent components analysis, and non-neuronal physiological signal regressors in sequential or concatenated combinations. The pipelines are evaluated on a dataset of cognitively normal individuals with repeat imaging and on datasets of studies of Autism Spectrum Disorder, Major Depressive Disorder, and Parkinson's Disease. Extensive metrics of motion artifact removal are measured, including resting state network recovery, Quality Control-Functional Connectivity (QC-FC) correlation, distance-dependent artifact, network modularity, and test-retest reliability of multiple rs-fMRI analyses. The results reveal limitations in previously proposed metrics, including the QC-FC correlation and modularity quality, and identify more robust artifact removal metrics. The results also reveal limitations in the concatenated regression approach, which is outperformed by the sequential regression approach in the test-retest reliability metrics. Finally, pipelines are recommended that perform well based on quantitative and qualitative comparisons across multiple datasets and robust metrics. These new insights and recommendations help address the need for effective motion artifact correction to reduce noise and confounds in rs-fMRI.

Caffeine is neuroprotective in animal models of PD and caffeine intake is inversely associated with the risk of Parkinson’s disease (PD). This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p = 0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.

Magnetic resonance guided high intensity focused ultrasound is a novel, non-invasive, image-guided procedure that is able to ablate intracranial tissue with submillimetre precision. It is currently FDA approved for essential tremor and tremor dominant Parkinson’s disease. The aim of this update is to review the limitations of current landmark-based targeting techniques of the ventral intermediate nucleus and demonstrate the role of emerging imaging techniques that are relevant for both magnetic resonance guided high intensity focused ultrasound and deep brain stimulation. A significant limitation of standard MRI sequences is that the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei cannot be clearly identified. This paper provides original, annotated images demarcating the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei on advanced MRI sequences such as fast grey matter acquisition T1 inversion recovery, quantitative susceptibility mapping, susceptibility weighted imaging, and diffusion tensor imaging tractography. Additionally, the paper reviews clinical efficacy of targeting with these novel MRI techniques when compared to current established landmark-based targeting techniques. The paper has widespread applicability to both deep brain stimulation and magnetic resonance guided high intensity focused ultrasound.

Background Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. Methods and findings In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson’s Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 × 10−2, Replication FDR-corrected p = 1.03 × 10−4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 × 10−2, Replication FDR-corrected p = 9.14 × 10−5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 × 10−3, Replication FDR-corrected p = 2.18 × 10−2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 × 10−4, Replication FDR-corrected p = 2.97 × 10−3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04–5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24–7.0, p = 0.014] for ACY1). GHR’s association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20–11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. Conclusions In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD., Alice Chen-Plotkin and colleagues investigate possible biomarkers for diagnosis and progression of Parkinson’s disease., Author summary Why was this study done? No blood tests currently exist that distinguish people with Parkinson’s disease (PD) from neurologically normal individuals or that predict the rate of disease progression in people who have already been diagnosed with PD. Blood tests that distinguish people with PD would be helpful for confirmation of diagnosis (diagnostic biomarkers), whereas blood tests that predict the rate of disease progression (prognostic biomarkers) would be helpful for clinical trials and clinical care. What did the researchers do and find? We screened more than 1,000 blood-based proteins from 527 people with PD, amyotrophic lateral sclerosis (ALS), or neither neurological disease in order to discover new diagnostic and prognostic biomarkers. We used one group of participants to identify potential biomarkers and then used a separate group of participants to confirm these biomarkers. We found that blood levels of four proteins—bone sialoprotein (BSP), osteomodulin (OMD), aminoacylase-1 (ACY1), and growth hormone receptor (GHR)—consistently differed in people with PD compared to people without PD. We found that lower GHR levels at baseline predicted a faster rate of cognitive decline in people with PD. What do these findings mean? Levels of some blood proteins consistently differ between people with versus without PD, and some of these proteins also predict which PD individuals may have faster progression of disease. It may be possible to develop blood-based tests to help confirm PD diagnosis and predict disease progression.

Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov , number NCT01280123 . Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset.

Objective To develop a process to improve patient outcomes from deep brain stimulation (DBS) surgery for Parkinson disease (PD), essential tremor (ET), and dystonia. Methods We employed standard quality improvement methodology using the Plan-Do-Study-Act process to improve patient selection, surgical DBS lead implantation, postoperative programming, and ongoing assessment of patient outcomes. Results The result of this quality improvement process was the development of a neuromodulation network. The key aspect of this program is rigorous patient assessment of both motor and non-motor outcomes tracked longitudinally using a REDCap database. We describe how this information is used to identify problems and to initiate Plan-Do-Study-Act cycles to address them. Preliminary outcomes data is presented for the cohort of PD and ET patients who have received surgery since the creation of the neuromodulation network. Conclusions Careful outcomes tracking is essential to ensure quality in a complex therapeutic endeavor like DBS surgery for movement disorders. The REDCap database system is well suited to store outcomes data for the purpose of ongoing quality assurance monitoring.

