Faculty Bibliography

Objective: Epilepsy is not a common co-morbidity of Parkinson's disease (PD). We report a case series of individuals with coexisting PD and epilepsy. Methods: Among the 1,200 patients with idiopathic PD at our institution, we identified seven with coexisting idiopathic seizure disorder. Subjects with documented or suspected secondary epilepsy were not included in this report. We could not obtain full clinical information on seizure history on one subject who was therefore excluded. Results: Of the 6 subjects included (3 Men, 3 Women; Ages 49-85; PD disease duration 1-15 years), 2 had seizures after PD onset (10 and 7 years after PD onset), 3 had adult-onset seizures before PD (6, 14, and 15 years before PD onset), and 1 subject had pediatric-onset seizures before PD (age 13). Three subjects had complex partial seizures, one of whomdeveloped 2 secondary generalized seizures, and three subjects had simple partial seizures. At last observation, one subject was H&Y stage 4, one was 2.5, three were 2, and one was 1. Based on UPDRS-I, 2 subjects exhibited mild cognitive impairment, 2 had moderate impairment, and 2 had no impairment. Conclusions: Although rare, epilepsy can coexist with PD. While this may be a chance association, it is possible that abnormal intracortical excitability in PD[1] may predispose patients to seizures. This limited data also suggests that patients with coexisting epilepsy may be at higher risk of developing cognitive impairment

Dopamine agonist withdrawal syndrome (DAWS) has been reported in patients with Parkinson's disease (PD) who rapidly decrease or stop their dopamine agonist (DA) treatment. Retrospective studies suggest a high prevalence of DAWS (14%-18%) in PD, but there are no prospective studies. We report data from the first pilot European multicenter prospective study addressing the frequency of probable DAWS (Rabinak-Nirenberg criteria) in PD patients. The self-completed Nonmotor Symptoms Questionnaire (which addresses the core features of DAWS) was administered at clinical follow-up at 1 month in 51 patients (33 male; mean age: 73.0 ± 9.9 years; PD duration: 12.2 ± 6.3 years) who had discontinued dopamine agonists. Twelve out of fifty-one patients (24%) met clinical criteria for DAWS, the most common symptoms of which were anxiety (91.7%), pain (50%), sweating (41.7%), and anhedonia (16.7%), after the withdrawal of a DA (ropinirole, pramipexole, or cabergoline). In this first prospective evaluation of DAWS in the clinic, preliminary data indicate a high rate after discontinuation of a range of DAs, particularly in the context of impulse control disorders. Larger, controlled studies are required to establish a definitive management pathway.

Impulse control disorders in Parkinson's disease are a group of impulsive behaviors most often associated with dopaminergic treatment. Presently, there is a lack of high quality evidence available to guide their management. This manuscript reviews current management strategies, before concentrating on the concept of dopamine agonist withdrawal syndrome and its implications for the management of impulse control disorders. Further, we focus on controversies, including the role of more recently available anti-parkinsonian drugs, and potential future approaches involving routes of drug delivery, nonpharmacological treatments (such as cognitive behavioral therapy and deep brain stimulation), and other as yet experimental strategies. (c) 2015 International Parkinson and Movement Disorder Society.

BACKGROUND AND PURPOSE: Cerebral mitochondrial dysfunction has been observed in Parkinson's disease (PD). If mitochondrial dysfunction is an early event contributing to PD development, then noninvasive techniques that detect disturbed energy metabolism in vivo might be useful tools for early diagnosis and treatment monitoring. In the present study, we tested the hypothesis that proton (1 H) and phosphorus (31 P) magnetic resonance spectroscopy (MRS) measures of brain metabolites are able to differentiate between individuals with early PD and healthy volunteers (HVs). METHODS: During this cross-sectional study including 20 subjects with early PD and 15 age-matched HV, ventricular lactate (anaerobic glycolysis); and regional levels of N-acetylaspartate (neuronal integrity); choline (membrane turnover); creatine (energy metabolism); ATP and other phosphate-containing compounds (oxidative phosphorylation) were determined using brain 1 H and 31 P MRS. RESULTS: No metabolic abnormalities were detectable in early-stage PD patients. Metabolite concentrations were not related to age, disease duration, or Unified Parkinson's Disease Rating Scale motor scores. DISCUSSION: In early PD, neither 1 H nor 31 P MRS were able to detect metabolic abnormalities, a finding that is in contrast to published data in more advanced PD cohorts. MRS under dynamic conditions might uncover latent energy deficits in early PD, thus warranting future study.

Parkinson's disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation (GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins' fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of "footprint-free" iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had approximately 50% GBA enzymatic activity, approximately 3-fold elevated alpha-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin's neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized alpha-synuclein and dopamine levels, suggesting a combination therapy for the affected twin.

IMPORTANCE Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00740714.