Showing papers in "Movement Disorders in 2011"

The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease

Abstract: The Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM) Review of Treatments for Parkinson's Disease (PD) was first published in 2002 and was updated in 2005 to cover clinical trial data up to January 2004 with the focus on motor symptoms of PD. In this revised version the MDS task force decided it was necessary to extend the review to non-motor symptoms. The objective of this work was to update previous EBM reviews on treat- ments for PD with a focus on non-motor symptoms. Level-I (randomized controlled trial, RCT) reports of pharmacological and nonpharmacological interventions for the non-motor symptoms of PD, published as full

The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease.

Abstract: Background: Non-motor symptoms are detrimental to health-related quality of life (HRQoL) of Parkinson's disease patients. In this study, the Non-Motor Symptoms Scale (NMSS) was used to assess the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. Methods: In a multicenter, international, cross sectional study on 411 Parkinson's disease patients, the NMSS was applied along with clinical (Hoehn and Yahr staging and SCOPA-Motor) and HRQoL measures (PDQ-39, and EQ-5D). Prevalence of non-motor symptoms was determined also through the NMSS. The association of NMSS and SCOPA-Motor with HRQoL measures and the differences in HRQoL scores between patients with and without non-motor symptoms in each NMSS domain were estimated by non-parametric statistics. Predictors of HRQoL were sought through multiple linear regression analyses. Results: Nocturia (68.4% of the sample), fatigue (65.9%), and dribbling saliva (56.7%), were the most frequent complaints. Total NMSS score: (1) showed a higher correlation coefficient (rS = 0.70) with the PDQ-39 Summary Index (SI) than SCOPA-Motor (rS = 0.58); (2) showed high-moderate correlation (rS = 0.60 − 0.38) with all PDQ-39 domains; and (3) was the best predictor of HRQoL as measured by the PDQ-39 SI. For each NMSS domain, patients with symptoms had significantly worse HRQoL scores than patients without symptoms. Discussion: To our knowledge, this is the first study to determine in a holistic manner the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. The results show that non-motor symptoms have, as a whole, a greater impact on HRQoL than motor symptoms and non-motor symptoms progression contributes importantly to HRQoL decline in patients with Parkinson's disease. © 2011 Movement Disorder Society

MDS Task Force on Mild Cognitive Impairment in Parkinson’s disease: Critical Review of PD-MCI

Abstract: There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson's disease. The Movement Disorder Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson's disease-mild cognitive impairment and its association with dementia. A comprehensive PubMed literature review was conducted using systematic inclusion and exclusion criteria. A mean of 26.7% (range, 18.9%-38.2%) of nondemented patients with Parkinson's disease have mild cognitive impairment. The frequency of Parkinson's disease-mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, nonamnestic is more common than amnestic impairment. A high proportion of patients with Parkinson's disease-mild cognitive impairment progress to dementia in a relatively short period of time. The primary conclusions of the Task Force are that: (1) Parkinson's disease-mild cognitive impairment is common, (2) there is significant heterogeneity within Parkinson's disease-mild cognitive impairment in the number and types of cognitive domain impairments, (3) Parkinson's disease-mild cognitive impairment appears to place patients at risk of progressing to dementia, and (4) formal diagnostic criteria for Parkinson's disease-mild cognitive impairment are needed.

Etiology and pathogenesis of Parkinson's disease.

Abstract: The past 25 years have seen a major expansion of knowledge concerning the cause of Parkinson's disease provided by an understanding of environmental and genetic factors that underlie the loss of nigral dopaminergic neurons. Based on the actions of toxins, postmortem investigations, and gene defects responsible for familial Parkinson's disease, there is now a general consensus about the mechanisms of cell death that contribute to neuronal loss in Parkinson's disease. Mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammatory change are considered to lead to cell dysfunction and death by apoptosis or autophagy. Ageing is the single most important risk factor for Parkinson's disease, and the biochemical changes that are a consequence of aging amplify these abnormalities in Parkinson's disease brain. What remains to be determined is the combination and sequence of events leading to cell death and whether this is identical in all brain regions where pathology occurs and in all individuals with Parkinson's disease. Focusing on those events that characterize Parkinson's disease, namely, mitochondrial dysfunction and Lewy body formation, may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection.

