Showing papers in "Movement Disorders in 2014"

The prevalence of Parkinson's disease: A systematic review and meta‐analysis

Abstract: Parkinson's Disease (PD) is a common neurodegenerative disorder. We sought to synthesize studies on the prevalence of PD to obtain an overall view of how the prevalence of this disease varies by age, by sex, and by geographic location. We searched MEDLINE and EMBASE for epidemiological studies of PD from 1985 to 2010. Data were analyzed by age group, geographic location, and sex. Geographic location was stratified by the following groups: 1) Asia, 2) Africa, 3) South America, and 4) Europe/North America/Australia. Meta-regression was used to determine whether a significant difference was present between groups. Forty-seven studies were included in the analysis. Meta-analysis of the worldwide data showed a rising prevalence of PD with age (all per 100,000): 41 in 40 to 49 years; 107 in 50 to 59 years; 173 in 55 to 64 years; 428 in 60 to 69 years; 425 in 65 to 74 years; 1087 in 70 to 79 years; and 1903 in older than age 80. A significant difference was seen in prevalence by geographic location only for individuals 70 to 79 years old, with a prevalence of 1,601 in individuals from North America, Europe, and Australia, compared with 646 in individuals from Asia (P < 0.05). A significant difference in prevalence by sex was found only for individuals 50 to 59 years old, with a prevalence of 41 in females and 134 in males (P < 0.05). PD prevalence increases steadily with age. Some differences in prevalence by geographic location and sex can be detected. © 2014 International Parkinson and Movement Disorder Society

Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease

Abstract: With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson's disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD. This review is a discussion article, intended as the introductory statement of the task force. Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration.

Cerebral organoids model human brain development and microcephaly

Abstract: Due to the complexity of the human brain, it is difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. In their report, Lancaster et al. established a human, pluripotent, stem cell-derived, three-dimensional culture system, termed cerebral organoids, which developed various discrete, although interdependent, brain regions. These regions include cerebral cortex-containing progenitor populations that organize and produce mature cortical neuron subtypes. Mammalian brain development begins with the expansion of the neuroepithelium to generate radial glial stem cells. In human brains, the organization of progenitor zones is markedly more elaborate; the subventricular zone (SVZ) is split by an inner fiber layer (IFL) into an inner SVZ and an outer SVZ (OSVZ). The OSVZ represents an entirely separate progenitor layer, populated by intermediate progenitors, and a unique stem cell subset termed outer radial glia, which are only present to a limited degree in rodents. Both the IFL and the OSVZ are completely absent in the mouse brain. Thus, these differences allow for the striking expansion in neuronal output and brain size seen in human brains. Primary microcephaly is a neurodevelopmental disorder in which brain size is markedly reduced and may be caused by autosomal recessive mutations in several genes. All genes encode for proteins localizing to the mitotic spindle apparatus. The pathogenesis of this disorder has been examined primarily in mouse models until now. However, mouse mutants have failed to recapitulate the severely reduced brain size seen in human patients. The use of cerebral organoids, as established by Lancaster et al., has the potential to recapitulate human brain development and, in particular, cerebral cortical development. This threedimensional culture system for driving brain tissue in vitro is a powerful tool for better understanding the pathogenesis of developmental brain disorders. Cerebral organoids develop a variety of regional identities, organized as discrete domains, capable of influencing one another. Lancaster et al. demonstrated premature neuronal differentiation in organoids using patient-specific induced pluripotent stem cells (iPSCs), a defect that could help to explain the disease phenotype of microcephaly. This patient had compound heterozygous, truncating mutations in the cyclin-dependent 5 regulatory subunit associated protein 2 gene (CDK5RAP2). Skin fibroblasts from this patient revealed a loss of CDK5RAP2, suggesting loss of function and consistent with previous reports of CDK5RAP2 mutations in patients with primary microcephaly. They also performed RNA interference to knock down endogenous CDK5RAP2 as an independent approach. Subsequently, this approach also led to premature neuronal differentiation at the expense of progenitors as well as patient organoids derived from the patient with CDK5RAP2 mutations. Embryo stem cells have limitations as models to elucidate disease mechanisms because of ethical issues. Since the discovery of iPSC technologies, it is possible to determine mechanisms of neurological disease using neuronal cells derived from patients. These findings suggest that in vitro culture systems like cerebral organoids may be good models in which to analyze aspects of human neurodevelopment and neurological disease and may provide new insights into the pathogenesis of these disorders.

Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice.

Abstract: Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions.

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

Abstract: Lewy body (LB) diseases are characterized by alpha-synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non-LB diseases including atypical parkinsonism and non-LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD. © 2014 International Parkinson and Movement Disorder Society

The neurobiological basis of cognitive impairment in Parkinson's disease.

Abstract: The recent formalization of clinical criteria for Parkinson's disease with dementia (PDD) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PDD occurs on the background of severe dopamine deficits with, the main pathological drivers of cognitive decline being a synergistic effect between alpha-synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin, and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the α-synuclein gene, lead to a clear increased risk of PDD, whereas others, such as parkin mutations, are associated with a reduced risk of PDD. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low-dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. Whereas dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies, and genetic factors in PD-MCI remains to be fully elucidated.

Health-related quality of life in early Parkinson's disease: The impact of nonmotor symptoms

Abstract: Nonmotor symptoms (NMS) are common in patients with established Parkinson's disease (PD) and have a major impact upon quality of life. We investigated the significance of NMS in relation to health-related quality of life (HRQoL) in patients with newly diagnosed PD. Patients and healthy controls were recruited as part of the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease Study. Prevalence of NMS was determined with the Non-Motor Symptom Questionnaire. HRQoL was recorded with the 39-item Parkinson's Disease Quality of Life Questionnaire (PDQ-39). Further assessments included measures of motor disability, depression, sleep, and cognition. One hundred and fifty-eight patients with newly diagnosed PD and 99 controls participated in this cross-sectional study. Patients reported greater numbers of NMS than controls (mean 8.3 ± 4.3 versus 2.8 ± 2.5 symptoms; P < 0.001). Patients reported lowest HRQoL in the domains assessing bodily discomfort, mobility, and activities of daily living. Motor and nonmotor symptoms impacted negatively upon HRQoL scores. Patients with the postural instability and gait difficulty motor subtype reported worse HRQoL, compared with those with tremor-dominant disease. Depression (P < 0.001), incomplete bowel emptying (P < 0.001), anxiety (P < 0.001), impaired concentration (P < 0.001), memory complaints (P < 0.001), and insomnia (P = 0.001) had the greatest negative impact upon HRQoL. NMS are common in patients with early PD and represent a significant cause of poorer health-related quality of life. Cognitive, neuropsychiatric, and sleep disturbances are particularly associated with reduced well-being. Screening and management of these symptoms should be prioritized at the time of diagnosis.

Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson's disease

Abstract: The Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) study compared the initiation of levodopa (l-dopa) therapy with l-dopa/carbidopa (LC) versus l-dopa/carbidopa/entacapone (LCE) in patients with Parkinson's disease. In the current study, the STRIDE-PD study population was investigated to determine the effect of l-dopa dose and other risk factors on the development of dyskinesia and wearing-off. Patients were randomized to receive LCE (n=373) or LC (n=372). Blinded assessments for dyskinesia and wearing-off were performed at 3-month intervals for the 134- to 208-week duration of the study. The patients were divided into 4 dose groups based on nominal l-dopa dose at the time of onset of dyskinesia (or at study conclusion if there was no dyskinesia): group 1, 600 mg/day (n=77). Similar analyses were performed with respect to wearing-off and any motor complication. The times to onset and frequency of dyskinesia, wearing-off, or any motor complication were compared using the log-rank test (overall trend test) and a Cox proportional hazards model (pairwise comparisons). A stepwise Cox proportional hazards model was used to screen predictive factors in a multivariate analysis. The risk of developing dyskinesia and wearing-off increased in an l-dopa dose-dependent manner (P<0.001 for both). Analyses using l-dopa equivalent doses produced comparable results. Factors that were predictive of dyskinesia, in rank order, were: young age at onset, higher l-dopa dose, low body weight, North American geographic region, LCE treatment group, female gender, and more severe Unified Parkinson's Disease Rating Scale (UPDRS) Part II. Multivariate analyses identified similar predictors for wearing-off but included baseline UPDRS Part III and excluded weight and treatment allocation. The risk of developing dyskinesia or wearing-off was closely linked to l-dopa dose. The current results suggest that physicians should use the lowest dose of l-dopa that provides satisfactory clinical control to minimize the risk of both dyskinesia and wearing-off.

