Rapid Eye Movement Sleep Behavior Disorder-like Symptoms Due to Arousal Responses Associated with Severe Obstructive Sleep Apnea-hypopnea.

A 78-year-old man suspected of having α-synucleinopathies received a high score on a validated questionnaire for rapid eye movement (REM) sleep behavior disorder (RBD). Although he did in fact have unpleasant dreams and vigorous behaviors, polysomnography (PSG) found only obstructive sleep apnea-hypopnea (OSAH). The RBD-like symptoms corresponded with arousal responses, namely augmented inspiratory effort and leg movements, to his frequent apnea-hypopnea events during REM sleep. Thus, severe OSAH might cause RBD-like symptoms. PSG can discriminate real RBD from RBD-like symptoms associated with severe OSAH and therefore may be essential for determining an appropriate course of treatment in certain patients.

Non-motor symptoms depending on motor severity in Japanese patients with Parkinson's disease: A multicenter cross-sectional study.

BACKGROUND: Although non-motor symptoms (NMS) in patients with Parkinson's disease (PD) often worsen as the severity of motor symptoms (MS) increases, few studies have assessed the associated factors of non-motor symptoms. OBJECTIVE: This study aims to determine whether the presence of NMS in PD patients is associated with or independent from the severity of MS considering confounders. METHODS: The registry of PD patients from seven facilities in Japan was used. Multiple logistic regression was performed with each domain and item of the Non-motor Symptoms Scale (NMSS) as objective variables. Severity of motor symptoms was assessed by Hoehn & Yahr stage (HY stage) as an explanatory variable. The analysis was adjusted for sex, age, disease duration, presence/absence of wearing off and dyskinesia, clinical phenotypes and Levodopa equivalent daily dose. RESULTS: A total of 1037 patients were analyzed. Analysis by NMSS domain showed higher odds ratios (ORs) in patients with higher HY stages compared with patients with lower HY stages for domains D1 (cardiovascular), D2 (sleep/fatigue), D3 (mood/apathy), D4 (perceptual problems/hallucinations), D5 (attention/memory), and D6 (gastrointestinal) (ORs: 1.54-2.72, P < .05). However, only domains D7 (urinary) and D8 (sexual dysfunction) were not associated with HY stage. Item 2 (fainting) and Item 14 (delusions) showed higher ORs in the HY stage 4-5 (ORs: 9.95 and 5.92, P < .05). CONCLUSIONS: Most NMS worsened with exacerbation of MS in PD patients, however some NMS domains were also affected with other factors. These findings contribute to the understanding of the clinical picture of PD and may improve personalized medicine and research in PD.

Repeated anti-N-methyl-D-aspartate receptor encephalitis coexisting with anti-myelin oligodendrocyte glycoprotein antibody-associated diseases: A case report.

The coexistence of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated diseases has been reported. We report the case of a 36-year-old woman who presented with repeated typical anti-NMDAR encephalitis coexisting with unusual symptoms not consistent with anti-NMDAR encephalitis. Apart from the anti-NMDAR encephalitis, her first episode was characterized by balance disability with bilateral medial frontal cortical lesions, suggesting the involvement of the cortico-reticular projections and the basal ganglia-brainstem projections. The second episode presented with Broca's aphasia caused by involvement of the Broca's area and lower part of the precentral gyrus. The detection of MOG-Ab in both episodes suggested the coexistence of MOG-Ab-associated diseases. Thus, an evaluation of MOG-Ab should be considered when anti-NMDAR encephalitis presenting with atypical symptoms is encountered.

Long-Term Selegiline Monotherapy for the Treatment of Early Parkinson Disease.