Glia: Initiators and progressors of pathology in Parkinson's disease

Abstract: Background: Glia are traditionally known as support cells for neurons, and their role in neurodegeneration has been largely considered secondary to neuronal dysfunction. We review newer concepts on glial function and assess glial changes in Parkinson's disease (PD) at the time of disease initiation when α-synuclein is accumulating in brain tissue but there is limited neuronal loss, and also as the disease progresses and neuronal loss is evident. Results: Of the two main types of astrocytes, only protoplasmic astrocytes are involved in PD, where they become nonreactive and accumulate α-synuclein. Experimental evidence has shown that astrocytic α-synuclein deposition initiates the noncell autonomous killing of neurons through microglial signaling. As the disease progresses, more protoplasmic astrocytes are affected by the disease with an increasing microglial response. Although there is still controversy on the role microglia play in neurodegeneration, there is evidence that microglia are activated early in PD and possibly assist with the clearance of extracellular α-synuclein at this time. Microglia transform to phagocytes and target neurons as the disease progresses but appear to become dysfunctional with increasing amounts of ingested debris. Only nonmyelinating oligodendroglial cells are affected in PD, and only late in the disease process. Conclusions: Glial cells are responsible for the progression of PD and play an important role in initiating the early tissue response. In particular, early dysfunction and α-synuclein accumulation in astrocytes causes recruitment of phagocytic microglia that attack selected neurons in restricted brain regions causing the clinical symptoms of PD. © 2011 Movement Disorder Society

Rotigotine effects on early morning motor function and sleep in Parkinson's disease: A double-blind, randomized, placebo-controlled study (RECOVER)

Abstract: In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS-2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society

Executive functions in Parkinson's disease: systematic review and meta-analysis.

Abstract: Impairment of executive function (EF) is commonly reported as a feature of PD. However, the exact pattern of executive impairment remains unclear. Also, there is an ongoing discussion surrounding the definition and conceptualization of EF, which might affect the clarity of research evidence on cognition in PD. The aim of this systematic review was to describe the pattern of executive impairment in early-stage PD emerging from the research literature and to identify critical issues for improving consistency in this field. The PsychInfo, MEDLINE, Science Direct, CINAHL, and Cochrane Library databases were searched using the term "Parkinson's disease" combined with each of 14 cognitive abilities defined as representing aspects of EF. The review was limited to studies that investigated EF as the central variable in early-stage, nondemented PD patients. The review identified 33 studies of EF that were operationalized in terms of 30 abilities tested by 60 measures and variously interpreted. Many measures were used only once, so only a small part of the available research evidence could be synthesized in the meta-analysis. The meta-analysis was undertaken using data from five commonly used tests of EF drawn from 18 studies. This revealed consistent evidence for cognitive difficulties across all five EF tests. Research on EF in PD is characterized by a considerable lack of clarity with regard to measure selection and interpretation. The findings support the view that EF impairments are evident in PD. However, the clinical significance of the cognitive abnormalities reported has yet to be clarified.

Parkinson's disease: The quintessential neuropsychiatric disorder

Abstract: Although diagnosed by characteristic motor features, Parkinson's disease may be preceded, and is frequently accompanied by, a wide range of cognitive and neuropsychiatric features. In addition to the most commonly studied disorders of dementia, depression, and psychosis, other relatively common and clinically significant psychiatric complications include impulse control disorders, anxiety symptoms, disorders of sleep and wakefulness, and apathy. These problems may be underrecognized and are frequently undertreated. The emergent focus on nonmotor aspects of Parkinson's disease over the past quarter of a century is highlighted by a nonlinear increase in the number of articles published devoted to this topic. Although the development of newer antidepressants, atypical antipsychotics, and cholinesterase inhibitors in recent years has had a positive benefit on the management of these troublesome and distressing symptoms, responses are frequently suboptimal, and this remains an area of major unmet therapeutic need.

Parkinson's disease sleep scale—validation of the revised version PDSS-2

Abstract: Background: The previous Parkinson's disease sleep scale (PDSS) is a 15-item visual analogue scale that assesses the profile of nocturnal disturbances in Parkinson's disease (PD) patients. Objective: To extend the scale so that it becomes a frequency measure scale with five categories and encompasses unmet needs such as restless legs syndrome, akinesia, pain, and sleep apnea. Methods: For validation of the PDSS-2, PD patients' ratings and investigators' interviews were compared to ratings from a semistructured interview with a caregiver/partner, and to related scales. PDSS-2 was repeated for test-retest-reliability after 1–3 days. Results: A total of 113 PD patients showed a mean (SD) total score of 16.5 (±8.9) (range: 2–40) indicating mild to moderate sleep disturbances. PDSS-2 item-total correlation for proving internal consistency was satisfactory (correlations >0.30). From a factor analysis, three subscales were derived: (1) “motor problems at night,” (2) “PD symptoms at night” and (3) “disturbed sleep.” The alpha coefficient for the total score was 0.73, for subscales 0.47 to 0.66. The test-retest-reliability intra-class-coefficient for the total score was 0.80, with 0.69 and 0.77 within the subscales. For discriminative validity, significant differences were found in the PDSS-2 total score depending on CGI and Hoehn and Yahr severity levels. A comparison between caregivers' and patients' ratings was carried out. Conclusion: The PDSS-2, with an extended spectrum of nocturnal disabilities and easier use for patients, is a reliable, valid, precise, and potentially treatment-responsive tool for measuring sleep disorders in PD. © 2011 Movement Disorder Society

Balance and falls in Parkinson's disease: A meta-analysis of the effect of exercise and motor training†‡