Parkinson disease (PD) is the second most common neurodegenerative disease, after Alzheimer disease, and results in both motor and nonmotor dysfunction. Dementia is one of the most disabling nonmotor features. It has been found in an estimated 80% of patients followed longitudinally for 8–20 years,1, 2 and it predicts mortality.3 Depression is twice as common in patients with PD as in healthy controls,4 affecting 31% of patients5; it may predate the onset of motor impairment.6 Counseling about prognosis is an important aspect of care for newly diagnosed patients. Given the importance of dementia and depression to the ultimate disease burden, it is worthwhile to try to correlate presenting motor features with risk of cognitive impairment and depressed mood. Most previous research (31 of 36 studies reviewed by Verreyt et al)7 on the relationship between cognition and the distribution of motor symptoms in PD has evaluated location of the predominant symptoms at the time of the study. However, the type and distribution of symptoms at disease onset are of greater interest because any relationship established between onset site and risk of cognitive impairment can be used to counsel patients when they are first diagnosed. Previous studies suggested a higher risk of cognitive impairment with bilateral onset of symptoms,8 but no difference in risk between right-side and left-side onset.8, 9 Studies looking at the type of symptoms at onset found that in patients with tremor as their first symptom, dementia was less common and more delayed than in those with bradykinesia as their presenting feature.10 Further, cognitive function was found to be better preserved when first symptoms appear on the right side of the body than on the left.11 Katzen et al, for example, studied motor symptom type and laterality at disease onset by evaluating neuropsychological test results in 58 patients and controls.12 The patients whose presenting feature was an isolated tremor in the right hand had fully intact cognitive function, but patients with left-sided onset of any motor symptom or right-sided onset of bradykinesia and/or rigidity had impaired neuropsychological performance. Studies evaluating the link between laterality of PD symptoms and depressed mood have also shown conflicting results. Of 3 studies considering predominant involvement at the time of the study, 1 found that right-side-predominant symptoms were associated with a greater number of depressive symptoms,13 1 found a strong association between left-sided symptoms and more severe depression,14 and 1 showed no difference.15 In 2 studies that assessed the relationship between depression severity and laterality of symptoms at disease onset, both found that right-sided onset was associated with more severe depressive symptoms.16, 17 In this study, we sought to determine whether side and type of motor symptoms at onset were associated with later cognitive function and depressive symptoms in a high-functioning, nondemented cohort of patients with PD.

Background: This evidence-based guideline is an update of the 2005 American Academy of Neurology practice parameter on the treatment of essential tremor (ET). Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 2004 and April 2010. Results and Recommendations: Conclusions and recommendations for the use of propranolol, primidone (Level A, established as effective); alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate (Level B, probably effective); nadolol, nimodipine, clonazepam, botulinum toxin A, deep brain stimulation, thalamotomy (Level C, possibly effective); and gamma knife thalamotomy (Level U, insufficient evidence) are unchanged from the previous guideline. Changes to conclusions and recommendations from the previous guideline include the following: 1) levetiracetam and 3,4-diaminopyridine probably do not reduce limb tremor in ET and should not be considered (Level B); 2) flunarizine possibly has no effect in treating limb tremor in ET and may not be considered (Level C); and 3) there is insufficient evidence to support or refute the use of pregabalin, zonisamide, or clozapine as treatment for ET (Level U). Neurology ® 2011;77:1752–1755

Three hundred patients with Parkinson's disease taking dopamine agonists were surveyed for the presence of compulsions. Fifty-eight reported active compulsions which had developed after initiation of dopamine agonists. These included 25 with sexual compulsions and 28 with self-described compulsive gambling, of whom 17 met criteria for pathologic gambling. Males were over-represented. Patients with any compulsion and those with pathologic gambling were about 6 years younger than those without compulsions. These behavioral problems were not associated with an individual dopamine agonist, nor dose or duration, nor concomitant levodopa. Follow-up of the pathologic gamblers 1 year after intervention, which was cessation of the dopamine agonist in most cases, found ongoing but controlled gambling in five and complete cessation within 4 months in the remainder.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Parkinsondisease (PD) is knowntoaffectmultipleneurotransmitter systems, resulting in both motor and nonmotor symptoms. Pain is an underrecognized but important nonmotor symptom of PD that may be verydisablingandisknownto impair quality of life.1 While significantprogresshasbeenmadeinamelioratingmotorsymptomsusing pharmacological, rehabilitative, and surgical treatments, thetreatmentofpain inthiscontexthasnotreceivedsufficientattention.Aliteraturereview2notedareportedprevalence ofpain inPDof40%to85%,yetonlyabouthalf ofpatientswith PDwhofeltpaintookanalgesics.ClassifyingPD-relatedpaininto its subtypes3 is important for rational treatment, and themost common subtypes of pain in PD are musculoskeletal and dystonic, with central neuropathic pain being the least common.2 Toaddresspainsuccessfully inPD,anunderstandingof itspathogenesis is important, yet this has remained elusive, in part because its causes areprotean. Just as certainmotor symptomsof PD aremore responsive to dopaminergic drugs and deep brain stimulation (DBS), somepainsubtypesmayrespondbetter than others to pharmacological and surgical intervention. Dysfunction of both dopaminergic and nondopaminergic basal ganglia pathwaysare likelytobe involvedinPD-relatedpain,whichmay explainwhysome typesofpain are responsive to levodopaand others are not.4 Deep brain stimulation of the subthalamic nucleus (STN) isnowanestablished treatmentofdisablingmotor symptoms in advanced PD, and it is therefore important to understand its effect on pain associated with PD. Previous reports5,6 on the effects of STNDBSonpain inPDshowthat the levelsofmusculoskeletal anddystonicpaindecreasedwhenassessed1yearafter surgery,but, toourknowledge, there isnoexisting information on the status of chronic pain. In this issue of JAMA Neurology, Jung and colleagues7 investigate the long-termeffect of STNDBSonpain in24patients withPDwhowereobservedfor8yearsafterundergoingtheprocedure for alleviating disabling motor symptoms. The beneficial effectsofSTNDBS in this cohort 3monthsafter surgeryand 24monthsafter surgeryhavebeenpreviouslypublished.8,9The subtypes of painwere classified according to Ford.3 The severity and body distribution of pain were compared between presurgical andpostsurgical states. Jungandcolleagues7notedsignificant improvement at 8 years in all pain types present preoperatively, regardlessofwhether thepreoperativepainwas responsive to levodopa or not.However, newpain, not present before surgery, developed in 75% of patients during prolonged follow-up. Musculoskeletal pain accounted for the majority of newpain cases. Although themean severity of painwas less at 8 years than at baseline,more patients experienced pain at the end of the observation period than preoperatively. Because previous studies on pain following STN DBS for PD are of short duration, the durability of the procedure’s effect on pain is not well established. The chief strength of the work by Jung and colleagues7 is the long follow-up period, which suggests that, althoughDBSmay relievepain for a time, this is not a durable effect owing to the onset of new, primarilymusculoskeletal pain.A recent report5wasconcordantwith the study by Jung and colleagues7 in showing the benefit of DBS on dystonic and musculoskeletal pain but was discordant in showingnoeffect ofDBSoncentral and radicular pain. Methodological differences, the subjective classification of pain, andamuchshorter observationperiod couldaccount for these discrepant findings. The study by Jung and colleagues7 has several limitations that the authors acknowledge, including a small cohort without a control group thatwas treatedmedically, the lack of correlation of pain scores with motor Unified Parkinson’s Disease Rating Scale scores (especially rigidity, which can potentially impact musculoskeletal pain), the lack of measures of disability or effect of pain on quality of life, and the lackofmoodandcognitiveassessments that can influencepain perception. In addition, an analysis of the effect of levodopa onpreoperative pain vs the effect of DBS onpainwas not performed. This would have been of interest in light of a previous report10 suggesting that the effects of DBS on pain can be predicted by measuring the effects of levodopa on pain. Despiteits limitations,thestudybyJungandcolleagues7providesanovelperspectiveon thedurabilityof thepain-relieving properties of STN DBS in PD. The authors direct our attention tothefactthatmusculoskeletalpainmayemergeyearsafterDBS, warranting individualized treatment. The next step is to pursueadeeperunderstandingof themechanismofpain inPD.Previous work11 with small numbers of participants has demonstrated altered pain processing in participants with PD who experienced pain comparedwith those who did not, such that STN DBS raises pain thresholds selectively in those who experiencepain.Althoughthere isagrowingconsensusthatSTNDBS decreases the level of pain in people with PD, the literature is mixed on the subtypes of pain that are responsive to DBS, and the study by Jung and colleagues7 shows that new pain arising years after the procedure is common. This underscores the importance of performing future trialswith larger cohorts, longer observational periods, and standard methods to enable effective interpretation of outcomes. For now,we have learned that STNDBS does not take the ouch out of PD in the long run. Related article page 504 Opinion

To examine the sensitivity and specificity of the Montreal Cognitive Assessment (MoCA), a brief cognitive screening measure previously validated for use in Parkinson's disease (PD), and Alzheimer's Disease-8 (AD8), an eight-item informant report used to screen for dementia, but not yet validated for use in PD, to identify cognitive impairment in a sample of 111 patients with PD.Cognitive impairment was determined based on a battery of neuropsychological measures, excluding the MoCA and AD8. Classification rates of both the MoCA and AD8 in identifying cognitive impairment were examined using logistic regression and receiver operator characteristic (ROC) analysis. Optimal cutoff scores were determined to maximize sensitivity and specificity.The MoCA correctly classified 78.4% of participants (p 0.001), and ROC analysis yielded an area under the curve (AUC) of 0.82. A MoCA cutoff score of25 yielded optimal sensitivity (0.77) and specificity (0.79) for identifying PD patients with cognitive impairment. Similar analyses for the AD8 were statistically nonsignificant, although the classification rate was 70.5%, with an AUC of 0.50.These results provide additional support for the MoCA, but not the AD8, in identifying cognitive impairment in patients with PD.

Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials.Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects.Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels).By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. © 2015 International Parkinson and Movement Disorder Society.

Elevated homocysteine (Hcy), prevalent in Parkinson's disease (PD), is potentially a modifiable risk factor for neurologic deterioration. We measured cognitive, affective and motor changes over 2 years in a cohort of people with early PD. Subjects whose Hcy had been elevated (>14 μmol/L, n =31) at baseline were compared with the rest ( n =66). Overall progression in 2 years did not significantly differ ( p =0.20). Four subjects with elevated and one with normal Hcy had died ( p =0.03). We conclude that hyperhomocysteinemia does not predict significantly worse progression over 2 years in early PD. The data raised the possibility of higher mortality, but the number of deaths was small.

Background Sex differences in Parkinson disease clinical features have been reported, but few studies have examined sex influences on use of dopaminergic medication in early Parkinson disease. The objective of this study was to test if there are differences in the type of dopaminergic medication used and levodopa equivalent daily dose between men and women with early Parkinson disease enrolled in a large multicenter study of Creatine as a potential disease modifying therapy – the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease Long-Term Study-1. Methods Baseline data of 1,741 participants from 45 participating sites were analyzed. Participants from the United States and Canada were enrolled within five years of Parkinson Disease diagnosis. Two outcome variables were studied: type of dopaminergic medication used and levodopa equivalent daily dose at baseline in the Long-Term Study-1. Chi-square statistic and linear regression models were used for statistical analysis. Results There were no statistically significant differences in the frequency of use of different types of dopaminergic medications at baseline between men and women with Parkinson Disease. A small but statistically significant difference was observed in the median unadjusted levodopa equivalent daily dose at baseline between women (300 mg) and men (325 mg), but this was not observed after controlling for disease duration (years since Parkinson disease diagnosis), disease severity (Unified Parkinson's Disease Rating Scale Motor and Activities of Daily Living Scores), and body weight. Conclusions In this large multicenter study, we did not observe sex differences in the type and dose of dopaminergic medications used in early Parkinson Disease. Further research is needed to evaluate the influence of male or female sex on use of dopaminergic medication in mid- and late-stage Parkinson Disease.

Although dysfunction of motor control is the hallmark of Parkinson’s disease (PD), nonmotor symptoms, such as those related to autonomic dysfunction, are common and potentially disabling manifestations of the disease. Such nonmotor features are not often formally assessed and may be frequently misdiagnosed, so the true prevalence of these abnormalities remains poorly defined [1–3]. It has been estimated that over the course of PD more than 90% of patients experience symptoms of autonomic dysfunction, which can have a negative impact on quality of life (QOL) and may increase the risk of adverse events [4]. Understanding the relationship between autonomic dysfunction and PD is difficult because these symptoms may be the result of other conditions (such as multiple system atrophy [MSA]), the aging process itself, or pharmacotherapy for PD. Identification of these symptoms and early implementation of treatment can make a major difference in patient QOL and can reduce the risk for symptom-associated morbidity.

Motor fluctuations in Parkinson's disease (PD) typically develop after 4-6 years of therapy, and affect approximately half of all patients. The wearing-off effect is the most common type, and "delayed-on," "no-on," and "on-off" effects, as well as dyskinesias, may also develop as the disease progresses. Collectively, motor fluctuations represent a significant source of disability in advanced PD patients, and their mitigation is a major goal of patient management. Adjunctive medications, including dopamine agonists, amantadine, MAO-B inhibitors, and COMT inhibitors, each may reduce the frequency or duration of "off" periods, but none does so completely, and each contributes its own side effects which may limit optimal dosing. Surgery is another strategy to reduce "off" time, and both pallidotomy and deep brain stimulation of the globus pallidus or the subthalamic nucleus have been shown to be highly effective in this regard. However, surgery may be contraindicated in elderly advanced patients who could most benefit from its effect on "off" time. The unmet need for treatment of "off" episodes suggests the potential utility of an agent such as apomorphine injectable, which can reliably trigger an "on" response within 10-15 minutes of injection.

Head injury can cause extrapyramidal movement disorders such as tremors, parkinsonism, dystonia, chorea, myoclonus, and tics. Pure adventitious movements are rare, but combinations with paresis, spasticity, apraxia, or ataxia occur in approximately 20% of cases of severe head injury, in many cases appearing or evolving in the months following the injury. Tremors may improve in time but many of the other syndromes tend to persist. Reversible causes such as medications or metabolic derangements are occasionally identifiable. Some of these adventitious movements can be improved using neuroactive drugs, botulinum toxin injections, or stereotactic brain surgery.

Objectives. To examine the urodynamic (UDS) attributes of detrusor overactivity (DO) in patients with Parkinson’s disease in comparison to DO in men without neurologic disease, in whom DO is presumably outlet obstruction induced. Methods. The UDS database was reviewed for three groups of patients: group 1, men with lower urinary tract symptoms (LUTS) and no known neurologic condition with DO (n 22); group 2, men with Parkinson’s disease and LUTS (n 39); and group 3, women with Parkinson’s disease and LUTS (n 18). Statistical analysis was used to compare the UDS parameters and diagnoses among the groups and to test for associations between Parkinson’s disease duration, Hoehn and Yahr score, and UDS findings. Results. Patients with Parkinson’s disease had a significantly lower median volume at first detrusor contraction than those with non-neurogenic DO. The percentage of group 1 patients with urge incontinence was significantly lower than that found in the other two groups (9.1% versus 53.8% and 55.6%, P 0.001 and 0.002, respectively). No statistically significant correlation between the duration or severity of Parkinson’s disease and UDS parameters was found. Conclusions. Men with non-neurogenic LUTS are less likely to have urge incontinence on UDS than either men or women with Parkinson’s disease. DO owing to Parkinson’s disease occurs earlier during filling compared with non-neurogenic DO, especially in women. The duration and severity of Parkinson’s disease are not predictive of the nature or severity of UDS abnormalities. UROLOGY 62: 651–655, 2003. © 2003 Elsevier Inc.

Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD=2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.

Background : The ratios of abducting to adducting eye movements (versional dysconjugacy index, VDI) for saccadic velocity and acceleration have been useful measures by which to objectively characterize internuclear ophthalmoparesis (INO). Amplitude measures of dysconjugacy have been less useful, given that many patients maintain the ability to ultimately reach a centrifugal fixation target and that traditional amplitude measures of VDI have focused on this ‘final amplitude’ (FA) position. Methods : We utilized infrared oculography to define a new amplitude measure of dysconjugacy in 42 multiple sclerosis (MS) patients with INO. The first-pass amplitude (FPA)-VDI is the ratio of abduction/adduction eye movement amplitudes computed at the time when the abducting eye initially achieves the centrifugal horizontal fixation target. Results : FPA-VDI values were significantly more sensitive and specific than FA-VDI values in demonstrating dysconjugacy in INO, and there was a 14-fold increase in dysconjugacy as measured by FPA-VDI Z -scores when compared to FA-VDI Z -scores. Conclusion : Consideration of velocity (pulse) and amplitude (step) components of dysconjugacy in patients with INO can provide a greater understanding of the dynamic aspects of this syndrome. We propose to characterize the relationship between the pathophysiology of INO and neuroradiologic measures of tissue injury in MS.

Objective To assess the suitability of instrumented gait and balance measures for diagnosis and estimation of disease severity in PD. Methods Each subject performed iTUG (instrumented Timed-Up-and-Go) and iSway (instrumented Sway) using the APDM ® Mobility Lab. MDS-UPDRS parts II and III, a postural instability and gait disorder (PIGD) score, the mobility subscale of the PDQ-39, and Hoehn & Yahr stage were measured in the PD cohort. Two sets of gait and balance variables were defined by high correlation with diagnosis or disease severity and were evaluated using multiple linear and logistic regressions, ROC analyses, and t-tests. Results 135 PD subjects and 66 age-matched controls were evaluated in this prospective cohort study. We found that both iTUG and iSway variables differentiated PD subjects from controls (area under the ROC curve was 0.82 and 0.75 respectively) and correlated with all PD severity measures ( R 2 ranging from 0.18 to 0.61). Objective exam-based scores correlated more strongly with iTUG than iSway. The chosen set of iTUG variables was abnormal in very mild disease. Age and gender influenced gait and balance parameters and were therefore controlled in all analyses. Interpretation Our study identified sets of iTUG and iSway variables which correlate with PD severity measures and differentiate PD subjects from controls. These gait and balance measures could potentially serve as markers of PD progression and are under evaluation for this purpose in the ongoing NIH Parkinson Disease Biomarker Program.

A 4-year experience with new-onset vertigo in a university-based MS population was retrospectively reviewed. Of 1,153 patients with MS, 25 could be clinically evaluated during the vertiginous episode. Of these, 13 (52%) were diagnosed with benign paroxysmal positioning vertigo and eight (32%) had acute MS exacerbations with corresponding lesions within the brainstem. All patients diagnosed with benign paroxysmal positioning vertigo were treated successfully with particle repositioning maneuvers.

To assess the lower urinary tract symptoms (LUTS) in men and women with mild to moderate Parkinson's disease (PD) using validated symptom questionnaires.Eighty men and 39 women with mild to moderate PD (Hoehn and Yahr score less than 3) were mailed LUTS questionnaires to complete and return. Men received the American Urological Association Symptom Index and women received the Urogenital Distress Inventory-6. Patients not responding by mail were called and asked to complete the survey over the telephone. Control populations of both symptomatic and asymptomatic men and women (without PD) were identified for comparison.The overall response rate was 78%. Men with early-stage PD had higher American Urological Association Symptom Index scores than age-matched controls (total score of 12.0 versus 7.7, P0.05) and scores similar to those reported for men with symptomatic benign prostatic hyperplasia (12.5). Specific items noted to be higher among the men with PD included questions regarding frequency and urgency. Women with PD had higher scores on the Urogenital Distress Inventory-6 than non-age-matched controls (total score of 4.8 versus 2.1, P0.05), but lower scores than an age-matched group of neurologically intact women presenting for urologic evaluation of LUTS (6.9, P0.05).On the basis of the responses to the validated symptom indexes, the development of LUTS appears to occur at an earlier stage of PD than was once appreciated. Prompt evaluation and treatment of patients with lower urinary tract complaints in the setting of PD may identify bladder dysfunction at an earlier, more treatable stage.

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.

Nine patients with advanced levodopa-responsive Parkinson's disease were enrolled in a double-blind, placebo-controlled crossover trial of intranasal apomorphine as rescue therapy for parkinsonian off-states. Patients were assigned in random order to each of four possible combinations of apomorphine, trimethobenzamide antiemetic, and their matched placebos and received detailed in-office motor scoring during each of the four study periods. Patients also completed diaries describing the effectiveness of the nasal spray for reversing off-states. A statistically significant reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score was seen following active apomorphine during in-office evaluation visits but not following placebo nasal spray. Patient diaries revealed that active apomorphine had a latency to onset of 11 minutes and a duration of 50 minutes. Significant nausea from apomorphine spray was seen in only one patient whereas nasal irritation was disabling in three and mild in two. We conclude that intranasal apomorphine is an effective rescue agent for parkinsonian off-states although nasal irritation is a limiting factor.

Eleven patients with levodopa-related motor fluctuations were scored before and after intranasal apomorphine monotherapy, and the motor responses were compared with those with levodopa/carbidopa in this openlabel study. Oral trimethobenzamide was used to prevent apomorphine-induced nausea. Three measures of motor performance were employed: (a) the Unified Parkinson's Disease Rating Scale (UPDRS) motor battery; (b) a timed hand-tapping test; and (c) the Webster's step-seconds test. The magnitude of the motor-score improvement after apomorphine administration was very similar to that after the usual doses of levodopa/carbidopa in the 10 patients completing the study; this was true for all three outcome measures. A major advantage of apomorphine was the rapid onset of clinical response, which typically occurred in < 10 min, as well as the ease of administration. Major side effects, beyond those experienced with levodopa/carbidopa, were limited to nausea and vomiting (three patients) and orthostatic hypotension (one patient); however, only a single patient dropped out of the study as a consequence. These results indicate that intranasal apomorphine is effective in rapidly relieving parkinsonian "off" states and that, for most patients, trimethobenzamide is an effective and well-tolerated antiemetic for use with apomorphine.