OBJECTIVES: The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patients with early Parkinson disease (PD). METHODS: We conducted a 56-week prospective study in patients with early PD (N = 134) who had previously completed the randomized, double-blind, placebo-controlled phase III trial of selegiline monotherapy for 12 weeks. In the present study, dosing was titrated from 2.5 to 10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week, the dosage was maintained at 10 mg/d until week 56. The primary outcome was any change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile, were also evaluated. RESULTS: Ninety-one (67.9%) patients completed the 56-week study. Treatment with selegiline significantly reduced total UPDRS score from week 4 (mean ± SD, -2.62 ± 3.83; P < 0.0001) to week 56 (-3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20 (-5.79 ± 5.57; P < 0.0001). In addition, we found similar improvements in the UPDRS parts II and III scores. The incidence rate of adverse drug reactions was 44.3% (58 patients) and did not increase during the period of 10 mg selegiline administration. CONCLUSIONS: Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early PD in this 56-week study.

A Randomized Double-Blind Placebo-Controlled Phase III Trial of Selegiline Monotherapy for Early Parkinson Disease.

BACKGROUND: In Japan, selegiline has been approved for combination therapy with levodopa for Parkinson disease (PD). We conducted a trial of selegiline monotherapy for early PD. METHODS: In this 12-week controlled phase III trial, a total of 292 subjects were randomized to receive placebo (n = 146) (full analysis set 140) or selegiline (n = 146) (full analysis set 139). The primary outcome measure was the change in the Unified Parkinson Disease Rating Scale part I + II + III total score from baseline to the final visit. Other secondary measures and a safety profile were evaluated. RESULTS: Selegiline monotherapy reduced the primary outcome measure by -6.26 ± 7.86 compared with the placebo -3.14 ± 6.98 (mean ± SD, P = 0.0005 by analysis of covariance). There was no significant difference in the number of adverse events between the 2 groups (P > 0.05). CONCLUSIONS: Selegiline monotherapy reduced the total Unified Parkinson Disease Rating Scale part I + II + III score and was well tolerated in Japanese patients with early PD.

Pharmacological treatment of early Parkinson's disease.

Initiation of medical treatment of early stage of Parkinson's disease (PD) is consisted of pharmacological and no-pharmacological treatment. When and which drug is rationale for initial treatment is still controversial except young-onset PD patient. Initial drug should be decided according to patient state, age of onset and present, severity and cognition. Dopamine agonist is rationale for young-onset PD patient at early stage. Disease modify therapy is not established.

Serum Tyrosine-to-Phenylalanine Ratio is Low in Parkinson's Disease.

BACKGROUND: Noninvasive biomarkers for Parkinson's disease (PD) are currently unavailable. OBJECTIVE: To search for a biomarker unique to PD in sweat and serum. METHODS: Sweat samples in 42 PD patients and 16 controls were analyzed using liquid chromatography/mass spectrometry (LC/MS). The principal component analysis (PCA) and the orthogonal projections to latent structures (OPLS) analysis were employed. Serum Phe and Tyr levels were determined using the HPLC-fluorescence detection system in 28 de novo PD patients, 52 L-Dopa-treated PD patients, and 27 controls. RESULTS: PCA and OPLS analyses of LC/MS of sweat samples revealed that Tyr, Phe, Leu (Ile), and Asp have high effect sizes to differentiate PD and controls. As Phe and Tyr are precursors of dopamine, we quantified the serum Phe and Tyr levels in de novo and treated PD patients, as well as in controls. Phe was high in de novo patients, but not in treated patients. In contrast, Tyr tended to be low in treated patients, but not in de novo patients. Tyr/Phe ratios were lower in both de novo and treated patients than in controls. The Tyr/Phe ratios were all higher than 0.82 in controls, whereas 49% of the de novo and treated patients had Tyr/Phe ratios less than 0.82. The low Tyr/Phe ratios were associated with male patients and low doses of entacapone. However, Tyr/Phe ratios were not different between male and female patients, and between patients with and without entacapone. CONCLUSIONS: The low serum Tyr/Phe ratio differentiates PD from controls with sensitivity = 0.49, specificity = 1.00, positive predictive value = 1.00, and negative predictive value = 0.40.