Abstract: This systematic review with meta-analysis aimed to determine the effects of exercise and motor training on the performance of balance-related activities and falls in people with Parkinson's disease. Sixteen randomized and quasi-randomized controlled trials that assessed the efficacy of exercise and/or motor training against no intervention or placebo intervention were included. The primary outcome measures were balance-related activity performance (15 trials) and falls (2 trials). The pooled estimate of the effect of exercise and motor training indicated significantly improved balance-related activity performance (Hedges' g, 0.33; 95% confidence interval, 0.11-0.55; P = .003), but there was no evidence of an effect on the proportion of fallers (risk ratio, 1.02; 95% confidence interval, 0.66-1.58, P = .94). Balance-related activity performance improved to a greater extent in the trials of programs involving highly challenging balance training, but the difference in effect sizes was not statistically significant (P = .166). Exercise and motor training can improve the performance of balance-related activities in people with Parkinson's disease. However, further research is required to determine if falls can be prevented in this population. © 2011 Movement Disorder Society. Language: en

Health-related quality-of-life scales in Parkinson's disease: critique and recommendations.

Abstract: Health-related quality of life is an im- portant patient-reported outcome used in intervention tri- als and for monitoring the consequences of health status on physical, mental, and social domains. Parkinson's dis- ease is a complex disorder that strongly affects patients' quality of life. Several health-related quality of life tools have been used in Parkinson's disease. A Movement Disorder Society Task Force was commissioned to rate the psychometric quality of available health-related qual- ity of life scales as applied to Parkinson's disease. Fol- lowing the methodology adopted by previous work of the Movement Disorder Society Task Force, a review of generic and specific health-related quality of life scales applied in studies on Parkinson's disease was com- pleted. Considering the scales from 3 perspectives—use in Parkinson's disease, use by multiple research groups, and clinimetric properties—a final classification as ''rec- ommended,'' ''suggested,'' or ''listed'' was applied to each reviewed instrument. Four generic scales (EuroQoL, Nottingham Health Profile, 36-Item Short-Form Health Survey, and Sickness Impact Profile) and 5 specific scales (39-Item Parkinson's Disease Questionnaire, Par- kinson's Disease Questionnaire Short Form, Parkinson's Disease Quality of Life Questionnaire, Parkinson's Impact Scale, and Scales for Outcomes in Parkinson's Disease- Psychosocial) reached the level of ''recommended.'' The 39-item Parkinson's Disease Questionnaire is the most thoroughly tested and applied questionnaire. Three other generic measures (Quality of Life Questionnaire 15D, Schedule for the Evaluation of Individual Quality of Life- Direct Weighting, and World Health Organization Quality of Life Assessment Short Version) and the specific Parkin- son's Disease Quality of Life Scale are ''suggested.'' With a little additional effort in completing the stipulated require- ments, they could reach the ''recommended'' level. At present there is a wide variety of health-related quality of life measures for application in the Parkinson's disease setting, and the task force does not recommend the devel- opment of a new scale. Selection of the most appropriate instrument for a particular objective requires consideration of the characteristics of each scale and the goals of the assessment. V C 2011 Movement Disorder Society

Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder

Abstract: Conversion disorder (CD) is characterized by unexplained neurological symptoms presumed related to psychological issues. The main hypotheses to explain conversion paralysis, characterized by a lack of movement, include impairments in either motor intention or disruption of motor execution, and further, that hyperactive self-monitoring, limbic processing or top-down regulation from higher order frontal regions may interfere with motor execution. We have recently shown that CD with positive abnormal or excessive motor symptoms was associated with greater amygdala activity to arousing stimuli along with greater functional connectivity between the amygdala and supplementary motor area. Here we studied patients with such symptoms focusing on motor initiation. Subjects performed either an internally or externally generated 2-button action selection task in a functional MRI study. Eleven CD patients without major depression and 11 age- and gender-matched normal volunteers were assessed. During both internally and externally generated movement, conversion disorder patients relative to normal volunteers had lower left supplementary motor area (SMA) (implicated in motor initiation) and higher right amygdala, left anterior insula, and bilateral posterior cingulate activity (implicated in assigning emotional salience). These findings were confirmed in a subgroup analysis of patients with tremor symptoms. During internally versus externally generated action in CD patients, the left SMA had lower functional connectivity with bilateral dorsolateral prefrontal cortices. We propose a theory in which previously mapped conversion motor representations may in an arousing context hijack the voluntary action selection system, which is both hypoactive and functionally disconnected from prefrontal top-down regulation.

