Jay S. Schneider

Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results

We present a clinimetric assessment of the Movement Disorder Society (MDS)‐sponsored revision of the Unified Parkinsons Disease Rating Scale (MDS‐UPDRS). The MDS‐UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS‐UPDRS has four parts, namely, I: Non‐motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item‐specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS‐UPDRS (65 items) to 877 English speaking (78% non‐Latino Caucasian) patients with Parkinsons disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS‐UPDRS showed high internal consistency (Cronbachs alpha = 0.79–0.93 across parts) and correlated with the original UPDRS (ρ = 0.96). MDS‐UPDRS across‐part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.

Parkinson's disease: sensory and motor problems in arms and hands.

Fifteen undemented patients with Parkinsons disease (PD) and 15 age-matched controls were given a battery of tests to assess sensorimotor integration in the arms. PD patients made more errors (p < 0.01) than controls, particularly in tests of proprioception. Age was not related to errors. Compared with controls, two-point discrimination thresholds were significantly higher (p <0.02) on the index finger of PD patients, but not on the forearm. Results confirm the sensorimotor deficits found earlier in an orofacial study, and imply that PD involves a generalized dysfunction of sensorimotor integration and proprioception, probably a result of impaired basal ganglia function in processing and integrating sensory input to organize and guide movement.

Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates

We tested the hypothesis that movement abnormalities induced by chronic manganese (Mn) exposure are mediated by dysfunction of the nigrostriatal dopamine system in the non-human primate striatum. Motor function and general activity of animals was monitored in parallel with chronic exposure to Mn and Positron Emission Tomography (PET) studies of in vivo dopamine release, dopamine transporters and dopamine receptors in the striatum. Analysis of metal concentrations in whole blood and brain was obtained and post-mortem analysis of brain tissue was used to confirm the in vivo PET findings. Chronic Mn exposure resulted in subtle motor function deficits that were associated with a marked decrease of in vivo dopamine release in the absence of a change in markers of dopamine (DA) terminal integrity or dopamine receptors in the striatum. These alterations in nigrostriatal DA system function were observed at blood Mn concentrations within the upper range of environmental, medical and occupational exposures in humans. These findings show that Mn-exposed non-human primates that exhibit subtle motor function deficits have an apparently intact but dysfunctional nigrostriatal DA system and provide a novel mechanism of Mn effects on the dopaminergic system.

Dopaminergic Neurons Derived from Human Induced Pluripotent Stem Cells Survive and Integrate into 6-OHDA-Lesioned Rats

Cell replacement therapy could be an important treatment strategy for Parkinsons disease (PD), which is caused by the degeneration of dopamine neurons in the midbrain (mDA). The success of this approach greatly relies on the discovery of an abundant source of cells capable of mDAergic function in the brain. With the paucity of available human fetal tissue, efforts have increasingly focused on renewable stem cells. Human induced pluripotent stem (hiPS) cells offer great promise in this regard. If hiPS cells can be differentiated into authentic mDA neuron, hiPS could provide a potential autologous source of transplant tissue when generated from PD patients, a clear advantage over human embryonic stem (hES) cells. Here, we report that mDA neurons can be derived from a commercially available hiPS cell line, IMR90 clone 4, using a modified hES differentiation protocol established in our lab. These cells express all the markers (Lmx1a, Aldh1a1, TH, TrkB), follow the same mDA lineage pathway as H9 hES cells, and have similar expression levels of DA and DOPAC. Moreover, when hiPS mDA progenitor cells are transplanted into 6-OHDA-lesioned PD rats, they survive long term and many develop into bona fide mDA neurons. Despite their differentiation and integration into the brain, many Nestin+ tumor-like cells remain at the site of the graft. Our data suggest that as with hES cells, selecting the appropriate population of mDA lineage cells and eliminating actively dividing hiPS cells before transplantation will be critical for the future success of hiPS cell replacement therapy in PD patients.

Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): Implications to manganese-induced parkinsonism

The long‐term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally‐exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using positron emission tomography (PET) in the non‐human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3–5.0 mg Mn/kg (n = 4), 5.0–6.7 mg Mn/kg (n = 5), or 8.3–10.0 mg Mn/kg (n = 3) for 7–59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine‐induced DA release measured by PET is markedly impaired in the striatum of Mn‐exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post‐mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals.

Enriched environment during development is protective against lead-induced neurotoxicity

It is known that children of lower socioeconomic status have a disproportionately higher risk of being exposed to lead and have a more negative outcome from that exposure than children who are raised under more fortunate circumstances. Yet, little is known about how environmental factors may influence the injurious effects on the brain of a neurotoxin such as lead. The present study used an animal model of lead poisoning to examine the extent to which different environmental milieus may modify the effects of lead on the developing brain. Young rats were raised in either enriched or impoverished environments and drank either distilled water or water with lead. Lead-exposed rats raised in the impoverished environment had spatial learning deficits and significantly decreased neurotrophic factor gene expression in the hippocampus. In contrast, the animals raised in the enriched environment were significantly protected against the behavioral and neurochemical toxicity of lead. These results demonstrate that impoverished environment may accentuate while enriched environment may ameliorate neurobehavioral and neurochemical toxicity from developmental lead exposure.

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00449865.

Attention and executive function deficits in chronic low-dose MPTP-treated non-human primates.

Parkinsons disease (PD) is a complex disorder consisting of motor deficits coupled with dysfunction in cognitive domains that are dependent upon the integrity of the frontal lobes and/or the fronto‐striatal axis. Although it is increasingly acknowledged that PD patients have attentional and executive function deficits, it has been difficult to model these in nonhuman primates because of the nature of the cognitive tasks that have been used previously. The present studies were conducted to further define the nature of the cognitive impairment in a nonhuman primate model of early parkinsonism consequent to chronic low dose MPTP exposure and to further validate this model in monkeys trained to perform a battery of attentional and executive function tasks. Following chronic low dose MPTP exposure, monkeys developed deficits in maintenance of a response set as well problems in shifting attentional sets, suggesting decreased mental flexibility. On other tasks inattentiveness, an impaired ability to sustain spatial attention or to focus attention, a deficit in motor readiness and planning, and impaired time estimation were also observed. These results provide direct evidence of attention and executive function deficits in a nonhuman primate model of early parkinsonism. Based on these findings, we suggest that in addition to being useful for studying the cognitive deficits related to early PD and for developing new therapeutics for these problems, this model and these testing procedures may also provide a useful large animal model for studying attention deficit disorder and for developing new therapeutics for that condition as well.

Effects of chronic manganese exposure on cognitive and motor functioning in non-human primates

Acute exposure to manganese is associated with complex behavioral/psychiatric signs that may include Parkinsonian motor features. However, little is known about the behavioral consequences of chronic manganese exposures. In this study, cynomolgus macaque monkeys were exposed to manganese sulfate (10-15 mg/kg/week) over an exposure period lasting 272+/-17 days. Prior to manganese exposure, animals were trained to perform tests of cognitive and motor functioning and overall behavior was assessed by ratings and by videotaped analyses. By the end of the manganese exposure period, animals developed subtle deficits in spatial working memory and had modest decreases in spontaneous activity and manual dexterity. In addition, stereotypic or compulsive-like behaviors such as compulsive grooming increased in frequency by the end of the manganese exposure period. Blood manganese levels measured at the end of the manganese exposure period ranged from 29.4 to 73.7 micro g/l (mean=55.7+/-10.8 (compared to levels of 5.1-14.2 micro g/l at baseline (mean=9.2+/-2.7)), placing them within the upper range of levels reported for human environmental, medical or occupational exposures. These results suggest that chronic exposure to levels of manganese achieved in this study may have detrimental effects on behavior, cognition and motor functioning.

Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates

Chronic manganese (Mn) exposure produces a neurological syndrome with psychiatric, cognitive, and parkinsonian features. Gene expression profiling in the frontal cortex of Cynomologous macaques receiving 3.3–5.0 mg Mn/kg weekly for 10 months showed that 61 genes were increased and four genes were decreased relative to controls from a total of 6766 genes. Gene changes were associated with cell cycle regulation, DNA repair, apoptosis, ubiquitin‐proteasome system, protein folding, cholesterol homeostasis, axonal/vesicular transport, and inflammation. Amyloid‐β (Aβ) precursor‐like protein 1, a member of the amyloid precursor protein family, was the most highly up‐regulated gene. Immunohistochemistry confirmed increased amyloid precursor‐like protein 1 protein expression and revealed the presence of diffuse Aβ plaques in Mn‐exposed frontal cortex. Cortical neurons and white matter fibers from Mn‐exposed animals accumulated silver grains indicative of on‐going degeneration. Cortical neurons also exhibited nuclear hypertrophy, intracytoplasmic vacuoles, and apoptosis stigmata. p53 immunolabeling was increased in the cytoplasm of neurons and in the nucleus and processes of glial cells in Mn‐exposed tissue. In summary, chronic Mn exposure produces a cellular stress response leading to neurodegenerative changes and diffuse Aβ plaques in the frontal cortex. These changes may explain the subtle cognitive deficits previously demonstrated in these same animals.