Prescribing pattern of anti-Parkinson drugs in Japan: a trend analysis from 2005 to 2010.

OBJECTIVE: Therapeutic options for Parkinson's disease mainly consist of L-dopa and dopamine agonists. However, in Japan, the product labeling of the ergot dopamine agonists, cabergoline and pergolide, was revised in April 2007 due to the risk of developing cardiac valvulopathy. Here, we describe the prescribing trends of anti-Parkinson drugs from 2005 through 2010 in Japan, and examined whether these trends changed after the drug safety measures in 2007. METHODS AND PATIENTS: We used medical claim data from January 2005 to December 2010 for Parkinson's disease patients older than 30 years who were prescribed anti-Parkinson drugs. We calculated the proportion of patients prescribed each drug for each year, and compared the proportions of first-line drugs prescribed before and after April 2007. We also examined the prescription variations of cabergoline/pergolide users one year before or after April 2007. RESULTS: L-dopa was the most frequently prescribed drug for Parkinson's disease (2005, 58%; 2010, 51%). The proportion of patients prescribed ergot dopamine agonists markedly decreased and non-ergot dopamine agonists increased after 2007. Among first-line drugs, the proportion of non-ergot agents increased after April 2007. Among 54 cabergoline/pergolide users, 24 (44%) discontinued these drugs, nine of whom switched to non-ergot agents. CONCLUSION: L-dopa was the mainstay of Parkinson's disease treatment between 2005 and 2010 in Japan. There was a decrease in ergot agents and an increase in non-ergot agents prescribed after the regulatory actions in 2007.

[Practical guideline of Parkinson's disease in Japan: evaluation and mission of future].

Japanese Society of Neurology (JSN) published Practical guideline for Parkinson's Disease (PD) in 2002 and revised version in 2012. This guideline was prepared according to the method of evidence-based medicine. We surveyed the daily practice of PD to expert neurologists for PD nationwide in Japan. Many specialists for PD reported that patients with PD had poor treatment by neurologists and neurosurgeons that was out of PD practical guideline. Some patients were treated with small dose levodopa despite of Hoehn-Yahr 3 stage. Another disabled patients were treated with dopamine agonists alone despite of over aged of 80. Many neurologists treated PD patients out of guideline. It is important to educate guideline to neurologists and general practioner.

YY1 binds to α-synuclein 3'-flanking region SNP and stimulates antisense noncoding RNA expression.

α-synuclein (SNCA) is an established susceptibility gene for Parkinson's disease (PD), one of the most common human neurodegenerative disorders. Increased SNCA is considered to lead to PD and dementia with Lewy bodies. Four single-nucleotide polymorphisms (SNPs) in SNCA 3' region were prominently associated with PD among different ethnic groups. To examine how these SNPs influence disease susceptibility, we analyzed their potential effects on SNCA gene expression. We found that rs356219 showed allele-specific features. Gel shift assay using nuclear extracts from SH-SY5Y cells showed binding of one or more proteins to the protective allele, rs356219-A. We purified the rs356219-A-protein complex with DNA affinity beads and identified a bound protein using mass spectrometry. This protein, YY1 (Yin Yang 1), is an ubiquitous transcription factor with multiple functions. We next investigated SNCA expression change in SH-SY5Y cells by YY1 transfection. We also analyzed the expression of antisense noncoding RNA (ncRNA) RP11-115D19.1 in SNCA 3'-flanking region, because rs356219 is located in intron of RP11-115D19.1. Little change was observed in SNCA expression levels; however, RP11-115D19.1 expression was prominently stimulated by YY1. In autopsied cortices, positive correlation was observed among RP11-115D19.1, SNCA and YY1 expression levels, suggesting their functional interactions in vivo. Knockdown of RP11-115D19.1 increased SNCA expression significantly in SH-SY5Y cells, suggesting its repressive effect on SNCA expression. Our findings of the protective allele-specific YY1 and antisense ncRNA raised a novel possible mechanism to regulate SNCA expression.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

OBJECTIVES: To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). METHODS: After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. RESULTS: Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. CONCLUSIONS: In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study.