The interplay of cholinergic function, attention, and falls in Parkinson's disease

Abstract: Dopamine loss in the substantia nigra causes several of the motor signs seen in Parkinson's disease, but there is now increasing evidence highlighting the importance of cholinergic loss in the pathophysiology of nonmotor symptoms. The nucleus basalis of Meynert supplies the majority of the cholinergic input to the cerebral cortex, with the pedunculopontine nucleus providing many subcortical structures with acetylcholine. Both these structures undergo degeneration in Parkinson's disease (PD), with more severe loss associated with cognitive impairment. The risk of dementia in PD is greater than that in control subjects, with impairments in attention, visuospatial function, and executive control dominating. Imaging studies have demonstrated degeneration of the cholinergic system in PD, Parkinson's disease dementia, and dementia with Lewy bodies, with improvements in attention seen following the introduction of cholinesterase inhibitors. Conversely, anticholinergic drugs are associated with cognitive decline, with neuropathology studies indicating the presence of increased neurofibrillary tangles and senile plaque formation. In addition, these drugs are also known to precipitate visual hallucinations, lending support to a cholinergic basis for visual hallucinations in PD. Gait, falls, and cognition may also be related, as evidenced by the findings that fallers perform less well on test of attention than nonfallers and that greater postural instability is associated with worse scores on attention and executive function. It is therefore feasible that cognition (namely, attention), visual hallucinations, falls, and gait are subserved by acetylcholine, and this is further explored in this clinically orientated review.

Milestones in research on the pathophysiology of Parkinson's disease.

Abstract: Progress in our understanding of the mechanisms underlying the cardinal motor abnormalities of Parkinson's disease (PD), in particular akinesia and bradykinesia and their treatment, has been remarkable. Notable accomplishments include insights into the functional organization of the basal ganglia and their place in the motor system as components of a family of parallel cortico-subcortical circuits that subserve motor and nonmotor functions and the development of models of the intrinsic organization of the basal ganglia, including delineation of the so-called direct, indirect, and hyperdirect pathways. Studies in primate models of PD have provided insight into the alterations of neuronal activity that are responsible for the motor features of PD, revealing both altered tonic levels of discharge and significant disturbances of the patterns of discharge throughout the motor circuitry and have led to the formulation of circuit models of PD, providing testable hypotheses for research and stimulating the development of new therapies. Most importantly, the discovery that lesions of the subthalamic nucleus, a key node of the indirect pathway, abolish the cardinal features of PD contributed to the renaissance in the use of surgical approaches to treating patients with PD, including ablation and deep brain stimulation.

Psychopathology and psychogenic movement disorders.

Abstract: Psychogenic movement disorder is defined as abnormal movements unrelated to a medical cause and presumed related to underlying psychological factors. Although psychological factors are of both clinical and pathophysiological relevance, very few studies to date have systematically assessed their role in psychogenic movement disorder. We sought to assess the role of previous life stress using validated quantitative measures in patients with psychogenic movement disorder compared with age- and sex-matched healthy volunteers as well as a convenience sample of patients with focal hand dystonia. Sixty-four patients with psychogenic movement disorder (72% female; mean age, 45.2 years [standard deviation, 15.2 years]), 38 healthy volunteers (74% female; mean age, 49 years [standard deviation, 13.7 years]), and 39 patients with focal hand dystonia (37% female; mean age, 48.7 years [standard deviation, 11.7 years]) were evaluated using a standardized psychological interview as well as validated quantitative scales to assess trauma and previous stressors, depression, anxiety, and personality traits. Patients with psychogenic movement disorder reported higher rates of childhood trauma, specifically greater emotional abuse and physical neglect, greater fear associated with traumatic events, and a greater number of traumatic episodes compared with healthy volunteers and patients with focal hand dystonia controlled for depressive symptoms and sex (Bonferroni corrected P < .005). There were no differences in categorical psychiatric diagnoses or scores on childhood physical or sexual abuse subscales, personality traits, or the dissociative experience scale. Our findings highlight a biopsychosocial approach toward the pathophysiology of psychogenic movement disorder, although the association with psychological issues is much less prominent than expected compared with the nonepileptic seizure population. A careful psychological assessment is indicated to optimize therapeutic modalities.

Prevalence and disease burden of primary restless legs syndrome: Results of a general population survey in the United States†

Abstract: To assess prevalence, disease burden, and costs of primary Restless Legs Syndrome (RLS) in the US. In 2007, 61,792 (20%) of 313,000 subjects from a representative US panel completed an online "global opinions" survey identifying respondents reporting all four diagnostic features of RLS. 4,484 met all criteria. 1,400 were randomly selected to complete a questionnaire to exclude those with diagnoses indicating possible secondary RLS. Those that did not have diagnoses associated with secondary RLS were asked to complete the Cambridge-Hopkins RLS questionnaire to exclude RLS mimics. Prevalence was estimated for the following groups: (1) RLS symptomatic, (2) primary RLS, and (3) primary RLS sufferers (symptoms ≥2/wk with moderate-to-severe distress). The primary RLS completed a larger online survey including the IRLS, EuroQol, Work Productivity and Activity Impairment questionnaire, and questions about healthcare resource use. The validated diagnostic tools and exclusion of medical conditions likely to cause RLS provide a very conservative estimate of US census-weighted prevalence of 2.4% for primary RLS and 1.5% for primary RLS sufferers. About 33% of respondents had a physician diagnosis of RLS. Primary RLS sufferers had a mean productivity loss of 1 day/wk. All RLS-related costs increased with RLS symptom severity, with increasingly significant decrements in health status, sleep disturbance, and work productivity. Even this very conservative approach finds RLS in this cohort to be common, under-diagnosed, and carried a significant personal and social burden.

Clinical subtypes of Parkinson's disease

Abstract: The clinical heterogeneity of Parkinson's disease (PD) may point at the existence of subtypes. Because subtypes likely reflect distinct underlying etiologies, their identification may facilitate future genetic and pharmacotherapeutic studies. Aim of this study was to identify subtypes by a data-driven approach applied to a broad spectrum of motor and nonmotor features of PD. Data of motor and nonmotor PD symptoms were collected in 802 patients in two different European prevalent cohorts. A model-based cluster analysis was conducted on baseline data of 344 patients of a Dutch cohort (PROPARK). Reproducibility of these results was tested in data of the second annual assessment of the same cohort and validated in an independent Spanish cohort (ELEP) of 357 patients. The subtypes were subsequently characterized on clinical and demographic variables. Four similar PD subtypes were identified in two different populations and are largely characterized by differences in the severity of nondopaminergic features and motor complications: Subtype 1 was mildly affected in all domains, Subtype 2 was predominantly characterized by severe motor complications, Subtype 3 was affected mainly on nondopaminergic domains without prominent motor complications, while Subtype 4 was severely affected on all domains. The subtypes had largely similar mean disease durations (nonsignificant differences between three clusters) but showed considerable differences with respect to their association with demographic and clinical variables. In prevalent disease, PD subtypes are largely characterized by the severity of nondopaminergic features and motor complications and likely reflect complex interactions between disease mechanisms, treatment, aging, and gender.

Neuropsychiatric symptoms in Parkinson's disease

Abstract: In their excellent review of neuropsychiatric problems in Parkinson’s disease (PD), the authors made one small error but more importantly raised an interesting question about drug trials. Also, as they wrote their article, both melperone (personal communication) and pimavanserin, subjected to randomized, double blind placebo controlled trials (DBPCT), failed to be efficacious. The authors erred in stating that clozapine was tested only on nondemented subjects. The American study had no exclusion for dementia and the mean mini-mental state exam scores were 21.7 in one treatment arm and 23.8 in the other. The French study required a MMSE score greater than 20. The mean score of their placebo treated group was 24.1. The authors noted that ‘‘more novel antipsychotics, such as ziprasidone and aripiprrazole, have not yet been tested systematically and preliminary reports are inconclusive.’’ There have been numerous reports of aripiprazole worsening motor function in PD patients but less so with ziprasidone. More importantly, it has been a common observation in both movement disorder clinics and psychiatry treatment centers (personal communications) that both aripiprazole and ziprasidone induce dose dependent parkinsonism quite commonly in patients who are too young to likely have idiopathic PD. What data would be sufficient to prevent a doomed attempt to test either of these drugs? I doubt the authors would be more likely to participate in a trial of either of these drugs than they would be in a study of risperidone, which also has no level I evidence against its use.

Beyond nine years of continuous subthalamic nucleus deep brain stimulation in Parkinson's disease.

Abstract: Deep brain stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease. The benefits of bilateral subthalamic stimulation are well documented, and some studies reported outcomes with a follow-up of 5 to 6 years; nevertheless, few data are available beyond 5 years. We report a long-term prospective evaluation of 14 consecutive parkinsonian patients, treated by bilateral subthalamic stimulation for at least 9 years. Motor symptoms, activity of daily living, and motor complications were evaluated by means of the Unified Parkinson's Disease Rating Scale, while cognition and mood were assessed with a specific neuropsychological test battery; medication intake, stimulation parameters, comorbidity, and adverse events were also recorded. Patients were evaluated before surgery and at 1, 5, and ≥9 years after surgery. At last follow-up, deep brain stimulation significantly improved the motor score by 42% compared to baseline, whereas activities of daily living were no longer improved; there was a 39% reduction in the dosage of dopaminergic drugs and a 59% improvement of L-dopa–related motor complications. The neuropsychological assessment showed that 4 patients (29%) developed a significant cognitive decline over the follow-up period. These results indicate a persistent effect of deep brain stimulation of the subthalamic nucleus on the cardinal motor symptoms in advanced Parkinson's disease patients in the long-term; however, a worsening of patients' disability, mainly due to disease progression, was observed. © 2011 Movement Disorder Society

Tourette syndrome: evolving concepts.

Abstract: Tourette syndrome is a common childhood-onset neurobehavioral disorder characterized by multiple motor and phonic tics affecting boys more frequently than girls. Premonitory sensory urges prior to tic execution are common, and this phenomenon helps to distinguish tics from other hyperkinetic movement disorders. Tourette syndrome is commonly associated with attention deficit hyperactivity disorder, obsessive-compulsive disorder, learning difficulties, and impulse control disorder. The pathophysiology of this complex disorder is not well understood. Involvement of basal ganglia-related circuits and dopaminergic system has been suggested by various imaging and postmortem studies. Although it is considered a genetic disorder, possibly modified by environmental factors, an intense search has thus far failed to find causative genes. Symptomatic treatment of tics chiefly utilizes various alpha adrenergic agonists, antidopaminergic drugs, topiramate, botulinum toxin, and deep brain stimulation. Habit reversal therapy and other behavioral approaches may be a reasonable option for some cases. Improved understanding of Tourette syndrome should lead to better symptomatic and more effective pathogenesis-targeted therapies.

Milestones in Parkinson's disease therapeutics

Abstract: In the mid-1980s, the treatment of Parkinson's disease was quite exclusively centered on dopatherapy and was focusing on dopamine systems and motor symptoms. A few dopamine agonists and a monoamine oxidase B inhibitor (selegiline) were used as adjuncts in advanced Parkinson's disease. In the early 2010s, levodopa remains the gold standard. New insights into the organization of the basal ganglia paved the way for deep brain stimulation, especially of the subthalamic nucleus, providing spectacular improvement of drug-refractory levodopa-induced motor complications. Novel dopamine agonists (pramipexole, ropinirole, rotigotine), catecholmethyltransferase inhibitors (entacapone), and monoamine oxidase B inhibitors (rasagiline) have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of dyskinesia, although this is achieved at the price of potentially disabling daytime somnolence or impulse control disorders. The demonstration of an antidyskinetic effect of the glutamate antagonist amantadine opened the door for novel nondopaminergic approaches of Parkinson's disease therapy. More recently, nonmotor symptoms (depression, dementia, and psychosis) have been the focus of the first randomized controlled trials in this field. Despite therapeutic advances, Parkinson's disease continues to be a relentlessly progressive disorder leading to severe disability. Neuroprotective interventions able to modify the progression of Parkinson's disease have stood out as a failed therapeutic goal over the last 2 decades, despite potentially encouraging results with compounds like rasagiline. Newer molecular targets, new animal models, novel clinical trial designs, and biomarkers to assess disease modification have created hope for future therapeutic interventions.

Milestones in Parkinson's disease—Clinical and pathologic features

Abstract: The identification of the widespread deposition of fibrillized α-synuclein in Lewy bodies and Lewy neurites in the brains of patients with Parkinson's disease in 1997 has had a profound impact on how the disease is now conceptualized. The previous focus on the loss of the dopaminergic nigrostriatal system, the concept of subcortical dementia, and the idea that Parkinson's disease was dominated by motor impairment have all given way to research assessing more diverse brain regions, clinical symptoms, and phenotypes. It is now recognized that Parkinson's disease is more than just a loss of midbrain dopaminergic neurons in association with Lewy bodies. There are now several theories on how the disease develops and progresses currently being validated in a variety of studies, although many of these theories have yet to incorporate the phenotypic clinical and pathological changes associated with age. A particularly exciting new area of research involves the cell-to-cell transmission of pathogenic proteins. The recent consensus definition of Parkinson's disease dementia will allow its pathologic substrates to be determined. These advances have progressed to a stage where the preclinical stages of Parkinson's disease and its specific signs and symptoms are being predicted and tested clinically. Such strategies herald a future wave of preventive strategies for Parkinson's disease and its clinical symptoms.

AFQ056 treatment of levodopa-induced dyskinesias: Results of 2 randomized controlled trials

Abstract: Study objectives were to assess the efficacy, safety, and tolerability of AFQ056 in Parkinson's disease patients with levodopa-induced dyskinesia. Two randomized, double-blind, placebo-controlled, parallel-group, in-patient studies for Parkinson's disease patients with moderate to severe levodopa-induced dyskinesia (study 1) and severe levodopa-induced dyskinesia (study 2) on stable dopaminergic therapy were performed. Patients received 25-150 mg AFQ056 or placebo twice daily for 16 days (both studies). Study 2 included a 4-day down-titration. Primary outcomes were the Lang-Fahn Activities of Daily Living Dyskinesia Scale (study 1), the modified Abnormal Involuntary Movement Scale (study 2), and the Unified Parkinson's Disease Rating Scale-part III (both studies). Secondary outcomes included the Unified Parkinson's Disease Rating Scale-part IV items 32-33. The primary analysis was change from baseline to day 16 on all outcomes. Treatment differences were assessed. Fifteen patients were randomized to AFQ056 and 16 to placebo in study 1; 14 patients were randomized to each group in study 2. AFQ056-treated patients showed significant improvements in dyskinesias on day 16 versus placebo (eg, Lang-Fahn Activities of Daily Living Dyskinesia Scale, P = .021 [study 1]; modified Abnormal Involuntary Movement Scale, P = .032 [study 2]). No significant changes were seen from baseline on day 16 on the Unified Parkinson's Disease Rating Scale-part III in either study. Adverse events were reported in both studies, including dizziness. Serious adverse events (most commonly worsening of dyskinesias, apparently associated with stopping treatment) were reported by 4 AFQ056-treated patients in study 1, and 3 patients (2 AFQ056-treated patient and 1 in the placebo group) in study 2. AFQ056 showed a clinically relevant and significant antidyskinetic effect without changing the antiparkinsonian effects of dopaminergic therapy. © 2011 Movement Disorder Society.