The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases.

Abstract: The phenotypic variability of progressive supranuclear palsy (PSP) may account for its frequent misdiagnosis, in particular in early stages of the disease. However, large multicenter studies to define the frequency and natural history of PSP phenotypes are missing. In a cohort of 100 autopsy-confirmed patients we studied the phenotypic spectrum of PSP by retrospective chart review. Patients were derived from five brain banks with expertise in neurodegenerative disorders with referrals from multiple academic hospitals. The clinical characteristics of the 100 cases showed remarkable heterogeneity. Most strikingly, only 24% of cases presented as Richardson's Syndrome (RS), and more than half of the cases either showed overlapping features of several predescribed phenotypes, or features not fitting proposed classification criteria for PSP phenotypes. Classification of patients according to predominant clinical features in the first 2 years of the disease course allowed a more comprehensive description of the phenotypic spectrum. These predominance types differed significantly with regard to survival time and frequency of cognitive deficits. In summary, the phenotypic spectrum of PSP may be broader and more variable than previously described in single-center studies. Thus, too strict clinical criteria defining distinct phenotypes may not reflect this variability. A more pragmatic clinical approach using predominance types could potentially be more helpful in the early recognition of and for making prognostic predictions for these patients. Given the limitations arising from the retrospective nature of this analysis, a systematic validation in a prospective cohort study is imperative.

A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy

Abstract: It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 weeks. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale; Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clinical Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examined. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clinical efficacy in patients with mild-to-moderate PSP.

Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations.

Abstract: Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia Many patients require add-on therapy to improve motor fluctuations without exacerbating dyskinesia The objective of this Phase III, multicenter, double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy and safety of safinamide, an α-aminoamide with dopaminergic and nondopaminergic mechanisms, as add-on to l-dopa in the treatment of patients with PD and motor fluctuations Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries) Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression-Change (CGI-C) At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 136 ± 2625 hours for safinamide 100 mg/day, 137 ± 2745 hours for safinamide 50 mg/day, and 097 ± 2375 hours for placebo Least squares means differences in both safinamide groups were significantly higher versus placebo Improvements in off time, UPDRS Part III, and CGI-C were significantly greater in both safinamide groups versus placebo There were no significant between-group differences for incidences of treatment-emergent adverse events (TEAEs) or TEAEs leading to discontinuation The addition of safinamide 50 mg/day or 100 mg/day to l-dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia

Genetic modifiers of Huntington's disease

Abstract: Huntington's disease (HD) is a devastating neurodegenerative disorder that directly affects more than 1 in 10,000 persons in Western societies but, as a family disorder with a long, costly, debilitating course, it has an indirect impact on a far greater proportion of the population. Although some palliative treatments are used, no effective treatment exists for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, approximately 15 years after diagnosis. Huntington's disease involves a movement disorder characterized by chorea, as well as a variety of psychiatric disturbances and intellectual decline, with a gradual loss of independence. A dire need exists for effective HD therapies to alleviate the suffering and costs to the individual, family, and health care system. In past decades, genetics, the study of DNA sequence variation and its consequences, provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. Now, advances in genetic technology offer an unbiased route to the identification of genetic factors that are disease-modifying agents in human patients. Such genetic modifiers are expected to highlight processes capable of altering the course of HD and therefore to provide new, human-validated targets for traditional drug development, with the goal of developing rational treatments to delay or prevent onset of HD clinical signs.