The authors compared the accuracy of clinical detection (by 279 physician observers) of internuclear ophthalmoparesis (INO) with that of quantitative infrared oculography. For the patients with mild adduction slowing, INO was not identified by 71%. Intermediate dysconjugacy was not detected by 25% of the evaluators. In the most severe cases, INO was not identified by only 6%. Oculographic techniques significantly enhance the precision of INO detection compared to the clinical exam.

When rotigotine patch was withdrawn from the US market, we prospectively gathered data on efficacy, side effects, and daytime sedation on patients while taking rotigotine and following the switch to alternate therapies.Patients rated the efficacy of rotigotine on a scale of 0-5 (ineffective to extremely effective) and completed the Epworth Sleepiness Scale. At a follow-up visit a mean of 3 months later, patients rated their change in efficacy and side effects on a scale of -3 to +3 (much worse to much better) and again completed the Epworth Sleepiness Scale.Thirty-three patients were switched to a single alternate treatment. On rotigotine, the average efficacy score was 3.5, and after switching, the average change in efficacy was -0.67 (worsening). Average change scores for efficacy and adverse effects were 0.25 and 0.38 for levodopa, -0.88 and -0.25 for ropinirole IR, -1.2 and -0.83 for ropinirole XL, -0.80 and 1.0 for pramipexole, and -1.0 and 0.50 for rasagiline, respectively. Average change in Epworth score on each alternate agent was -3.9, -2.3, 1.3, 3.0, and 1.Rotigotine was an effective treatment with all groups deteriorating after switch except for the levodopa group. Fifty-eight percent of patients preferred rotigotine versus 36% preferring the alternate treatment.

Objective To compare student performance, attitudes, and career plans based on whether the neurology clerkship was taken in the third or fourth year. Design During the 1-year transition when the neurology clerkship was officially moved from the fourth to the third year at our institution, students took the identical clinical clerkship and were mixed together at each clinical site where faculty were blinded to student's year. Setting University of Texas Southwestern Medical School. Participants Third- and fourth-year medical students. Main Outcome Measures Performance, enthusiasm, and match results were analyzed by year of medical school for differences. Results There was a statistical trend toward better performance of third-year students as measured by the clinical evaluation grade (88.4 vs 87.4; P = .051) but this represented only a 1% difference. No difference was noted on the National Board of Medical Examiners neurology shelf examination score (73.8 vs 74.9; P = .20). Students' enthusiasm for neurologic learning was significantly higher in third- as compared with fourth-year students ( P = .004). The probability that students would choose a career in neurology was higher for third- than fourth-year students ( P P = .17). Conclusions Our findings support the belief among academic neurologists that students who take the neurology clerkship in the third year have greater enthusiasm for the field and look more favorably on neurology as a possible career than those taking the neurology clerkship in their fourth year. Nevertheless, our findings do not support the notion that third-year placement results in superior achievement.

Given the magnitude of the problem of motor fluctuations in patients who have Parkinson's disease treated with levodopa, a significant effort has been expended by physicians, researchers, and pharmaceutical manufacturers over the years to find effective treatments. This article briefly reviews the medical options for managing motor fluctuations that are in common use in the United States or that are expected to be available soon.

The authors previously developed an optical stereotactic probe employing near-infrared (NIR) spectroscopy to provide intraoperative localization by distinguishing gray matter from white matter. In the current study they extend and further validate this technology.Near-infrared probes were inserted 203 times during 138 procedures for movement disorders. Detailed validation with postoperative imaging was obtained for 121 of these procedures and with microelectrode recording (MER) for 30 procedures. Probes were constructed to interrogate tissue perpendicular to the probe path and to incorporate hollow channels for microelectrodes, deep brain stimulation (DBS) electrodes, and other payloads.The NIR data were highly correlated to imaging and MER recordings for thalamic targets. The NIR data were highly sensitive but less specific relative to imaging for subthalamic targets, confirming the ability to detect the subthalamic nucleus and to provide warnings of inaccurate localization. The difference between the NIR- and MER-detected midpoints of the subthalamic nucleus along the chosen tracks was 1.1 +/- 1.2 mm (SD). Data obtained during insertion and withdrawal of the NIR probe suggested that DBS electrodes may push their targets ahead of their paths. There was one symptomatic morbidity. Detailed NIR data could be obtained from a 7-cm track in less than 10 minutes.The NIR probe is a straightforward, quick, and robust tool for intraoperative localization during functional neurosurgery. Potential future applications include localization of targets for epilepsy and psychiatric disorders, and incorporation of NIR guidance into probes designed to convey various payloads.