Milestones in PD genetics.

Abstract: Over the last 25 years, genetic findings have profoundly changed our views on the etiology of Parkinson's disease. Linkage studies and positional cloning strategies have identified mutations in a number of genes that cause several monogenic autosomal-dominant or autosomal-recessive forms of the disorder. Although most of these Mendelian forms of Parkinson's disease are rare, whole-genome association studies have more recently provided convincing evidence that low-penetrance variants in at least some of these, but also in several other genes, play a direct role in the etiology of the common sporadic disease as well. In addition, rare variants with intermediate-effect strengths in genes such as Gaucher's disease-associated glucocerebrosidase A have been discovered as important risk factors. "Next-generation" sequencing technologies are expected by some to identify many more of these variants. Thus, an increasingly complex network of genes contributing in different ways to disease risk and progression is emerging. These findings may provide the "genetic entry points" to identify molecular targets and readouts necessary to design rational disease-modifying treatments.

Cerebrospinal fluid Tau/α-synuclein ratio in Parkinson's disease and degenerative dementias†‡

Abstract: Although alpha-synuclein is the main constituent of Lewy bodies, cerebrospinal fluid determination on its own does not seem fundamental for the diagnosis of synucleinopathies. We evaluated whether the combination of classical biomarkers, Aβ(1-42) , total tau, phosphorylated tau, and α-synuclein can improve discrimination of Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, and frontotemporal dementia. Aβ(1-42) , total tau, phosphorylated tau, and α-synuclein were measured in a series of patients with Parkinson's disease (n = 38), dementia with Lewy bodies (n = 32), Alzheimer's disease (n = 48), frontotemporal dementia (n = 31), and age-matched control patients with other neurological diseases (n = 32). Mean α-synuclein levels in cerebrospinal fluid were significantly lower in the pathological groups than in cognitively healthy subjects. An inverse correlation of α-synuclein with total tau (r = -0.196, P < .01) was observed. In the group of patients with Parkinson's disease, Aβ(1-42) , total tau, and phosphorylated tau values were similar to controls, whereas total tau/α-synuclein and phosphorylated tau/α-synuclein ratios showed the lowest values. Cerebrospinal fluid α-synuclein alone did not provide relevant information for Parkinson's disease diagnosis, showing low specificity (area under the curve, 0.662; sensitivity, 94%; specificity, 25%). Instead, a better performance was obtained with the total tau/α-syn ratio (area under the curve, 0.765; sensitivity, 89%; specificity, 61%). Combined determination of α-synuclein and classical biomarkers in cerebrospinal fluid shows differential patterns in neurodegenerative disorders. In particular, total tau/α-synuclein and phosphorylated tau/α-synuclein ratios can contribute to the discrimination of Parkinson's disease. © 2011 Movement Disorder Society.

The Modified Bradykinesia Rating Scale for Parkinson’s Disease: Reliability and Comparison with Kinematic Measures

Abstract: Bradykinesia encompasses slowness, decreased movement amplitude, and dysrhythmia. Unified Parkinson's Disease Rating Scale-based bradykinesia-related items require that clinicians condense abnormalities in speed, amplitude, fatiguing, hesitations, and arrests into a single score. The objective of this study was to evaluate the reliability of a modified bradykinesia rating scale, which separately assesses speed, amplitude, and rhythm and its correlation with kinematic measures from motion sensors. Fifty patients with Parkinson's disease performed Unified Parkinson's Disease Rating Scale-directed finger tapping, hand grasping, and pronation-supination while wearing motion sensors. Videos were rated blindly and independently by 4 clinicians. The modified bradykinesia rating scale and Unified Parkinson's Disease Rating Scale demonstrated similar inter- and intrarater reliability. Raters placed greater weight on amplitude than on speed or rhythm when assigning a Unified Parkinson's Disease Rating Scale score. Modified bradykinesia rating scale scores for speed, amplitude, and rhythm correlated highly with quantitative kinematic variables. The modified bradykinesia rating scale separately captures bradykinesia components with interrater and intrarater reliability similar to that of the Unified Parkinson's Disease Rating Scale. Kinematic sensors can accurately quantify speed, amplitude, and rhythm to aid in the development and evaluation of novel therapies in Parkinson's disease.