Mortality in Parkinson's disease: A systematic review and meta-analysis

Abstract: This study was undertaken to perform a systematic review and meta-analysis of studies of mortality in Parkinson's disease (PD) and to investigate which factors were associated with mortality. We conducted comprehensive searches of studies reporting a ratio of mortality in PD versus controls, descriptive survival measures, or factors predicting survival; assessed study quality; and extracted relevant data. Descriptive analysis, meta-analysis, and meta-regression were performed as appropriate. Eighty-eight studies were included in the review with variable study methods and quality. Almost all studies reported increased mortality in PD (vs. controls), with mortality ratios ranging from 0.9 to 3.8, with major between-study heterogeneity. Inception cohorts were more consistent with a pooled mortality ratio of approximately 1.5. Inception cohorts, measurements at longer follow-up duration, and older study recruitment year were associated with lower mortality ratios, but these findings were not robust in sensitivity analyses. Within studies, mortality ratios increased over time. No robust evidence was found that mortality has decreased after the introduction of levodopa (L-dopa). On average, PD survival reduced by approximately 5% every year of follow-up, although there was significant heterogeneity. In post-mortem studies, mean duration until death ranged from 6.9 to 14.3 years. Increasing age and presence of dementia were most commonly associated with increased mortality. Parkinson's disease is associated with increased mortality, but major heterogeneity is seen in estimates of mortality, which is probably explained by variable methodology and patient selection. Individual-patient-data meta-analysis of high-quality inception studies with long-term follow-up would be the optimal way to investigate the factors influencing mortality.

Cerebrospinal fluid lysosomal enzymes and alpha-synuclein in Parkinson's disease.

Abstract: To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β-glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α-synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β-glucocerebrosidase, β-mannosidase, β-hexosaminidase, and β-galactosidase were measured with established enzymatic assays, while α-synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β-glucocerebrosidase-encoding gene (GBA1). In the PD group, β-glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β-hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α-synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α-synuclein oligomers, with a higher oligomeric/total α-synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β-glucocerebrosidase activity, oligomeric/total α-synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD.

Cognitive deficits in Parkinson's disease: A cognitive neuroscience perspective

Abstract: Progress in characterization of the nature, neural basis, and treatment of cognitive deficits in Parkinson's disease is reviewed from the perspective of cognitive neuroscience. An initial emphasis on fronto-striatal executive deficits is surveyed along with the discoveries of disruption as well as remediation of certain impairments by dopaminergic mediation and their association with theories of reinforcement learning. Subsequent focus on large cohorts has revealed considerable heterogeneity in the cognitive impairments as well as a suggestion of at least two distinct syndromes, with the dopamine-dependent fronto-striatal deficits being somewhat independent of other signs commonly associated with Parkinson's disease dementia. The utility is proposed of a new, integrated cognitive neuroscience approach based on combining genetic and neuroimaging methodologies with neuropsychological and, ultimately, psychopharmacological approaches.

Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.

Abstract: Parkinson’s disease (PD) is a multifocal degenerative disorder for which there is no cure. The majority of cases are sporadic with unknown etiology. Recent data indicate that untreated patients with de novo PD have increased colonic permeability and that both de novo and premotor patients have pathological expression of α-synuclein (α-syn) in their colon. Both endpoints potentially can serve as disease biomarkers and even may initiate PD events through gut-derived, lipopolysaccharide (LPS)-induced neuronal injury. Animal models could be ideal for interrogating the potential role of the intestines in the pathogenesis of PD; however, few current animal models of PD encompass these nonmotor features. We sought to establish a progressive model of PD that includes the gastrointestinal (GI) dysfunction present in human patients. C57/BL6 mice were systemically administered one dose of either LPS (2.5 mg/kg) or saline and were sacrificed in monthly intervals (n=5 mice for 5 months) to create a time-course. Small and large intestinal permeability was assessed by analyzing the urinary output of orally ingested sugar probes through capillary column gas chromatography. α-Syn expression was assessed by counting the number of mildly, moderately, and severely affected myenteric ganglia neurons throughout the GI tract, and the counts were validated by quantitative optical density measurements. Nigrostriatal integrity was assessed by tyrosine hydroxylase immunohistochemistry stereology and densitometry. LPS caused an immediate and progressive increase in α-syn expression in the large intestine but not in the small intestine. Intestinal permeability of the whole gut (large and small intestines) progressively increased between months 2 and 4 after LPS administration but returned to baseline levels at month 5. Selective measurements demonstrated that intestinal permeability in the small intestine remained largely intact, suggesting that gut leakiness was predominately in the large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity.

Two-Year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease

Abstract: In a 6-month double-blind, placebo-controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON-time without increasing dyskinesia. Further long-term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON-time over 24 months. Other efficacy endpoints included change in ON-time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2-year, controlled study of add-on safinamide in mid-to-late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON-time (without troublesome dyskinesia), OFF-time, activities of daily living, motor symptoms, quality of life, and symptoms of depression.

Cognitive impairment in multiple system atrophy: A position statement by the neuropsychology task force of the MDS multiple system atrophy (MODIMSA) study group

Abstract: Consensus diagnostic criteria for multiple system atrophy consider dementia as a nonsupporting feature, despite emerging evidence demonstrating that cognitive impairments are an integral part of the disease. Cognitive disturbances in multiple system atrophy occur across a wide spectrum from mild single domain deficits to impairments in multiple domains and even to frank dementia in some cases. Frontal-executive dysfunction is the most common presentation, while memory and visuospatial functions also may be impaired. Imaging and neuropathological findings support the concept that cognitive impairments in MSA originate from striatofrontal deafferentation, with additional contributions from intrinsic cortical degeneration and cerebellar pathology. Based on a comprehensive evidence-based review, the authors propose future avenues of research that ultimately may lead to diagnostic criteria for cognitive impairment and dementia associated with multiple system atrophy.

Coordinated reset neuromodulation for Parkinson's disease: proof-of-concept study.

Abstract: Background The discovery of abnormal synchronization of neuronal activity in the basal ganglia in Parkinson's disease (PD) has prompted the development of novel neuromodulation paradigms. Coordinated reset neuromodulation intends to specifically counteract excessive synchronization and to induce cumulative unlearning of pathological synaptic connectivity and neuronal synchrony. Methods In this prospective case series, six PD patients were evaluated before and after coordinated reset neuromodulation according to a standardized protocol that included both electrophysiological recordings and clinical assessments. Results Coordinated reset neuromodulation of the subthalamic nucleus (STN) applied to six PD patients in an externalized setting during three stimulation days induced a significant and cumulative reduction of beta band activity that correlated with a significant improvement of motor function. Conclusions These results highlight the potential effects of coordinated reset neuromodulation of the STN in PD patients and encourage further development of this approach as an alternative to conventional high-frequency deep brain stimulation in PD. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse

Abstract: Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial.

Norepinephrine deficiency in Parkinson's disease: The case for noradrenergic enhancement

Abstract: The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long- established identity of Parkinson's disease (PD) as primar- ily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodege- nerative sequence of PD. Growing evidence supports ear- lier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sym- pathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked defi- ciency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have under- gone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibi- tion, presynaptic a2-adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydrox- yphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strat- egies have the potential for augmenting the effects of dopa- minergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE defi- ciency, which may precede development of motor symp- toms, could provide a window of opportunity for neuroprotective interventions. V C 2014 International Parkin-

The Parkinson Anxiety Scale (PAS): Development and validation of a new anxiety scale

Abstract: Existing anxiety rating scales have limited construct validity in patients with Parkinson's disease (PD). This study was undertaken to develop and validate a new anxiety rating scale, the Parkinson Anxiety Scale (PAS), that would overcome the limitations of existing scales. The general structure of the PAS was based on the outcome of a Delphi procedure. Item selection was based on a canonical correlation analysis and a Rasch analysis of items of the Hamilton Anxiety Rating Scale (HARS) and the Beck Anxiety Inventory (BAI) from a previously published study. Validation was done in a cross-sectional international multicenter study involving 362 patients with idiopathic PD. Patients underwent a single screening session in which the PAS was administered, along with the Hamilton Depression Rating Scale, the HARS, and the BAI. The Mini International Neuropsychiatric Interview was administered to establish Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses of anxiety and depressive disorders. The PAS is a 12-item observer or patient-rated scale with three subscales, for persistent, episodic anxiety and avoidance behavior. Properties for acceptability and reliability met predetermined criteria. The convergent and known groups validity was good. The scale has a satisfactory factorial structure. The area under the receiver operating characteristics curve and Youden index of the PAS are higher than that of existing anxiety rating scales. The PAS is a reliable and valid anxiety measure for use in PD patients. It is easy and brief to administer, and has better clinimetric properties than existing anxiety rating scales. The sensitivity to change of the PAS remains to be assessed.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor.

Abstract: Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N-methyl-D-aspartate receptor (NMDAR). We measured autoantibodies against NMDAR and dopamine-2 receptor (D2R) expressed at the cell surface in the stored acute serum of 9 children with HSE, 3 of whom had a relapsing course with chorea. The 3 patients with chorea had elevated autoantibodies against NMDAR (n = 1), D2R (n = 1), or both (n = 1), whereas patients without chorea were negative (n = 6). The prospectively identified patient with chorea and NMDAR autoantibodies improved after early treatment with steroids, intravenous immunoglobulin, and cyclophosphamide, with reduction in serum NMDAR antibody titers. These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.

Diagnostic Criteria for Huntington's Disease Based on Natural History

Abstract: Huntington's disease (HD) is currently diagnosed based on the presence of motor signs indicating 99% "diagnostic confidence" for HD. Recent advances in the understanding of HD natural history and neurobiology indicate that disease-related brain changes begin at least 12 to 15 years before the formal diagnosis based on motor onset. Furthermore, subtle motor dysfunction, cognitive changes, and behavioral alterations are often seen before diagnosis made according to the current criteria. As disease-modifying treatments are developed, likely beginning therapy early will be desirable. We therefore suggest that expanded diagnostic criteria for HD should be adapted to better reflect the natural history of the disease, to enable the conduct of clinical trials in premanifest subjects targeting prevention of neurodegeneration, and to facilitate earlier symptomatic treatment. We propose a new set of criteria for HD diagnostic categories in the International Classification of Diseases that reflect our current understanding of HD natural history and pathogenesis. Based on defined criteria, for example, the Diagnostic Confidence Level and the Total Functional Capacity scales of the Unified Huntington's Disease Rating Scale, HD should be divided in the categories "genetically confirmed" with the subcategories "presymptomatic," "prodromal," and "manifest" and "not genetically confirmed" subdivided into "clinically at risk," "clinically prodromal," and "clinically manifest."

Paroxysmal dyskinesias revisited: A review of 500 genetically proven cases and a new classification

Abstract: Paroxysmal movement disorders are a heterogeneous group of conditions manifesting as episodic dyskinesia with sudden onset and lasting a variable duration. Based on the difference of precipitating factors, three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), non-kinesigenic (PNKD), and exercise induced (PED). The elucidation of the genetic cause of various forms of paroxysmal dyskinesia has led to better clinical definitions based on genotype-phenotype correlations in the familial forms. However, it has been increasingly recognized that (1) there is a marked pleiotropy of mutations in such genes with still expanding clinical spectra; and (2) not all patients clinically presenting with either PKD, PNKD, or PED have mutations in these genes. We aimed to review the clinical features of 500 genetically proven cases published to date. Based on our results, it is clear that there is not a complete phenotypic-genotypic correlation, and therefore we suggest an algorithm to lead the genetic analyses. Given the fact that the reliability of current clinical categorization is not entirely valid, we further propose a novel classification for paroxysmal dyskinesias, which takes into account the recent genetic discoveries in this field.

Multisource ascertainment of Huntington disease in Canada: Prevalence and population at risk

Abstract: There is uncertainty surrounding the accuracy of prevalence estimates for Huntington's disease (HD). The aims of this study were to provide a best estimate of the prevalence and population at risk for HD in the province of British Columbia (BC), Canada, in 2012. HD patients with a clinical and/or genetic diagnosis of HD and individuals at risk for HD were ascertained from multiple sources. Clinical and genetic data were obtained from all available medical, social service, and genetic testing records. Six hundred and thirty-one HD patients and 3,763 individuals at 25% or 50% risk for HD were identified. Prevalence of HD was estimated at 13.7 per 100,000 (95% confidence interval [CI]: 12.6-14.8 per 100,000) in the general population, and 17.2 per 100,000 (95% CI: 15.8-18.6 per 100,000) in the Caucasian population. The population at 25% to 50% risk was estimated at 81.6 per 100,000 (95% CI: 79.0-84.2 per 100,000) individuals. These figures suggest there may be up to 4,700 individuals affected with HD and 14,000 at 50% risk for HD in Canada as well as up to 43,000 individuals affected with HD and 123,000 at 50% risk for HD in the United States. This is the first direct assessment of HD epidemiology in Canada in over three decades. These findings suggest that underascertainment may have led to previous underestimates of prevalence, namely, in Caucasian populations, and will aid in the planning of appropriate resource allocation and service delivery for the HD community.

Neuropathology of multiple system atrophy: new thoughts about pathogenesis.

Abstract: Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA-P and MSA-C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA-C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded α-Synuclein (α-Syn). In addition to the ectopic appearance of α-Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of α-Syn-triggered neurodegeneration are not completely understood, neuron-to-oligodendrocyte transfer of α-Syn by prion-like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system-specific pattern of neurodegeneration.

The past, present, and future of telemedicine for Parkinson's disease.

Abstract: Travel distance, growing disability, and uneven distribution of doctors limit access to care for most Parkinson's disease (PD) patients worldwide. Telemedicine, the use of telecommunications technology to deliver care at a distance, can help overcome these barriers. In this report, we describe the past, present, and likely future applications of telemedicine to PD. Historically, telemedicine has relied on expensive equipment to connect single patients to a specialist in pilot programs in wealthy nations. As the cost of video conferencing has plummeted, these efforts have expanded in scale and scope, now reaching larger parts of the world and extending the focus from care to training of remote providers. Policy, especially limited reimbursement, currently hinders the growth and adoption of these new care models. As these policies change and technology advances and spreads, the following will likely develop: integrated care networks that connect patients to a wide range of providers; education programs that support patients and health care providers; and new research applications that include remote monitoring and remote visits. Together, these developments will enable more individuals with PD to connect to care, increase access to expertise for patients and providers, and allow more-extensive, less-expensive participation in research.

Cognition in corticobasal syndrome and progressive supranuclear palsy: A review

Abstract: Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) represent challenging neurodegenerative disorders for clinicians and nonclinical scientists alike. Although initially lumped together as "Parkinson's-Plus" syndromes, CBS and PSP are clinically and pathologically distinct from Parkinson's disease. It is now clear that behavioral and cognitive changes are common in both syndromes and affect impact quality of life and carer burden considerably. We briefly review the clinical, pathological, and neuroradiological features of each syndrome, followed by more detailed descriptions of the behavioral and cognitive deficits encountered in CBS and PSP. Clinically and pathologically heterogeneous, CBS is characterized by a wide range of cognitive and behavioral disturbances. impairments in executive function and memory are common, but nonspecific. In contrast, deficits in language and visuospatial abilities appear to be more distinctive features of CBS; the relevance of specific patterns of impairment to the underlying histopathology, or prognosis, remains to be fully elucidated. As in CBS, behavioral and cognitive changes are almost universal in PSP, with a wide range of reported deficits. Apathy is very common, often paradoxically accompanied by impulsivity. Executive dysfunction is prominent, but memory and visuospatial deficits also occur. An emerging field is the study of social cognition, which appears impaired in both syndromes. As therapeutic strategies for neurodegenerative pathologies emerge, more specific diagnostic tools in CBS and PSP will be required. Careful clinicopathological correlation, and the development of biomarkers for specific histopathologies, will be important milestones on the road to effective treatments.

Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial.

Abstract: It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high-resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: -1.3% ± 1.4% vs. -3.1% ± 2.3%, respectively), cerebrum (-1.3% ± 1.5% vs. -3.2% ± 2.1%, respectively), parietal lobe (-1.6% ± 1.9% vs. -4.1% ± 3.0%, respectively), and occipital lobe (-0.3% ± 1.8% vs. -2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.