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Parkinson's disease is a neurological disease which involves the selective destruction of some brain cells preferentially over others. The brain is able to compensate for considerable damage, and the available evidence suggests that the symptoms of Parkinson's disease appear only after the destruction of neurons (nerve cells) surpasses the brain's ability for compensation. Parkinson's disease largely results from the destruction of special brain cells within a region called the substantia nigra; by some estimates as many as 90 percent of these neurons may be destroyed before the brain can no longer compensate and disease symptoms appear. Therefore, the disease is present, and destroying neurons in the substantia nigra, long before it is recognized by the patient and physician. Evidence is accumulating that the drug selegiline may significantly slow the progression of Parkinson's disease, and so the initiation of treatment prior to the onset of symptoms might provide important clinical benefit. Just how long is Parkinson's disease present before the symptoms actually appear? Since there is no reliable test for the presence of Parkinson's disease, there is no way of answering with certainty. However, estimates may be made on the basis of neuropathological observations of brain tissue specimens obtained at autopsy. The characteristic pathological observation in Parkinson's disease is the Lewy body, which is a structure visible in the cytoplasm of some brain cells under the microscope. Lewy bodies are also found in cells of the substantia nigra of about 10 percent of people over age 60 who do not have symptoms of Parkinson's disease. If the assumption is made that Lewy bodies represent an early stage in the long progression towards brain cell destruction, then calculations suggest that the delay between the appearance of Lewy bodies and the development of the symptoms of Parkinson's disease must be about 30 years. The cells of the substantia nigra may be examined, of course, only at autopsy, and so other means must be found to diagnose Parkinson's disease in its presymptomatic stages. The search is underway to evaluate many techniques of medical imaging, biochemical analysis, and genetic screening for the diagnosis of presymptomatic Parkinson's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objectives: To examine the distribution of striatal dopaminergic function in humans with parkinsonism induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) to determine if there is a caudate-putamen gradient as is seen in idiopathic Parkinson's disease.Methods: We scanned nine humans exposed to MPTP with parkinsonism ranging from minimal to severe using [(18)F]fluorodopa (FD) and high resolution PET. The results were compared with those of 10 patients with Parkinson's disease and six normal subjects.Results: In the MPTP group there was an equal degree of reduction of dopaminergic function in the caudate and putamen. This was different from the greater putaminal than caudate loss in Parkinson's disease (p<0.001).Conclusions: Parkinson's disease is not caused by transient exposure to MPTP. [ABSTRACT FROM AUTHOR]

Background: IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD)., Methods: In this open-label study, patients underwent 6weeks of conversion to IPX066 from their prior controlled-release (CR)±immediate-release (IR) CD-LD therapy and 6months of maintenance (with an additional 6months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance., Results: Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5times/day compared with 2.6times/day for CR plus 4.6times/day for IR previously (and 4.7times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance, ≥43.8% of patients were much or very much improved from their previous treatment, and ≥68.8% were at least minimally improved. Adverse events were consistent with those reported in prior IPX066 studies., Conclusions: These results suggest that advanced PD patients using CR CD-LD±IR can be safely converted to IPX066, with high likelihood of achieving a stable regimen, less frequent LD dosing, and improved overall clinical benefit., Trial Registration: Clinicaltrials.govNCT01411137., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

The purpose of this study was to assess the genotype-phenotype of PINK1 mutations. We genotyped eight known mutations in three clinic-based cohorts with Parkinsonism and found one homozygous p.L347P mutation in PINK1. Clinically, hypo-osmia and profound diurnal variation of symptoms were identified as novel features; fluorodopa positron emission tomography revealed striking decline in striatal fluorodopa uptake. We suggest that it may be possible to clinically separate this form of Parkinsonism from dopa-responsive dystonia and Parkin-related Parkinsonism. Furthermore, as this mutation has only been reported in Filipinos (two originated from Luzon island), our results support the hypothesis of a common founder.

Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction.

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.

Background: Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism., Methods: We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation., Results: Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications., Conclusions: Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.

The olfactory function of 6 patients whose parkinsonism was the result of intravenous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was compared to that of 12 age-matched patients with idiopathic Parkinson's disease (PD) and 10 age-matched normal control subjects. Unlike their PD counterparts, the olfactory test scores of patients with MPTP-induced parkinsonism did not differ significantly from those of control subjects. These findings suggest that MPTP-induced parkinsonism, unlike idiopathic PD, is unaccompanied, on average, by major alterations in the ability to smell.

There is convincing evidence that monotherapy with 10 mg of selegiline daily substantially delays parkinsonian disability, although whether this delay is due to a symptomatic or protective mechanism remains a matter of debate. Evidence against a symptomatic effect is that the wash-out evaluation in two double-blind, placebo-controlled studies failed to detect clinical decline 1 month after discontinuing selegiline. Yet it can be argued that 1 month was not long enough to eliminate the biologic effect of the drug. Thus further studies are required to answer this question definitively. Nonetheless, because selegiline delays the requirement for levodopa therapy and appears to be relatively safe when used as monotherapy, it seems reasonable to recommend this drug as initial treatment when Parkinson's disease is first diagnosed. There is little doubt that future therapeutic and diagnostic strategies for Parkinson's disease and other neurodegenerative diseases will be profoundly influenced if this drug is unequivocally demonstrated to slow progression of Parkinson's disease. Such a finding would be a potent argument for developing biomarkers of preclinical disease because early intervention with such protective therapy might even halt the disease before symptoms develop.

We assessed clinical and electrophysiologic characteristics of tremor in patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Four of seven patients with moderate to severe MPTP-induced parkinsonism exhibited a tremor indistinguishable from the characteristic rest tremor of Parkinson's disease (PD). The pathology induced by MPTP in one human case is confined to the substantia nigra, but in nonhuman primates, the locus ceruleus or the ventral tegmental area can also be affected. These findings suggest that the pathophysiology of rest tremor in PD might result from damage to either the substantia nigra alone or in combination with damage to one or more of these other regions.

In human and subhuman primates, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces irreversible clinical, biochemical and neuropathological alterations highly reminiscent of those observed in Parkinson's disease. The MPTP model has provided the best available tool to date for the assessment of efficacy and side-effects of symptomatic treatments of Parkinson's disease. In addition, the mechanism of action of MPTP has offered a basis for the development of novel therapeutic strategies aimed at the prevention of Parkinson's disease.

The effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that produces the symptoms of Parkinson's disease, can be fully prevented in experimental animals by inhibiting monoamine oxidase B. On the basis of this observation, a double-blind, placebo-controlled study in patients with early Parkinson's disease was initiated to determine whether deprenyl (a selective monoamine oxidase B inhibitor) would delay the need for L-dopa therapy by slowing the progression of the disease. Fifty-four patients were randomly assigned to deprenyl (10 mg/day) or placebo treatment groups and followed until L-dopa therapy was indicated or until the patient had been in the study for 3 years. Analysis of Kaplan-Meier survival curves for each group showed that deprenyl delayed the need for L-dopa therapy; the average time until L-dopa was needed was 312.1 days for patients in the placebo group and 548.9 days for patients in the deprenyl group. Disease progression, as monitored by five different assessment scales, was slowed (by 40 to 83% per year) in the deprenyl group compared to placebo. Therefore, early deprenyl therapy delays the requirement for antiparkinsonian medication, possibly by slowing progression of the disease.

The selective monoamine oxidase (MAO) B inhibitor L-deprenyl (Eldepryl, Jumex, Movergan, Selegiline) has gained acceptance as a useful form of adjunctive therapy in the treatment of Parkinson's disease. It has recently been suggested that deprenyl might be effective in altering the course of Parkinson's disease by actually slowing its progression. The rationale for this "new therapeutic strategy" rests on several lines of evidence which can be categorized as theoretical, experimental and empirical. We present details of an "in progress" double-blind, placebo-controlled, prospective clinical drug trial using deprenyl in patients with early, untreated Parkinson's disease. This study is designed to directly test the hypothesis that deprenyl may be effective in favorably altering its natural history. Rigorously testing this new hypothesis could have a major impact on current concepts regarding the treatment and management of Parkinson's disease.

Seven patients developed chronic and severe parkinsonism after repeatedly injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously. Levodopa and bromocriptine controlled the symptoms; however, within months, five of the seven patients experienced dyskinesias or on-off fluctuations. Therefore, neither prolonged levodopa treatment nor progressive disease was necessary for on-off phenomena. Because the neurotoxic effects of MPTP seem limited to the substantia nigra, damage to this system alone may produce all the motor features of Parkinson's disease. MPTP differs from other neurotoxins in that it consistently produces a pure parkinsonian state.