T1‐Weighted MRI shows stage‐dependent substantia nigra signal loss in Parkinson's disease

Abstract: Depigmentation of the substantia nigra is a conspicuous pathological feature of Parkinson's disease and related to a loss of neuromelanin. Similar to melanin, neuromelanin has paramagnetic properties resulting in signal increase on specific T1-weighted magnetic resonance imaging. The aim of this study was to assess signal changes in the substantia nigra in patients with Parkinson's disease using an optimized neuromelanin-sensitive T1 scan. Ten patients with Parkinson's disease and 12 matched controls underwent high-resolution T1-weighted magnetic resonance imaging with magnetization transfer effect at 3T. The size and signal intensity of the substantia nigra pars compacta were determined as the number of pixels with signal intensity higher than background signal intensity+3 standard deviations and regional contrast ratio. Patients were subclassified as early stage (n=6) and late stage (n=4) using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Parkinson's disease staging scale. The T1 hyperintense area in the substantia nigra was substantially smaller in patients compared with controls (-60%, P<.01), and contrast was reduced (-3%, P<.05). Size reduction was even more pronounced in more advanced disease (-78%) than in early-stage disease (-47%). We present preliminary findings using a modified T1-weighted magnetic resonance imaging technique showing stage-dependent substantia nigra signal reduction in Parkinson's disease as a putative marker of neuromelanin loss. Our data suggest that reduction in the size of neuromelanin-rich substantia nigra correlates well with postmortem observations of dopaminergic neuron loss. Further validation of our results could potentially lead to development of a new biomarker of disease progression in Parkinson's disease.

Visual symptoms in Parkinson's disease and Parkinson's disease dementia.

Abstract: Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.

Combined R2* and Diffusion Tensor Imaging Changes in the Substantia Nigra in Parkinson's Disease

Abstract: Recent magnetic resonance imaging studies suggest an increased transverse relaxation rate and reduced diffusion tensor imaging fractional anisotropy values in the substantia nigra in Parkinson's disease. The transverse relaxation rate and fractional anisotropy changes may reflect different aspects of Parkinson's disease-related pathological processes (ie, tissue iron deposition and microstructure disorganization). This study investigated the combined changes of transverse relaxation rate and fractional anisotropy in the substantia nigra in Parkinson's disease. High-resolution magnetic resonance imaging (T2-weighted, T2*, and diffusion tensor imaging) were obtained from 16 Parkinson's disease patients and 16 controls. Bilateral substantia nigras were delineated manually on T2-weighted images and coregistered to transverse relaxation rate and fractional anisotropy maps. The mean transverse relaxation rate and fractional anisotropy values in each substantia nigra were then calculated and compared between Parkinson's disease subjects and controls. Logistic regression, followed by receiver operating characteristic curve analysis, was employed to investigate the sensitivity and specificity of the combined measures for differentiating Parkinson's disease subjects from controls. Compared with controls, Parkinson's disease subjects demonstrated increased transverse relaxation rate (P<.0001) and reduced fractional anisotropy (P=.0365) in the substantia nigra. There was no significant correlation between transverse relaxation rate and fractional anisotropy values. Logistic regression analyses indicated that the combined use of transverse relaxation rate and fractional anisotropy values provides excellent discrimination between Parkinson's disease subjects and controls (c-statistic=0.996) compared with transverse relaxation rate (c-statistic=0.930) or fractional anisotropy (c-statistic=0.742) alone. This study shows that the combined use of transverse relaxation rate and fractional anisotropy measures in the substantia nigra of Parkinson's disease enhances sensitivity and specificity in differentiating Parkinson's disease from controls. Further studies are warranted to evaluate the pathophysiological correlations of these magnetic resonance imaging measurements and their effectiveness in assisting in diagnosing Parkinson's disease and following its progression.

Anxiety rating scales in Parkinson's disease: A validation study of the Hamilton anxiety rating scale, the Beck anxiety inventory, and the hospital anxiety and depression scale

Abstract: Background: Anxiety is a prevalent and disabling condition in Parkinson's disease (PD). The lack of anxiety rating scales validated for this population hampers research into anxiety in PD. The aim of this study is to assess the clinimetric properties of the Hamilton anxiety rating scale (HARS), the Beck anxiety inventory (BAI), and the hospital anxiety and depression scale (HADS) in PD patients. Design: Three hundred forty-two PD patients underwent a standardized assessment including a structured interview for diagnostic and statistical manual diagnoses of anxiety disorders and completion of the HARS, BAI, and HADS. Inter-rater reliability of the HARS was assessed in 60 patients; test-retest reliability of the BAI and HADS in 213 and 217 patients, respectively. Results: Thirty-four percent of patients suffered from an anxiety disorder, whereas an additional 11.4% had clinically significant anxiety symptoms in the absence of a diagnosis of anxiety disorder. Acceptability, score distribution, and known groups validity over different levels of anxiety were adequate. Inter-rater reliability for the HARS and test-retest reliability for the BAI and HADS were good. The HARS, but not the BAI and HADS, had a satisfactory inter-item correlation, convergent validity and factorial structure. For all scales, the positive predictive value was poor, and the negative predictive value was moderate. Conclusions: Given the adequate known groups validity of all three rating scales, each of these scales is likely to be useful in clinical practice or research for evaluation of symptom severity. Limitations in the construct validity of the anxiety scales in this study raise questions regarding suitability for their use in PD. © 2011 Movement Disorder Society