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A total of 956 individuals with Parkinson's disease (PD) from 430 multiplex PD pedigrees were screened for 12 previously reported, pathogenic LRRK2 mutations: R793M, L1114L, I1371V, R1441C, R1441G, R1441H, Y1699C, M1869T, I2012T, I2020T, G2385R, and IVS31 +3G > A. Previous screening identified the LRRK2 G2019S mutation in 5% of our families. Only 1 of the 12 newly screened mutations, R1441C, was detected in a single family in our patient cohort. These results indicate that, although the G2019S mutation remains the most common mutation identified in familial PD patients, other mutations in LRRK2 are infrequent.

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.

Background Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. Methods In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. Results Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. Conclusion Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

OBJECTIVE To report the results of the 12-week, prospective, open label extension of the 4-week, multicenter, placebo-controlled, double-blind PSYCLOPS (PSYchosis and CLOzapine in the treatment of Parkinsonism) trial. This extension examined the chronic safety and efficacy of clozapine in the treatment of drug-induced psychosis in Parkinson's disease (PD). BACKGROUND Psychosis is a serious late complication of PD and may be a harbinger to increased mortality. Clozapine, the first atypical antipsychotic, was shown in several small open label studies to improve psychosis without worsening of motor symptoms. This was recently confirmed in the double-blind PSYCLOPS trial. METHODS The 53 patients who completed the double-blind portion of PSYCLOPS were evaluated on their original randomized treatment (clozapine or placebo), then had study medication stopped. All were started on clozapine. The patients from both treatment groups were evaluated every 4 weeks over a 12-week period using standardized measures for psychosis and PD. RESULTS The mean dose of clozapine was 28.78 mg/day. Those originally treated with placebo improved significantly in Brief Psychiatric Rating Scale and clinical global scores for psychosis to the same degree as the group originally randomized to clozapine in the double-blind study. Both groups maintained their response to week 16 (end of the combined double-blind and open label portions). There was no worsening of motor features as measured by the Unified Parkinson's disease rating scale. Eighteen patients were either hospitalized or died during the trial. The most common reasons were pulmonary. CONCLUSIONS Low-dose clozapine is effective in treating drug-induced psychosis without worsening motor features of PD, and the response is maintained for at least 4 months. Patients with psychosis and PD were previously described as a group with high risk for morbidity and mortality. The high risk continues despite antipsychotic therapy. Mov. Disord. 16:135–139, 2001. © 2001 Movement Disorder Society.

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.

The epsilon4 allele of the apolipoprotein E gene (APOE4) has been consistently associated with a greater risk of Alzheimer's disease (AD) as well as an earlier onset of AD. It is possible that APOE4 may also play a role in the etiology of other neurodegenerative disorders, such as Parkinson's disease (PD). APOE genotype, age of onset, disease duration, smoking history, and dementia status were collected for families with PD, yielding 324 Caucasian families with complete information. Logistic regression employing one individual per family and including age of onset and disease duration as covariates demonstrated a significantly increased risk of dementia for those individuals having inherited at least one epsilon4 allele (OR=3.37; P=0.002). Survival analyses also demonstrated a significantly earlier age of onset for those subjects with at least one epsilon4 allele (59.7 years) as compared with those homozygous for the more common epsilon3 allele (62.4 years; P=0.009). Thus, consistent with previous studies, we find evidence that the presence of an epsilon4 allele results in significantly earlier onset of PD and a greater likelihood of dementia. It appears the similarities between PD and AD may be due to an overlap in the diseases' genetic etiology.

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

Four open-label studies have reported beneficial effects of clozapine on the tremor of idiopathic Parkinson's disease (PD). We performed a double-blind crossover trial with a 2-week washout, comparing low-dose clozapine to benztropine for the treatment of tremor in PD. Twenty-two subjects enrolled and 19 completed the study. Benztropine and clozapine were equally effective in improving tremor and the motor score of the United Parkinson's Disease Rating Scale at mean doses of 3.0 and 39 mg/day, respectively. Significant adverse events were experienced with each drug, but leukopenia was not encountered. We conclude that the atypical antipsychotic drug clozapine is helpful in the treatment of tremor in PD and should be considered when all other drug therapies fail.

A patient with Alzheimer's disease and mild features of parkinsonism was treated with tacrine. Tremor and gait dysfunction worsened but responded to the addition of levodopa without adversely affecting cognitive function. The implications for experimental treatment strategies of patients with combined Alzheimer's and Parkinson's disease are discussed.

Clozapine is an atypical neuroleptic medication that is free of parkinsonian side effects and that has been reported to ameliorate the tremor of Parkinson's disease. We report (with videotape illustration) the dramatic improvement of severe yet classic rest tremors in one elderly nonpsychotic patient with Parkinson's disease and significant improvement in four others. We believe that clozapine, in low doses, may be a useful medication for the treatment of rest tremor in Parkinson's disease, even in cases without mental abnormalities.

Long-term management of patients with Parkinson's disease includes close monitoring and frequent dose adjustment. In a small selected group of patients, complete withdrawal of L-dopa (drug holiday) and slow reintroduction of lower doses of this drug assured continued benefit for six to 24 months. We studied 45 drug holidays in 45 patients with idiopathic Parkinson's disease. Average preholiday L-dopa dose was 2,970 mg/d; at 24 months, it was 263 mg/d. The drug holiday resulted in reduced adverse drug effects (dyskinesias, "on-off" phenomenon, hallucinations, and confusion), and improved functional ratings at one, six, 12, and 24 months after the drug holiday.

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Nineteen patients with mild-to-moderate Parkinson's disease completed a 1-year open label study of a controlled release preparation of carbidopa/L-DOPA (Sinemet CR). Twelve patients were thought to have improved compared with baseline, and only one was worse. The total daily dose of L-DOPA was not significantly changed, but dosing frequency was almost halved. Patients with complex drug schedules on standard Sinemet liked the drug most. "Wearing off" patients also benefitted from the change, whereas "on/off" patients did not do significantly better on Sinemet CR.

This article gives an overview of Parkinson's disease, a common neurological disorder. Inpatient care at Boston University Medical Center is discussed, stressing the importance of a comprehensive team approach to the patient with moderate to severe parkinsonism. Management of the patient during a drug holiday is discussed. A case history including a nursing care plan is presented. Guidelines, protocols, and nursing care standards for the care of the patient with parkinsonism are discussed.

Clozapine is an antipsychotic medication that is virtually free of ertrapyramidal side effects. We report our successful treatment of 6 patients with idiopathic Parkinson9s disease and various psychoses using clozapine on a chronic basis along with carbidopa/L-dopa.