The objectives of this study were to evaluate the efficacy of istradefylline at an oral dose of 20 mg or 40 mg once daily for 12 weeks in Parkinson's disease (PD) patients with motor complications on levodopa therapy based on the change in the daily OFF time compared with placebo and to assess the safety at these doses. A total of 363 subjects were randomly assigned to receive 20 mg/day istradefylline (n = 119), 40 mg/day istradefylline (n = 125), or placebo (n = 119). The primary outcome variable was the change from baseline at endpoint in daily OFF time based on patients' ON/OFF diaries. At endpoint, the daily OFF time reduced from baseline by 1.31 hours for 20 mg/day istradefylline (P = 0.013 as compared to the placebo), 1.58 hours for 40 mg/day istradefylline (P < 0.001), and 0.66 hours for placebo; istradefylline significantly reduced the daily OFF time compared with placebo. The UPDRS Part III subscale score (ON state) reduced by 5.7 at endpoint in both istradefylline groups and 3.7 in the placebo group (P = 0.006 for 20 mg/day and P = 0.006 for 40 mg/day group as compared with placebo). The most commonly reported drug-related treatment emergent adverse event (TEAE) was dyskinesia, which occurred in 2.5% (3/119) of subjects receiving placebo, 8.5% (10/118) receiving 20 mg/day istradefylline, and 6.4% (8/125) receiving 40 mg/day istradefylline. We conclude that istradefylline at 20 mg and 40 mg once daily is effective in relieving wearing-off fluctuations of PD patients. In addition, istradefylline was well tolerated at both doses.

Amantadine for dyskinesias in Parkinson's disease: a randomized controlled trial.

BACKGROUND: Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias. METHODS: In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg/day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function). RESULTS: RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores. CONCLUSIONS: Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60-70% of patients. TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000000780.

Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease.

To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

A reassessment of risks and benefits of dopamine agonists in Parkinson's disease.

Neurologists have several choices of drugs that have been shown to be effective for the treatment of the symptoms of Parkinson's disease. Among the first options are the dopamine agonists, which are commonly used both as an early monotherapy and as an adjunct therapy to levodopa. However, before starting any treatment, the overall benefit-to-risk ratio to individual patients must be considered. For the dopamine agonists, the available evidence on their symptomatic efficacy, effect on long-term levodopa-related motor complications, putative effect on progression of disease, and adverse event profile must be taken into account. Recently, the occurrence of adverse events such as leg oedema, daytime somnolence, impulse control disorders, and fibrosis have increasingly been recognised. The risks of these potentially serious adverse events must therefore be taken into account and treatment decisions should be based on considerations of risks versus benefits for individual patients.

Mutations for Gaucher disease confer high susceptibility to Parkinson disease.

BACKGROUND: Increased frequency of pathogenic variants in GBA, the causative gene for Gaucher disease, has been suggested to be associated with Parkinson disease (PD). OBJECTIVES: To conduct comprehensive resequencing of GBA to identify all sequence variants and to investigate the association of these variants with PD. DESIGN: Case-control study. SETTING: Multicenter university-based study. PARTICIPANTS: Five hundred thirty-four patients with PD, 34 families in which multiple patients with PD are present, and 544 control subjects. MAIN OUTCOME MEASURES: Disease status and GBA variations. RESULTS: Comprehensive resequencing of GBA in 534 patients with PD and 544 controls revealed 27 sequence variants: 11 pathogenic variants associated with Gaucher disease, 11 nonsynonymous variants not associated with Gaucher disease, and 5 synonymous variants. Fifty patients with PD (9.4%) had 1 of the 11 pathogenic variants in the heterozygous state, whereas only 2 controls (0.37%) had such variants (odds ratio, 28.0). Among the pathogenic variants, R120W and L444P/RecNciI were highly prevalent, and each showed a significant association with PD. Furthermore, other rare pathogenic variants were found in 13 patients with PD but not in the controls, further confirming the role of these rare variants in the susceptibility to PD. Patients with PD carrying pathogenic variants were significantly younger than those not carrying them. In addition, concordance of PD states and pathogenic variants was observed in 8 multiplex families with PD. CONCLUSION: Heterozygous pathogenic variants in GBA confer a high risk for sporadic PD, even for familial clustering, and are associated with significantly earlier age at onset of disease.

LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson's disease (PD) in European-derived populations, but far less is known about LRRK2 mutations and susceptibility alleles in Asians. To address this issue, we sequenced the LRRK2 coding region in 36 patients with familial PD, then genotyped variants of interest in an additional 595 PD cases and 1,641 controls who were all of Japanese ancestry. We also performed a meta-analysis of studies on G2385R, a polymorphism previously reported to associate with PD. One pathogenic (G2019S) and one putative pathogenic (R1067Q) mutation were each observed in two patients with sporadic PD. The overall mutation frequency among patients was 0.6%. G2385R was highly associated with PD under a dominant model in our dataset (adjusted OR, 1.83; 95% CI, 1.31-2.54; P = 3.3 x 10(-4)) and similar results were seen in the meta-analysis (summary OR assuming fixed effects, 2.55; 95% CI, 2.10-3.10). G2385R represents the first consistently replicated common PD susceptibility variant in a non-European population and its effect size is substantially greater than that reported for other well-validated genetic risk factors for the disease. However, LRRK2 mutations appear to be rare among Japanese patients with PD.

LRRK2 P755L variant in sporadic Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology with probable involvement of genetic-environmental factors. The majority of PD cases (approximately 90-95%) are sporadic, while familial cases account for approximately 5-10% of PD. In a recent report, a heterozygous LRRK2 P755L mutation within LRRK2 exon 19 was found in 2% of Chinese sporadic PD patients and in 0% of normal controls or Caucasians, suggesting that the mutation is disease-associated with ethnic specificity. To further evaluate the role of LRRK2 P755L variant in sporadic PD, we performed direct sequencing of LRRK2 exon 19 in 501 Japanese sporadic PD patients (male 249, female 252, aged 28-92 years, mean 65.0 years) and 583 controls of the Japanese general population as an extended association study. In this group, we found six patients (6/501 = 1.2%) and eight controls of the general population (8/583 = 1.6%) with a heterozygous P755L variant (P = 0.80, chi(2) = 0.064). No other variants were found in exon 19. Together with previous reports, our extended case-controlled study of large sample size suggests that LRRK2 P755L is a non-disease-associated polymorphism in PD patients.

Calbindin 1, fibroblast growth factor 20, and alpha-synuclein in sporadic Parkinson's disease.

Parkinson's disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes identified alpha-synuclein (SNCA) as a susceptibility gene for sporadic PD (P = 1.7 x 10(-11)). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P = 0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes, but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P < 0.01; 882 cases and 938 control subjects). We replicated the association analysis for these SNPs in a second independent sample set (521 cases and 1,003 control subjects). One SNP, rs1805874 in calbindin 1 (CALB1), showed significance in both analyses (P = 7.1 x 10(-5); recessive model). When the analysis was stratified relative to the SNCA genotype, the odds ratio of CALB1 tended to increase according to the number of protective alleles in SNCA. In contrast, FGF20 was significant only in the subgroup of SNCA homozygote of risk allele. CALB1 is a calcium-binding protein that widely is expressed in neurons. A relative sparing of CALB1-positive dopaminergic neurons is observed in PD brains, compared with CALB1-negative neurons. Our genetic analysis suggests that CALB1 is associated with PD independently of SNCA, and that FGF20 is associated with PD synergistically with SNCA.

Dopamine agonists in Parkinson's disease.

Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson's disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm.