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Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.

Spiral drawing has been used for the assessment of the impact of therapy on motor performance in various movement disorders (e.g. in Parkinson's disease, especially for tremor and hypokinesia). Nevertheless, there are only few guidelines available providing some kind of standardized interpretation. The published protocol with the highest standard is that of Bain and Findley. Kinetic tremor assessed by spiral drawing is not quantified by alternative approaches so far and is not even considered by most rating scales. However, kinetic tremor is quite common and represents a significant impairment in the everyday life of parkinsonian patients. More complex instrumental methods for the quantification of kinetic tremor have not been practical as they, e.g., require relatively expensive equipment or have an unfavourable effort/benefit ratio. We pursued an alternative approach, where we scan drawn spirals to a computer-algorithm that calculates the tremor amplitude. Our standardized method can be applied without difficulty in patients needing only paper and pencil. The evaluation is fully automated, and therefore, it is appropriate for the assessment of therapeutic efficacy in very large populations. The objectivity of the approach represents a significant advantage. In the actual paper, we present how we analyzed the original spirals published by Bain and Findley to validate our computerized assessment. We found a highly significant connection between both methods (explained variance: 88.9%).

Frequent assessment of the symptoms in Parkinson's disease (PD) is important in both clinical and experimental settings, especially when motor fluctuations are present. Patient diaries are increasingly used in studies, allowing patients to stay in their home environments. However, traditional paper diaries may not reflect reality because of a lack in compliance or retrospective data entries. This study presents a comparison between paper diaries and a new method, real-time data capture with a hand-held computer (electronic diary). Twenty patients with PD diagnosed at least 5 years previously were randomly assigned to use either a paper diary or an electronic diary on 8 days during 1 month. Questions were answered every 2 hours over a 12-hour period on each day. Median compliance was 88% with the electronic diary and 98% with the paper diary, although strict compliance to the scheduled times by patients using the paper diary was 78%. Neither age nor earlier experience with computers affected the patient's ability to use the electronic diary. Electronic diaries can be used for self-assessment of PD symptoms. The real-time feature provides fast access to clean data with knowledge of true compliance.

International audience; Background: Statins represent candidates for drug repurposing in Parkinson's disease (PD). Few studies examined the role of reverse causation, statin subgroups, and dose–response relations based on time-varying exposures. Objectives: We examined whether statin use is associated with PD incidence while attempting to overcome the limitations described previously, especially reverse causation. Method: We used data from the E3N cohort study of French women (follow-up, 2004–2018). Incident PD was ascertained using multiple sources and validated by experts. New statin users were identified through linked drug claims. We set up a nested case-control study to describe trajectories of statin prescriptions and medical consultations before diagnosis. We used time-varying multivariable Cox proportional hazards regression models to examine the statins–PD association. Exposure indexes included ever use, cumulative duration/dose, and mean daily dose and were lagged by 5 years to address reverse causation. Results: The case-control study (693 cases, 13,784 controls) showed differences in case-control trajectories, with changes in the 5 years before diagnosis in cases. Of 73,925 women (aged 54–79 years), 524 developed PD and 11,552 started using statins in lagged analyses. Ever use of any statin was not associated with PD (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.67–1.11). Alternatively, ever use of lipophilic statins was significantly associated with lower PD incidence (HR = 0.70, 95% CI = 0.51–0.98), with a dose–response relation for the mean daily dose (P-linear trend = 0.02). There was no association for hydrophilic statins. Conclusion: Use of lipophilic statins at least 5 years earlier was associated with reduced PD incidence in women, with a dose–response relation for the mean daily dose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

There is no clear consensus regarding the frequency (and hence, the risk), of dyskinesias or motor fluctuations during chronic levodopa therapy for Parkinson's disease (PD). Multiple clinical series have tabulated these frequencies since the advent of levodopa over 30 years ago. We were interested in determining: (1) the aggregate frequency figures in the existing literature; and (2) how clinical series from the early levodopa era, which included patients with longer durations of parkinsonism, compare to more recent (modern era) series. We searched MEDLINE for all English language publications reporting the cumulative frequency of levodopa-induced dyskinesias or motor fluctuations during discrete intervals of treatment. This generated 2,478 publications spanning 1966 through September 2000. Papers with appropriate titles or abstracts were reviewed; reference lists from published clinical series were a source of additional papers for review. This ultimately yielded 74 publications with adequate data, relating to 112 intervals of levodopa treatment. Series that included patients with PD-onset well before levodopa availability (pre-levodopa era) were separately analyzed from all subsequent series. Series were grouped by duration of levodopa therapy and the median frequencies of dyskinesias and motor fluctuations were tabulated for each group. The data were analyzed both with and without adjustment for the number (N) in each series. Among series containing pre-levodopa era patients, the median dyskinesia frequency was already 50% by 5-6 months of treatment. This contrasts with the modern era series where dyskinesias were reported later in treatment. The median dyskinesia frequency was slightly less than 40% by 4-6 years of levodopa therapy among modern era patients. Motor fluctuations (wearing-off) were not tabulated in most of the early levodopa series. Among modern era reports, motor fluctuations were nil during the first year of levodopa therapy but were experienced by approximately 40% of patients by 4-6 years of treatment. Similar results were found when the analyses were restricted to only prospective studies where levodopa motor complications were targeted outcome measures. The conclusions reached were: (1) patients from the pre-levodopa era experienced dyskinesias much earlier during levodopa treatment than modern era patients, perhaps because of longer durations of pre-existing PD; (2) in the present era, patients treated with levodopa therapy for 4-6 years have approximately a 40% likelihood of experiencing motor fluctuations and a risk of dyskinesias just short of 40%; and (3) these findings represent incident data and the prevalence of clinically important morbidity may be substantially less.

Much has been learned in the last two decades about the pathophysiology of Parkinson’s disease (PD), leading to the availability of a highly effective symptomatic treatment, which is still lacking for most other neurodegenerative diseases. However the clinical care of PD still bears many challenges: Differential diagnosis of idiopathic and atypical parkinsonian disorders is challenging, especially at early stages. Levodopa, the standard of care for idiopathic PD, is efficacious for a limited time, and disease modifying therapies have been elusive.1 Differential diagnosis and development of mechanism-based treatments for PD will be facilitated by neuroimaging biomarkers that can noninvasively assess aspects of the underlying pathology. PET and SPECT imaging provide great insight on the striatal dopaminergic dysfunction in PD2, but are not widely available and require injections of radioactive tracers making repeat scanning problematic. Despite highly successful applications of radionuclide imaging in Parkinsonian disorders, it is clear that the need for robust neuroimaging biomarkers of other aspects of PD pathology remains. In particular, robust, validated imaging biomarkers of the nigral pathology, the hallmark of PD, are lacking. This need has spurred great interest in MR-based biomarkers for PD. Because conventional MR images of patients with idiopathic PD are typically normal3, recent years marked the development and application of many novel MRI methods to evaluate the SN in PD.4 Amongst these, 1H magnetic resonance spectroscopy (MRS) received considerable interest as it enables non-invasive detection of cellular and metabolic alterations in the central nervous system5 and therefore is ideally suited to assess pathological changes in the absence of gross morphological alterations. Many attempts to investigate the SN by MRS suffered from substantial partial volume effects because the studies utilized relatively large volumes-of-interest (VOI) around the SN.6–9 In addition to the small size and location of the SN in the midbrain, broad intrinsic linewidths due to high iron content make MRS of the SN challenging. In this issue of Movement Disorders, Seraji-Bozorgzad et al10 report a longitudinal MRS investigation of the SN by magnetic resonance spectroscopic imaging (MRSI) at higher resolution than most prior reports (point spread function corrected VOI 2mL). They scanned 23 medication naive patients with PD twice, at baseline and 3 months later and report: 1) lower total N-acetylaspartate-to-total creatine ratios (tNAA/tCr) than a small healthy control group (N=6) at baseline; 2) a 4% decrease in tNAA/tCr in patients, but not controls, over 3 months and 3) side-to side asymmetry in tNAA/tCr in the PD, but not in the control group, consistent with the known pathological asymmetry in early PD. tNAA has been validated as a marker of neuronal viability and tCr may reflect energy status or glial activation.5, 11 Therefore a decrease in tNAA/tCr ratio may represent neuronal dysfunction or deficits in energy metabolism / gliosis or both. The paper is an important addition to MRS literature in PD that has mostly been cross-sectional. The authors took advantage of the sensitivity and resolution advantages of 3 tesla (3T) and utilized a clinically feasible protocol that only took 30 minutes. However MRS findings in PD have been widely variable12, with some papers reporting lower tNAA/tCr in patients vs. controls, while many, including studies of the SN at high field, reporting no significant differences between patients and controls.13, 14 The medication status of patients may be important in this respect as patients enrolled in most prior studies have been on PD medications and MRS alterations may only be present in the drug naive cohort.15, 16 Another reason for the discrepancy with prior reports on the SN may be the choice of the echo time. Namely, a difference in tNAA/tCr may have been caused by differential T2 effects of the disease on tNAA vs. tCr at the long echo time utilized–especially considering that altered T2 values have been reported in the SN in PD, probably due to iron accumulation.17 It is unlikely that a better alignment of the VOI with the SN enabled the detection of neurochemical alterations in the Seraji-Bozorgzad study since a recent 7T single-voxel MRS study that did not detect a difference in tNAA or tCr in PD vs. controls14, utilized an even smaller VOI with minimal partial volume effects. Finally, the inability to consistently demonstrate neurochemical alterations in early-moderate PD by different groups may be a testament to the heterogeneity in disease cohorts, as suggested recently.18 In any case, the Seraji-Bozorgzad study10 has accomplished substantial improvement in the reproducibility of metabolite ratio measurements in the SN (Fig. 1c) relative to other recent reports of MRSI of the SN19, which is essential for robust clinical applications. Therefore the study provides motivation to further investigate the potential of MRS/I as a longitudinal biomarker for early PD in larger cohorts and over longer durations of disease progression. Regarding the asymmetry observed in tNAA/tCr in PD10, it will be critical to delineate if the tNAA/tCr was lower in VOIs encompassing the SN contralateral to the clinically more severely affected side of patients.

Parkinson's disease (PD) mortality rates in Michigan counties for 1986-1988 were calculated with respect to potential heavy metal exposure (iron, zinc, copper, mercury, magnesium, and manganese) from industry based on recent census data. Individuals were counted as a PD death if the diagnosis was listed as an "underlying" or "related" cause of death on the death certificate. Counties with an industry in the paper, chemical, iron, or copper related-industrial categories (ICs) had statistically significantly (p0.05) higher PD death rates than counties without these industries. Significant correlations of chemical (rs = 0.22; p = 0.05), paper (rs = 0.22; p = 0.05) and iron (rs = 0.29; p = 0.008) industry densities with PD death rates were also present. Counties were divided into high (15/100,000 individuals 45 years old and over) and low (= 15/100,000) PD death rate counties by cluster analysis. Geographically, counties with high PD mortality were located mainly in the southern half of the lower peninsula and eastern half of the upper peninsula; low PD death rate counties formed two distinct clusters in the western edge of the upper peninsula and the north-central portion of the lower peninsula. Other possible risk factors that may explain the varied distribution of PD death rates in Michigan were examined. Those significantly correlated with PD mortality included population density (rs = 0.31; p = 0.005), farming density (rs = 0.25; p = 0.02), and well water use (rs = -0.24; p = 0.03). These ecologic findings suggest a geographic association between PD mortality and the industrial use of heavy metals.

In a recent workshop on "Defining research priorities in dystonia,", there was absolutely no reference to sex as a factor in disease pathogenesis. In this viewpoint paper, we argue that the most distinctive aspects of adult onset isolated focal dystonia are the marked sex-related differences demonstrated by epidemiological, clinical, and laboratory studies in patients with adult onset dystonia, particularly in cervical dystonia, the most common presentation. We propose that the future focus of research should be on neurobiological mechanisms underlying the profound sexual dimorphism in this disorder. Targeting research into gamma aminobutyric acid (GABA)ergic function, which also shows similar sexual dimorphism, would be most productive in elucidating the pathogenesis of adult onset dystonia. © 2021 International Parkinson and Movement Disorder Society.

The placebo effect is a phenomenon produced when an inert substance administered like a regular treatment improves the clinical outcome. Parkinson's disease (PD) is one of the main clinical disorders for which the placebo response rates are high. The first evidence of the neurobiological mechanisms underlying the placebo effect in PD stems from 2001, when de la Fuente-Fernandez and colleagues demonstrated that a placebo injection led to the release of dopamine in the striatal nuclei of PD measured with positron emission tomography technology. Since then, several studies have been conducted to investigate the neurobiological underpinnings of placebo responses. This article presents a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Of an initial yield of 143 papers, 19 were included. The lessons learned from these studies are threefold: (i) motor improvement is dependent on the activation of the entire nigrostriatal pathway induced by dopamine release in the dorsal striatum; (ii) the magnitude of placebo-induced effects is modulated by an expectancy of improvement, which is in turn related to the release of dopamine within the ventral striatum; (iii) the functioning of the neural pathways underlying the placebo response can be tuned by prior exposure and learning strategies. In conclusion, although the neural network underlying the placebo effect in PD has been largely confirmed and accepted, what remains to be established is how, when, and where the expectation of reward (mediated by the ventral striatum) interacts with the primary motor system (mediated by the dorsal striatum) to induce clinical improvement in motor symptoms. © 2018 International Parkinson and Movement Disorder Society.

Dystonia is a common movement disorder. In this paper, we review the literature on cognitive function in idiopathic and DYT1 dystonia. In idiopathic or DYT1 dystonia, cognition is largely intact with only isolated executive dysfunction. Dystonia patients also have increased temporal and spatial discrimination thresholds, considered endophenotypes of the disorder because deficits are also shown by unaffected relatives and nonmanifesting carriers of the DYT1 mutation. Anticholinergic medication in high doses can be associated with memory impairment in dystonia. The successful treatment of dystonia with botulinum toxin injections or deep brain stimulation does not produce any major adverse effects on cognition. The aspects of cognition that require further investigation in future studies of dystonia include inhibitory control, decision making, and social cognition. © 2017 International Parkinson and Movement Disorder Society.

Forty years ago, C.D. Marsden proposed that blepharospasm should be considered a form of adult-onset focal dystonia. In the present paper, we provide a comprehensive overview of the findings regarding blepharospasm reported in the past 40 years. Although prolonged spasms of the orbicularis oculi muscles remain the clinical hallmark of blepharospasm, patients with blepharospasm may be characterized by various types of involuntary activation of periocular muscles. In addition to motor features, blepharospasm patients may also have nonmotor manifestations, including psychiatric, mild cognitive, and sensory disturbances. The various motor and nonmotor symptoms are not present in all patients, suggesting that blepharospasm is phenomenologically a heterogeneous condition. This emphasizes the need for tools for severity assessment that take into account both motor and nonmotor manifestations. The cause of blepharospasm remains elusive, but several lines of evidence indicate that blepharospasm is a multifactorial condition in which one, or several, as yet unknown genes together with epigenetic and environmental factors combine to reach the threshold of the disease. Although blepharospasm was originally believed to be solely a basal ganglia disorder, neurophysiological and neuroimaging evidence point to anatomical and functional involvement of several brain regions. The contribution of multiple areas has led to the hypothesis that blepharospasm should be considered as a network disorder, and this might reflect the varying occurrence of motor and nonmotor manifestations in blepharospasm patients. Despite advances in the aetiology and pathophysiology, treatment remains symptomatic. © 2017 International Parkinson and Movement Disorder Society.

Background: Several clinician, informant, and self-report instruments for tics and associated phenomena have been developed that differ in construct, comprehensiveness, and ease of administration. Objective: A Movement Disorders Society subcommittee aimed to rate psychometric quality of severity and screening instruments for tics and related sensory phenomena. Methods: Following the methodology adopted by previous Movement Disorders Society subcommittee papers, a review of severity and screening instruments for tics was completed, applying a classification as “recommended,” “suggested,” or “listed” to each instrument. Results: A total of 5 severity scales (Yale Global Tic Severity Scale, Tourette Syndrome Clinical Global Impression, Tourette's Disorder Scale, Shapiro Tourette syndrome Severity Scale, Premonitory Urges for Tics Scale) were “recommended,” and 6 (Rush Video-Based Tic Rating Scale, Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey, Tourette Syndrome Global Scale, Global Tic Rating Scale, Parent Tic Questionnaire, Tourette Syndrome Symptom List) were “suggested.” A total of 2 screening instruments (Motor tic, Obsession and compulsions, Vocal tic Evaluation Survey and Autism-Tics, Attention Deficit/Hyperactivity Disorder and Other Comorbidities Inventory) were “recommended,” whereas 2 others (Apter 4-questions screening and Proxy Report Questionnaire for Parents and Teachers) were “suggested.” Conclusions: Our review does not support the need for developing new tic severity or screening instruments. Potential objectives of future research include developing a rating instrument targeting the full spectrum of tic-related abnormal behaviors, assessing/screening malignant forms of tic disorders, and developing patient-reported outcome measures. © 2017 International Parkinson and Movement Disorder Society.

Background: Micrographia occurs in approximately 60% of people with Parkinson’s disease (PD). Although handwriting is an important task in daily life, it is not clear whether relearning and consolidation, or the solid storage in motor memory, of this skill is possible in PD. Objectives: To conduct for the first time a controlled study into the effects of intensive motor learning to improve micrographia in PD. Methods: In this placebo-controlled study, 38 right-handed people with PD were randomized into two groups, receiving one of two equally time-intensive training programs (30min/day, 5 days/week for 6 weeks). The experimental group (N=18) performed amplitude training focused at improving writing size. The placebo group (N=20) received stretch and relaxation exercises. Participant's writing skills were assessed using a touch-sensitive writing tablet and a pen-and-paper test, pre- and post-training and after a 6-week retention period. The primary outcome was change in amplitude during several tests of consolidation: 1) transfer, using trained and untrained sequences performed with and without target zones; and 2) automatization, using single- and dual-task sequences. Results: The group receiving amplitude training significantly improved in amplitude and variability of amplitude on the transfer and automatization task. Effect sizes varied between 7 and 17% and these benefits were maintained after the 6-week retention period. Moreover, there was transfer to daily life writing. Conclusions: These results show automatization, transfer and retention of increased writing size (diminished micrographia) after intensive amplitude training, indicating that consolidation of motor learning is possible in PD. ispartof: Movement Disorders vol:31 issue:8 pages:1209-1216 ispartof: location:United States status: published

Micrographia, an abnormal reduction in writing size, is a specific behavioral deficit associated with Parkinson's disease (PD). In recent years, the availability of graphic tablets has made it possible to study micrographia in unprecedented detail. Consequently, a growing number of studies show that PD patients also exhibit impaired handwriting kinematics. Is micrographia still the most characteristic feature of PD-related handwriting deficits? To answer this question, we identified studies that investigated handwriting in PD, either with conventional pencil-and-paper measures or with graphic tablets, and we reported their findings on key spatiotemporal and kinematic variables. We found that kinematic variables (velocity, fluency) differentiate better between control participants and PD patients, and between off- and on-treatment PD patients, than the traditional measure of static writing size. Although reduced writing size is an important feature of PD handwriting, the deficit is not restricted to micrographia stricto sensu. Therefore, we propose the term PD dysgraphia, which encompasses all deficits characteristic of Parkinsonian handwriting. We conclude that the computerized analysis of handwriting movements is a simple and useful tool that can contribute to both diagnosis and follow-up of PD.

Cognitive impairment in Parkinson's disease is heterogeneous both in severity and pattern and subject to influences both integral to and external to the disease. Diagnostic Criteria have been developed by the Movement Disorders Society that help to guide clinicians and researchers to an accurate diagnosis of Parkinson's disease - mild cognitive impairment or Parkinson's disease dementia. To operationalize these criteria, and to assess the pattern and severity of cognitive dysfunction we need: (1) Valid measures of cognitive abilities covering the major domains of cognition, (2) amethod to determine whether or not the performance represents a decline from a person's previous level of functioning, and (3) an assessment of how the individual's cognitive abilities enable (or disable) function in day to day activities. This paper will discuss the methods of assessment and the measures that can be used to make a comprehensive assessment of cognition in Parkinson's disease.

The definition of dystonia has been a subject of much debate and controversy for the last century. In this paper, a practical definition of dystonia for the movement disorders expert is presented, based on a new algorithm. © 2013 Movement Disorder Society.

Parkinson's disease (PD) can present with a variety of motor disorders that fluctuate throughout the day, making assessment a challenging task. Paper-based measurement tools can be burdensome to the patient and clinician and lack the temporal resolution needed to accurately and objectively track changes in motor symptom severity throughout the day. Wearable sensor-based systems that continuously monitor PD motor disorders may help to solve this problem, although critical shortcomings persist in identifying multiple disorders at high temporal resolution during unconstrained activity. The purpose of this study was to advance the current state of the art by (1) introducing hybrid sensor technology to concurrently acquire surface electromyographic (sEMG) and accelerometer data during unconstrained activity and (2) analyzing the data using dynamic neural network algorithms to capture the evolving temporal characteristics of the sensor data and improve motor disorder recognition of tremor and dyskinesia. Algorithms were trained (n=11 patients) and tested (n=8 patients; n=4 controls) to recognize tremor and dyskinesia at 1-second resolution based on sensor data features and expert annotation of video recording during 4-hour monitoring periods of unconstrained daily activity. The algorithms were able to make accurate distinctions between tremor, dyskinesia, and normal movement despite the presence of diverse voluntary activity. Motor disorder severity classifications averaged 94.9% sensitivity and 97.1% specificity based on 1 sensor per symptomatic limb. These initial findings indicate that new sensor technology and software algorithms can be effective in enhancing wearable sensor-based system performance for monitoring PD motor disorders during unconstrained activities.

The aim of this study was to analyze the efficacy of a cognitive training program on cognitive performance and quality of life in nondemented Parkinson's disease patients. Participants who met UK Brain Bank diagnosis criteria for Parkinson's disease, with I-III Hoehn & Yahr, aged 50-80, and nondemented (Mini-Mental State Examination ≥ 23) were recruited. Patient's cognitive performance and functional and quality-of-life measures were assessed with standardized neuropsychological tests and scales at baseline and after 4 weeks. Subjects were randomly and blindly allocated by age and premorbid intelligence (Vocabulary, Wechsler Adult Intelligence Scale-III) into 2 groups: an experimental group and a control group. The experimental group received 4 weeks of 3 weekly 45-minute sessions using multimedia software and paper-and-pencil cognitive exercises, and the control group received speech therapy. A total of 28 patients were analyzed. Compared with the control group participants (n = 12), the experimental group participants (n = 16) demonstrated improved performance in tests of attention, information processing speed, memory, visuospatial and visuoconstructive abilities, semantic verbal fluency, and executive functions. There were no observable benefits in self-reported quality of life or cognitive difficulties in activities of daily living. We concluded that intensive cognitive training may be a useful tool in the management of cognitive functions in Parkinson's disease. © 2011 Movement Disorder Society.

The relationship between essential tremor (ET) and Parkinson's disease (PD) has been debated for years. Whether ET is actually a risk factor for developing PD, or whether the relationship is merely coincidental remains unclear. In this issue of Movement Disorders Fekete and Jankovic discuss clinical, epidemiological, genetic, neuroimaging, pathological, and therapeutic evidence which they interpret as proving a causal relationship between these disorders. This paper will discuss mainly the pathological data and the lack of clear evidence that the disorders are causally related. A major confounding factor when trying to determine whether ET and PD are related is the fact that currently we have limited knowledge regarding the cause of these two disorders. It is very likely that these are syndromes and not diseases with a single cause and therefore if a link exists it may well be in a subgroup of these individuals. As there is no diagnostic test for either ET or PD, and the only definitive diagnostic finding for either is the presence of Lewy bodies and neuronal loss in the substantia nigra (SN) of subjects with PD, neuropathologic studies will be the focus of this review. Clinically there appears to be clear overlap between ET and PD. Postural and kinetic tremor are common in PD while the presence of rest tremor is common in ET. Bradykinesia and rigidity can occur in ET and at what point patients with these findings become clinically classified as PD is unclear. Finally, it is clear that there are patients with long-standing ET who go on to develop PD, but whether this is greater than the general population, as suggested in some studies,1 and even if it is, whether the actual cause of PD in these cases relates to ET or other factors, has not been established. Until the cause(s) of these disorders are delineated, linking the two may be impossible. In our opinion all of these issues very much require well designed longitudinal cohort studies that have pathologic confirmation as the gold standard outcome measure. From a clinico-pathological standpoint there are two ways one can approach determining whether ET and PD are related: 1) Is there an increased occurrence of Lewy bodies in cases of ET, and 2) Is there an increase in ET in subjects with Lewy body pathology. We will first address published reports of Lewy bodies in ET.

French neurologist Georges Gilles de la Tourette first described the syndrome which earned him eponymous fame in 1885. However, a publication dated 1873 by Armand Trousseau included a detailed account of what is currently know as Gilles de la Tourette syndrome (GTS). In Gilles de la Tourette's celebrated 1885 paper, there is a brief mention of the clinical picture described earlier by Trousseau, but Gilles de la burette somewhat disregarded it. We present the first English translation of Trousseau's description and argue that this description is more akin to modern conceptualization of GTS than the description of Gilles de la Tourette himself. (C) 2010 Movement Disorder Society

Postencephalitic parkinsonism has been considered unique among disorders with parkinsonian features because it is believed to have a unitary etiology associated with the virus that presumably caused encephalitis lethargica. Careful analysis of the historical record, however, suggests that this relationship is more complex than commonly perceived. In most cases, the diagnosis of acute encephalitis lethargica was made post hoc, and virtually any catarrh-like illness was considered to have represented encephalitis lethargica, often after an oral history-taking that was undoubtedly subject to patient recall and physician bias. Also, postencephalitic parkinsonism and oculogyric crises were not recognized as sequelae to encephalitis lethargica until well after other sequelae such as movement disorders and mental disturbances had been identified (see previous paper). We suggest here that the relationship between encephalitis lethargica and postencephalitic parkinsonism is not simplistic, i.e., encephalitis lethargica was not solely responsible for the etiology of postencephalitic parkinsonism, thus aligning the latter with most other parkinsonian disorders that are now believed to have multiple causes.

This article and the subsequent one suggest that the currently accepted view of a simplistic (direct) relationship between encephalitis lethargica (EL) and postencephalitic Parkinsonism (PEP) is based on a incomplete evaluation of the epidemic period literature. In this article we provide a detailed analysis of the literature from the period that demonstrates that Parkinsonism was not initially part of acute EL symptomatology, that PEP was not typically the prevailing type of chronic EL and that oculogyric crises were never part of acute EL symptomatology and not initially associated with PEP. The second paper uses these finding, and also examines the clinical justifications for concluding that all patients with PEP had prior acute episodes of EL, to reevaluate the presumed direct etiologic relationship between EL and PEP.

The Greek term astasia-abasia literally translates to mean inability to stand and to walk. Although today we would classify the syndrome as a conversion disorder, it was considered a separate disease by Paul Blocq (1860-1896), who described this phenomenon as the inability to maintain an upright posture, despite normal function of the legs in the bed. Paul Blocq's original 1888 articles on astasia abasia were read, partly translated from French to English, and the cases were summarized. A review of a selection of the literature following Blocq's description on astasia abasia was performed. Present day literature was consulted as well. Blocq reviewed what was known about astasia abasia in two papers. Although he was the first to use the combined term astasia abasia, he referred to similar descriptions of Charcot, Richer, Mitchell, Jaccoud, Roméi, and Erlenmeyer. Blocq's contribution was in compiling the experiences and observations of preeminent 19th century neurologists. He recognized that paralysis, jumping, fits, tremor, and bizarre behavior could all be associated with the syndrome. He distinguished the disorder from hysteria. Moreover, he presented a formal delineation of the gait disorder and provided a pathophysiologic concept. Prognosis was considered favorable. Paul Blocq directed attention to psychogenic gait disorders by publishing a small case series on astasia abasia. Today, these case descriptions would be likely considered cases of conversion or psychogenic gait disorder, with or without other conversion/psychogenic movement disorders.

2006, there was, no single instrument (questionnaire or scale) for attempting a comprehensive assessment of the wide range of nonmotor symptoms (NMS) of Parkinson's disease (PD). The PD nonmotor group, a multidisciplinary group of experts including patient group representatives developed and validated the NMS screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self completed screening tool designed to draw attention to the presence of NMS. In this paper, we present the results gathered from 545 patients using the definitive version of the NMSQuest highlighting the prevalence of the wide range of NMS flagged in the NMSQuest from consecutive PD patients in an international setting.

In essential tremor (ET) research, it is important to obtain standardized, objective data on tremor severity. Often, it is not possible to carry out in-person or videotaped neurological examinations. In place of these, handwriting samples can be collected, but they do not capture all of the variance in tremor severity. Although additional tests of tremor severity (finger-nose-finger [FNF] test) might be of use, these would need to be modified to allow ET patients to mail their results to the study investigator for rating. We modified the standard FNF test (sFNF) by asking subjects to hold a pen during this activity and mark a paper target. The purpose of this report was to determine whether the modified FNF (mFNF) test was feasible and valid. Of 70 subjects, 65 (92.9%) were able to complete the mFNF, demonstrating that it was feasible. The scores of the mFNF correlated highly with those of the sFNF (r = 0.56-0.85; all P < 0.001), indicating the mFNF is a valid measure of tremor severity. In addition, using the regression equation, sFNF = 0.174(mFNF) + 0.743, a sFNF score can be derived easily from the mFNF score. The mFNF may be used to collect valuable data on tremor severity in pathological, genetic, and epidemiological field studies of ET, in which in-person or videotaped neurological examinations are not possible.

In this issue of the journal Ruth Walker and colleagues describe the genetic diagnosis of neuroacanthocytosis disorders using a fairly new but rapidly prevailing genetic method, exome sequencing.1 This work highlights a standing problem in diseases with a great deal of genetic heterogeneity, how to reach a molecular diagnosis. Perhaps more importantly, it illustrates how this issue may be overcome quite routinely in the near future. Although not unique, the marked genetic heterogeneity associated with many clinical presentations represents a diagnostic problem that is pronounced in movement disorders. Illustrative examples abound, there are at least 19 identified genetic causes of autosomal dominant ataxia,2 primary dystonia may be caused by known mutations at 10 different loci,3 recessive parkinsonism by mutations in at least 6 different genes,4–9 and in the case of neuroacanthocytosis, there are four genes known to contain disease causing mutations, including a very large gene, VPS13A.1 Facing genetically heterogeneous but clearly familial disorders in the clinic, a physician faces a decision about genetic testing that must balance cost, time, likelihood of a positive result, and the impact of any result on treatment, prognosis, and the patients family. A common approach is to test the most likely candidate mutations or genes first, progressing steadily through alternates until a verdict is reached, or the most plausible and testable candidate pool is exhausted. This iterative approach can be highly inefficient; it may take a substantial amount of time and money to find a mutation and oftentimes we still fail to identify the causal genetic lesion. There are many reasons for this: while there remain a large number of single gene disorders for which we don't know the genetic cause, many gene tests are not routinely available, and variants are frequently discovered that are of unknown significance. The quite broad phenotypic heterogeneity associated with a large number of gene mutations also presents a hurdle to identifying the specific genetic cause of clinical presentations. We know that single-gene movement disorders can present with phenotypes outside of the norm. Patients with a pathogenic LRRK2 mutation most commonly present with typical Parkinson’s disease (PD);10 however, some of the earliest LRRK2 families described included patients with presentations such as amyotrophy, dystonia, and dementia.11 Likewise, PLA2G6 mutations, which were originally associated with infantile neuroaxonal dystrophy, are known to also cause dystonia-parkinsonism.7, 12 VCP mutations can lead to any one or a combination of frontotemporal dementia, inclusion body myopathy, amyotrophic lateral sclerosis, and Paget’s disease of bone.13 It is also reasonable to suspect that the same genetic lesion may result in different clinical presentations based on genetic background, and this may be evident across diverse populations. There already exists some support of this in ataxia, where ATXN2 and ATXN3 expansion mutations, primarily described in Caucasian spinocerebellar ataxia patients, may present as a dopa-responsive and quite pure parkinsonism in patients of Asian or African lineage.14–16 Given the challenges of substantial genetic and phenotypic heterogeneity, what is needed is a way to screen all gene candidates for a disorder, including those outside of immediately plausible candidate gene pool. Such a method needs to be quick and cost effective and should ideally provide unequivocal results that are easily interpretable. Exome sequencing promises to best some of these challenges. In essence this method aims to produce genetic sequence data on every protein coding DNA basepair of the human genome, representing about 1/100th of the diploid genome, or approximately 70 million base pairs per individual. There are a number of approaches to this but they each center on creating a library from a genomic DNA sample, which is enriched for the genetic regions of interest, then analyzed using a second-generation sequencer. This method generates billions of basepairs of information in quite short order. Sample preparation and sequencing takes ~ 3 weeks; but many samples can be sequenced in parallel. Following this, a computationally intensive but increasingly stable and accessible analysis generates a report of all variants detected, their population frequencies, predicted effect on the protein product, and whether the variants have been described before. Current costs for an exome sequence run at around $1000. In the paper by Ruth Walker and coworkers this is exactly the approach that was taken. In this study the investigators performed exome sequencing in two unrelated individuals with neuroacanthocytosis. In both individuals this method revealed compound heterozygous mutations in VPS13A, a known genetic cause of this disorder. So is exome sequencing the panacea to current limitations faced in clinical testing? The information it provides is certainly extensive, now quite accurate, and has been used to make genetic diagnosis, including unanticipated diagnosis.17 There are, however, some limitations to the method that bear consideration. In its current form exome sequence does not quite capture all of the protein coding genome, and is generally unable to capture or accurately sequence about 10% of this content. Exome sequencing is not particularly good at identifying repeat mutations (i.e. triplet repeats seen in spinocerebellar ataxias for instance), and although improving, methods for detecting gene deletions and duplications using exome data are not well established. Currently, exome sequencing is not clinically validated, and will likely require additional follow up with established mutation discovery methods once a candidate variant has been identified. Despite these limitations, the comprehensive nature of exome means that this remains an attractive method for genetic testing; indeed companies are now offering this as part of a diagnostic service. Given the breadth of sequencing afforded by this method, it is also useful to consider the ramifications of unanticipated genetic findings. What are the consequences of a collateral discovery of a BRCA1 mutation in a patient without cancer, or in identifying a carrier of a recessive mutation who is about to start a family? One of the earliest exome sequencing studies provides an example of this, finding not only the cause of Miller syndrome (DHODH mutation), a rare multiple malformation disorder, but also showing genetically that one of the patients had primary ciliary dyskinesia as a result of DNAH5 mutations.18 These are clearly complex issues, that will require a shift in our view of genetic data (and perhaps genetic determinism), most importantly this will require an informed discussion with patients seeking genetic diagnosis using this method. One early consequence of diagnostic exome sequencing is the identification of a large number of variants of unknown significance and an opportunity exists here. It is likely that clinical diagnostic services will be the primary producer of sequences in monogenic or suspected genetic disease, eventually outstripping the throughput of research laboratories. What is called for is a centralized database of variants identified, linked with phenotypes, and this resource should be available for all of these clinical services to both data mine and contribute to. This provides an opportunity to build statistical confidence in the pathogenic role (or not) of identified variants based on data accumulating worldwide. While these are likely to be difficult waters to navigate, particularly using clinical data for research and maintaining subject anonymity, this seems a worthy goal, likely to identify new genes, new mutations and perhaps new risk variants; ultimately such a service would greatly help genetic diagnostic accuracy and risk prediction. Clearly exome sequencing is already making an impact in the research arena, and is now the primary method in identifying novel genetic causes of disease. This has been discussed extensively elsewhere, so I will not go into details here, but there exists a burgeoning gene discovery literature that includes examples in movement disorders (EIF4G1 and VPS35 mutations in PD, TGM6 mutations in SCA).19–22 Lastly, it is worth noting that exome sequencing likely represents a half step toward a complete genetic solution for genetic diagnosis, in the form of whole genome sequencing. This method that has already been used to find new genetic causes of disease in the research setting.23 One would expect this approach to rapidly find its way into the diagnostic field, probably replacing exome sequencing, because whole genome sequencing provides much more complete coverage and is better positioned to identify both structural and non-protein coding mutations. Many of the challenges that we will face with the implementation and interpretation of exome data will prepare us for whole genome sequencing data, although we will likely have to be more thoughtful about how we approach low risk variability. The use of exome sequencing, and the inevitable transition to whole genome sequencing in clinical diagnosis presents us with a host of opportunities, challenges, and food for thought.