Although most studies have suggested an increased risk of valvulopathy (primarily regurgitation) with pergolide mesylate use, one study suggested that this problem may also occur with use of the non-ergot-derived dopamine agonists pramipexole dihydrochloride and ropinirole hydrochloride.To determine if cardiac valve regurgitation occurs more commonly in patients with Parkinson disease (PD) treated with pergolide than in those treated with nonergot agonists at a comparable dose.A case-control study of echocardiographic findings of valve function in patients receiving dopamine agonists for PD.University-based referral center. Patients Thirty-six patients with idiopathic PD taking pergolide were compared with a matched control group of patients taking nonergot agonists with regard to the frequency and severity of cardiac valve regurgitation. Main Outcome Measure Valve scores (1 indicates trace; 2, mild; 3, moderate; and 4, severe) for the pergolide group were compared with those for the nonergot agonist control group.The mean +/- SD valve regurgitation scores in the matched pergolide group compared with the nonergot group were as follows: aortic, 0.83 +/- 1.23 vs 0.19 +/- 0.53 (P = .01); mitral, 1.42 +/- 1.0 vs 0.39 +/- 0.65 (P.001); and tricuspid, 1.43 +/- 1.0 vs 0.19 +/- 0.53 (P.001). Lifetime exposure to a dopamine agonist was not statistically different between the pergolide and nonergot agonist groups (P = .18).These data strengthen the conclusion that pergolide contributes to cardiac valve regurgitation when used in the long term as a treatment for PD. There appears to be low risk of cardiac valve regurgitation when using non-ergot-derived dopamine agonists.

Importance There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. Objective To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. Design, Setting, and Patients The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Interventions Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). Main Outcomes and Measures The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. Results The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t 1865.8 = −0.75 (2-sided P = .45). There were no detectable differences ( P Conclusions and Relevance Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. Trial Registration clinicaltrials.gov Identifier:NCT00449865

Background: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use. Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. Results and Conclusions: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET. NEUROLOGY 2005;64:2008-2020 Background and justification. Essential tremor (ET) is a common adult tremor disorder, with preva- lence estimates from population studies ranging from 0.4% to 5%. 1,2 The incidence and prevalence of ET increase with advancing age. 2 ET is characterized by the presence of postural and kinetic tremor. 3 In classic ET, upper limbs (95% of patients) and less commonly the head (34%), lower limbs (30%), voice (12%), tongue (7%), face (5%), and trunk (5%) exhibit a postural or kinetic tremor. 4 ET has been referred to as a benign

Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) μmol/L increased to 10.1 (3.1) μmol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L-dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 μmol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined. © 2004 Movement Disorder Society

Objective: To determine if pergolide injures heart valves, by comparing echocardiographic findings in pergolide-treated patients with those of a historical control group. Methods: Letters were sent to all patients in the authors’ practice believed to be taking pergolide, and those responders who wished to continue it were urged to undergo echocardiography. Echocardiograms were obtained on 46 patients, and scores for valvular regurgitation were compared with those from an age-matched control group derived from the Framingham Study. The composite valve regurgitation score was modeled as a linear function of total milligrams lifetime use of pergolide, controlling for age. Results: Eighty-nine percent of pergolide-treated patients had some degree of valvular insufficiency. For each of the three valves for which there are control data, we found an approximately 2- to 3-fold increased risk of abnormal valves in the pergolide patients (odds ratio [OR] ≈ 3) and an estimated 14-fold increased risk of concerning tricuspid regurgitation (OR = 18.4). The composite valve score (the sum of valve scores for each of the four valves) was a function of lifetime pergolide use. Conclusion: Pergolide may injure cardiac valves, resulting most commonly in tricuspid regurgitation.

Patients with MS exhibit a broad diversity of ocular motor syndromes. We describe a patient with relapsing-remitting MS who developed an unusual variation of the dorsal midbrain syndrome, character ized by monocular convergent-retraction nystagmus in the right eye, accompanied by divergent-retraction nystagmus in the fellow eye upon attempted upward gaze. Examination also revealed a skew deviation with a left hyperdeviation and severe adductio n limitation in the left eye during attempted right gaze. We propose that a left INO accounted for the inability of the left eye to adduct (and result in convergent-retraction) during attempted upward saccades. We consider the patho physiologic mechanisms responsible for our observations and review important details of the dorsal midbrain ocular motor circuitr y.

Background An elevated plasma homocysteine (Hcy) level has been prospectively associated with an increased risk of vascular and degenerative dementias. An Hcy elevation is prevalent in patients with Parkinson disease (PD) in part because levodopa metabolism produces Hcy. The clinical relevance of an elevated Hcy level in patients with PD is unknown. Objective To determine if hyperhomocysteinemia in patients with PD is associated with depression or with cognitive or physical impairments. Design Ninety-seven people with a mean (SD) PD duration of 3.6 (1.6) years completed the Beck Depression Inventory, a battery of 11 cognitive tests, and the motor and function components of the Unified Parkinson's Disease Rating Scale. Normalized scores for the affective, cognitive, and physical measures were compared between those with a normal Hcy level (n = 66) and those with hyperhomocysteinemia (n = 31) (Hcy level, >1.89 mg/L [>14 µmol/L]), controlling for age, sex, disease duration, and treatment. Results Subjects with an elevated Hcy level were slightly older (68 vs 62 years), but had similar plasma concentrations of vitamin B 12 and folate. Hyperhomocysteinemic patients were more depressed ( P = .02) and had worse cognition ( P Conclusions Patients with PD and hyperhomocysteinemia are more likely to be depressed and to perform worse on neuropsychometric tasks compared with normohomocysteinemic patients. Further research is warranted to see if hyperhomocysteinemia is a reversible risk factor for neuropsychiatric burden in patients with PD.

Context Huntington chorea, like levodopa-induced dyskinesias, may be responsive to amantadine hydrochloride treatment. Objectives To measure the effect of amantadine treatment on Huntington chorea and to test a hypothesis that the adventitious movements are associated with reduced central proprioception that can be corrected by amantadine treatment. Design A randomized placebo-controlled cross-over trial with 2 weeks of treatment. Setting A tertiary referral center. Participants Twenty-four subjects with Huntington disease took amantadine hydrochloride, 100 mg 3 times daily for 2 weeks, and placebo for 2 weeks. Methods Chorea of the face, trunk, and limbs while seated was videotaped at baseline and after each study phase. Segments were viewed in random order by blinded reviewers and scored. Proprioception was determined using arm restraints in which the right and left elbows were set at slightly different angles, and the errors in selecting the more extended elbow over 40 trials were recorded. Results The chorea score was not correlated with a proprioception deficit. Neither chorea nor proprioception were significantly affected by amantadine therapy. The chorea score was 9.6 (3.1) points at baseline and 9.7 (3.7) points when the patient was receiving amantadine therapy. The 95% confidence interval for the difference between placebo effect and amantadine effect was −1.43 to 1.0 points. Despite this, 19 subjects felt improved during the amantadine phase compared with 6 subjects improved in the placebo phase (P= .006) and the quality of life was better (P Conclusions Elbow proprioception was not shown to be related to Huntington chorea. Amantadine hydrochloride treatment at doses of 300 mg/d had no effect, on average, for Huntington chorea, although most patients felt subjectively better during the short course of amantadine treatment.

Objective: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appro priate diagnostic techniques and treatment interventions. Background: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessar y treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. A ll patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appro priate for the specific diagnosis. Conclusions: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.

Background Adult polyglucosan body disease (PGBD) is rare and typically presents with upper and lower motor neuron involvement and neurogenic bladder. Extrapyramidal features are unusual in PGBD and are presumed secondary to widespread pathology that includes the basal ganglia. There are no prior reports of Lewy bodies in PGBD. Objective To report a unique finding of Lewy bodies in a patient with PGBD. Report of a Case A 46-year-old woman initially presented with a 4-year history of resting tremor. The tremor responded to levodopa therapy. Several months later, she developed upper and lower motor neuron involvement and other clinical features of PGBD. A sural nerve biopsy specimen revealed intra-axonal polyglucosan bodies that confirmed the clinical diagnosis. Bulbar and limb weakness progressed, and she developed dementia. She died 6 years after onset. At autopsy, extensive polyglucosan body formation was found in many regions of the central nervous system. In addition, numerous α-synuclein staining Lewy bodies were observed in the substantia nigra, accompanied by marked neuron depopulation. Conclusions To our knowledge, this is the first report of adult PGBD associated with Lewy bodies and levodopa-responsive tremor. Although polyglucosan bodies were seen in substantia nigra, it is most likely that our patient had coexisting Parkinson disease.

In 2 patients with essential tremor, thalamotomy in the ventralis intermedius (VIM) provided lasting tremor relief after thalamic stimulation of the VIM failed. These cases illustrate that the effects of deep brain stimulation might not be those of simple inhibition, and that thalamotomy should be considered when deep brain stimulation does not succeed.

Background: Thalamic deep brain stimulation ameliorates essential and parkinsonian tremors refractory to medications. Stimulus voltage, polarity configuration, frequency, and pulsewidth can each be adjusted in order to optimize tremor control and maximize battery life. The relative impacts of these programmable variables have not previously been quantified. Methods: The thalamus of 11 patients (bilaterally in 2) was studied 4 to 59 months postoperatively. The stimulator was inactivated and medications withheld for 12 hours, and optimal electrode contacts were selected. Stimulation followed at a range of voltages (0, 1, 2, 3, or 4 V), pulsewidths (60, 90, or 120 μs), and frequencies (130, 160, or 185 Hz) for both monopolar and bipolar configurations. Seventy-eight combinations of variables were programmed in random sequence. Postural and action tremors were measured with an electromagnetic tracker, tremor was subjectively graded, and side effects were noted. Results: Voltage was consistently predictive of tremor response. Mean postural tremor amplitude in PD fell from 6.4 cm at 0 V to 2.6, 1.0, 0.3, and 0 cm at 1 through 4 V (bipolar configuration). The voltage response curve for essential tremor was flatter. The monopolar configuration was 10 to 25% more effective than bipolar. The longest pulsewidth tested was up to 30% more effective than the shortest, but frequency changes had little effect on tremor amplitude. Side effects occurred only with monopolar stimulation, and the only setting that was intolerable for the majority was 4 V, 120 μs, and 185 Hz. Conclusion: Bipolar deep brain stimulation at 90 μs, 130 Hz, adjusting the voltage up to 3 V, tends to be effective and well tolerated. Monopolar provides similar benefits for lower voltage, but side effects become common at 3 or 4 V.

An individual's age at onset of Parkinson disease (PD) can be collected through a variety of sources, including medical records, family report, and clinical observation. The most common source of PD age at onset information in the research setting is family-report, which is then typically used to classify a subject as juvenile, young, or late age at onset. The reliability of the family-reported age at onset of PD has not been rigorously examined. The present study used data from individuals diagnosed with PD to evaluate the reliability of age at onset information by comparing data obtained from three sources: 1) the subject's medical records, 2) a Family History Questionnaire, and 3) a Subject History Questionnaire. Among the 149 subjects with data for all three age at onset sources, the estimated reliability was R = 0.94. Similar reliability was observed when the sample was stratified based on gender, age at examination, disease duration, first symptom of PD, and years of education. The three measures of age at onset of PD show excellent agreement, strengthening confidence in the reliability of the reported age of clinical onset for PD.