Friedreich ataxia (FRDA) is the most common of the early-onset hereditary ataxias in Indo-European and North African populations. The disease was first described in 1863 by Nicholaus Friedreich, Professor of Medicine in Heidelberg. Friedreich’s papers reported the essential clinical and pathological features of the disease, a “degenerative atrophy of the posterior columns of the spinal cord” leading to progressive ataxia, sensory loss and muscle weakness, often associated with scoliosis, foot deformity and heart disease. However, the subsequent description of atypical cases and of clinically similar diseases clouded classification for many years. Diagnostic criteria were established in the late 1970s, after a renewed interest in the disease prompted several rigorous clinical studies. The Quebec Collaborative Group described the typical features of the disease in well-established cases.1 Harding modified some of the Quebec Collaborative Group diagnostic criteria to include cases at an early stage of the disease.2 According to Harding, essential clinical features include: i) autosomal recessive inheritance ii) onset before 25 years of age iii) progressive limb and gait ataxia iv) absent tendon reflexes in the legs v) electrophysiologic evidence of axonal sensory neuropathy, followed within five years of onset by: dysarrhria, areflexia at all four limbs, distal loss of position and vibration sense, extensor plantar responses and pyramidal weakness of the legs

We read with interest the paper by Zech et al. where they report a new European dystonia family with a homozygous PRKRA mutation. Our group recently identified a new Brazilian family with compound heterozygous variants in PRKRA and a pure dystonia phenotype of variable severity. The proband is a 37- year-old Brazilian woman of Portuguese ancestry, the fifth child of non-consanguineous parents, who was first assessed at age 8 reporting a history of dystonia since age 4. Birth history was uneventful and, except for speech delay, development milestones were normal until age 4. Dystonia onset was in the right upper limb and generalized in four years, with severe involvement of cervical region, trunk and limbs, but mild dysarthria and dysphonia. No parkinsonian or pyramidal signs were observed. Laboratory screening for Wilson’s disease was negative and brain image at ages 8 and 16 were normal. She was not responsive to levodopa and response to anticholinergic drugs was poor. At first, family history of dystonia was negative. Among her five siblings, three were healthy and two were deceased (one from Pertussis at eight months, and another from unknown causes at one month). At age 23 she was enrolled in a genetic study of dystonia, and screening for TOR1A and THAP1 was negative.2 At that time, both parents and three siblings were examined by movement disorders specialists. Her younger sister, aged 19, had a very subtle dystonic posture in the third and fourth fingers of the left hand and was rated as possible dystonia. She was not aware of the age of onset. At age 28 she developed cervical dystonia and marked dysphonia. When the sibling became affected, the family history was consistent with possible recessive inheritance, which in turn, led us to screen PRKRA using Sanger sequencing. In both affected patients, we identified novel variants in exon 2, c.G230C (p.Cys77Ser), and in exon 7, c.G638T (p.Cys213Phe). The first is in the DRBM1 functional domain. A variant affecting the same amino acid c.T637C (p.Cys213Arg), together with c.C665T (p.Pro222Leu) has been previously described in a patient with dystonia, whose symptoms developed after a febrile illness and who had volume loss in the basal ganglia.3 All unaffected family members carry a single variant. The father and two siblings carry the c.G230C variant, the mother carries c.G638T. None of these variants were found in 240 Brazilian control chromosomes and only p.Cys213Phe was reported at an extremely low frequency (7.916e-06) in the Exome Aggregation Consortium (ExAC) (http://exac.broadinstitute.org). Three out of four in silico predictions support these variants as disease causing (Table 1). Both variants are highly conserved. Since PRKRA was first identified as a dystonia cause,4 only three other families/individuals have been found with mutations.1,3,5 The Brazilian and Polish families with the p.Pro222Leu variant share a dystonia-parkinsonism phenotype and the disease haplotype that could represent a founder mutation1. Herein we report two novel mutations in siblings with isolated dystonia confirming PRKRA as a causative disease gene. Moreover, we suggest that PRKRA mutations may be a more widespread cause of generalized dystonia and screening should be considered in familial cases with putative autosomal recessive inheritance. Table 1 In silico analysis and frequency of PRKRA variants

Studies have reported the presence of mild bradykinesia in patients with essential tremor (ET).1 Based on these studies, we hypothesized that ET patients, and especially those with rest tremor, might exhibit micrographia in comparison with age-matched controls. 100 ET cases and 100 controls were enrolled in a clinical-epidemiological study at Columbia University Medical Center. Each signed informed consent approved by Medical Center Ethics Board, and had a detailed assessment (questionnaires, videotaped examination). Tremor severity measurements included the Tremor Disability Questionnaire (TDQ)2 and total tremor score (TTS).2 Each subject copied 3 standardized phrases (21 words) in a set of 3 boxes (12.8 × 166.6, 25.5 × 166.6, and 12.8 × 166.6 mm) on a sheet of paper. Writing samples were scanned (600 dpi) and filed in JPEG format. A movement disorder neurologist (H.R.M-H.) measured the height and width (mm) of the most commonly repeated letters (“t” [used 9×], “e” [used 8×], “a” [used 7×], “r” [used 7×]) using the software program GIMP version 2.8 (GNU Image Manipulating Program). For “i” (used 7×), only height was measured. Cases and controls were similar in demographic characteristics (Table). For each of the most commonly repeated letters, height and width measurements were higher in cases than controls (68 of 69 p values < 0.05). Mean width and mean height measurements for each letter (nine comparisons), were greater in cases than controls (Table). For each letter, we also compared the dimensions (height and width) of the first vs. last letter; only “e” showed a decrement (Supplementary table). An increment of letter height was observed (in cases and controls) for “as” and “ts” and in width for “as” and “ŕs”. Table Demographic and clinical characteristics of 100 ET cases and 100 controls The 15 cases with rest tremor were compared to 85 without rest tremor, in terms of height and width measurements. In 66 of 69 comparisons, the two groups were similar; in 3 of 69 comparisons (heights of “i1”, “i5”, and “a2”), the dimensions were smaller in ET cases with rest tremor. Mean dimensions were correlated with tremor duration in 5 of 9 comparisons (Pearson’s r = 0.22 - 0.33, p

The identification of genetic mutations that cause Parkinson's disease (PD) in rare families has been the bedrock of investigation into the molecular pathogenesis of PD. These mutations are used to understand and model disease, in a process aimed at finding viable points of therapeutic intervention that are based on etiology, rather than being based on symptomatic relief. Two papers, published back to back in the American Journal of Human Genetics, expand the repertoire of genetic tools with which to understand the basis of PD by the discovery of a mutation linked to PD in the gene VPS35.1, 2 Both studies used exome sequencing, a method to sequence all of the protein coding regions of the genome in parallel, in large families with PD. In the work by Vilarino-Guell and colleagues, the authors sequenced cousins from a large Swiss kindred with autosomal dominant, late onset PD. Following a series of screening and filtering steps, the authors provide evidence that a mutation in VPS35 (p.D620N) is responsible for disease in this family and in 4 of ~4000 unrelated PD cases screened. The mutation was absent from more than 3000 control samples. In the work by Zimprich and colleagues, the authors performed exome sequencing in an Austrian family with autosomal dominant PD. This group identified the same mutation in VPS35, p.D620N, segregating with disease and then went on to show that this mutation was a cause of disease in two additional families. Both groups found additional mutations in VPS35; in contrast to the p.D620N mutation, the evidence for pathogenicity of the additional variants was not compelling, and thus their role in disease remains unclear. The clinical phenotype of VPS35 linked disease is reported to fulfill London Brain Bank criteria, with an age at onset of disease in the early fifties. VPS35 encodes the vacuolar protein sorting ortholog 35, a part of a large multimeric complex called the retromer complex. This complex is believed to play an integral role in retrograde transport of proteins from endosomes to the trans-Golgi network. While VPS35 mutations appear to be quite a rare cause of PD, they provide another valuable window into the etiology of this complex disorder.