Long-Term Intake of Folate, Vitamin B6, and Vitamin B12 and the Incidence of Parkinson's Disease in a Sample of U.S. Women and Men.

BACKGROUND: Folate and vitamins B6 and B12 have been proposed as protective against the development of Parkinson's disease (PD). Two prior longitudinal studies were inconclusive. OBJECTIVE: The aim was to examine the association of long-term intake of folate, vitamin B6, and vitamin B12 with the incidence of PD. METHODS: The study population comprised 80,965 women (Nurses' Health Study, 1984-2016) and 48,837 men (Health Professionals Follow-up Study, 1986-2016) followed prospectively for the development of PD. Intake of B vitamins was measured at baseline and every 4 years thereafter using food frequency questionnaires. We estimated the hazard ratio (HR) and 95% confidence interval (CI) of PD based on quintiles of cumulative average intake adjusting for potential confounders. Secondary analyses considered different lagged exposure periods as well as baseline and recent intakes. RESULTS: In separate analyses of cumulative average intake, total folate, B6, and B12 were not associated with the risk of PD. Results from 8-, 12-, and 16-year lag analyses were consistent with these findings. Results for baseline intake of folate and B6 also pointed toward a null association. In contrast, a lower PD risk was observed among individuals with higher baseline total intake of B12 (pooled HR top vs. bottom quintile: 0.80; 95% CI: 0.67-0.95; P-trend = 0.01); results from 20-year lag analyses were consistent with this finding. CONCLUSIONS: Our results do not support the hypothesis that a higher intake of folate or vitamin B6 would reduce PD risk in this population. Our results provide moderate support for a possible protective effect of vitamin B12 on the development of PD. © 2023 International Parkinson and Movement Disorder Society.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

OBJECTIVE: To understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery. METHODS: Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 µl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 µl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 µl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes. RESULTS: MRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life. INTERPRETATION: Novel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714.

Data-driven evolution of neurosurgical gene therapy delivery in Parkinson's disease.

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

Relationship of Cerebrospinal Fluid Vitamin B12 Status Markers With Parkinson's Disease Progression.

BACKGROUND: Using blood specimens from untreated early Parkinson's disease (PD) patients from the DATATOP trial, we found that subjects in the low serum vitamin B12 tertile experienced greater annualized change in ambulatory capacity score, whereas those with moderately elevated (>15 µmol/L) total homocysteine had greater annualized declines in the Mini-Mental State Exam. METHODS: In this this study we sought to determine whether levels of cerebrospinal fluid (CSF) B12 markers were also associated with progression of PD. RESULTS: The annualized change in the UPDRS "walking" item, a component of the ambulatory capacity score, was worse in the low B12 tertile. No association with change in the Mini-Mental State Exam was seen for those 7% with the highest baseline CSF total homocysteine. CONCLUSIONS: In these untreated early-PD subjects, low CSF B12 predicted greater worsening of the UPDRS "walking" item, whereas CSF total homocysteine was not associated with progression of cognitive impairment. These findings extend and partially support our findings in serum. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Aromatic L-Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson's Disease.

BACKGROUND: As Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements. OBJECTIVES: This substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration. METHODS: Participants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion. RESULTS: Of 15 PD-1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre-VY-AADC01 and 2 participants post-VY-AADC01 administration. CONCLUSIONS: VY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Vitamin B12 and Homocysteine Levels Predict Different Outcomes in Early Parkinson's Disease.

BACKGROUND: In moderately advanced Parkinson's disease (PD), low serum vitamin B12 levels are common and are associated with neuropathy and cognitive impairment. However, little is known about B12 in early PD. OBJECTIVE: To determine the prevalence of low vitamin B12 status in early PD and whether it is associated with clinical progression. METHODS: We measured vitamin B12 and other B12 status determinants (methylmalonic acid, homocysteine, and holotranscobalamin) in 680 baseline and 456 follow-up serum samples collected from DATATOP participants with early, untreated PD. Borderline low B12 status was defined as serum B12 <184 pmol/L (250 pg/mL), and elevated homocysteine was defined as >15 µmol/L. Outcomes included the UPDRS, ambulatory capacity score (sum of UPDRS items 13-15, 29&30), and MMSE, calculated as annualized rates of change. RESULTS: At baseline, 13% had borderline low B12 levels, 7% had elevated homocysteine, whereas 2% had both. Elevated homocysteine at baseline was associated with worse scores on the baseline MMSE. Analysis of study outcomes showed that compared with the other tertiles, participants in the low B12 tertile (<234 pmol/L; 317 pg/mL) developed greater morbidity as assessed by greater annualized worsening of the ambulatory capacity score. Elevated homocysteine was associated with greater annualized decline in MMSE (-1.96 vs. 0.06; P = 0001). Blood count indices were not associated with B12 or homocysteine status. CONCLUSIONS: In this study of early PD, low B12 status was common. Low B12 at baseline predicted greater worsening of mobility whereas elevated homocysteine predicted greater cognitive decline. Given that low B12 and elevated homocysteine can improve with vitamin supplementation, future studies should test whether prevention or early correction of these nutritionally modifiable conditions slows development of disability. © 2018 International Parkinson and Movement Disorder Society.

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.

Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling.

The NF-κB essential modulator NEMO is the core regulatory component of the inhibitor of κB kinase complex, which is a critical checkpoint in canonical NF-κB signaling downstream of innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1ß, NEMO binds to linear or M1-linked ubiquitin chains generated by LUBAC, promoting its oligomerization and subsequent activation of the associated kinases. Here we show that M1-ubiquitin chains induce phase separation of NEMO and the formation of NEMO assemblies in cells after exposure to IL-1ß. Phase separation is promoted by both binding of NEMO to linear ubiquitin chains and covalent linkage of M1-ubiquitin to NEMO and is essential but not sufficient for its phase separation. Supporting the functional relevance of NEMO phase separation in signaling, a pathogenic NEMO mutant, which is impaired in both binding and linkage to linear ubiquitin chains, does not undergo phase separation and is defective in mediating IL-1ß-induced NF-κB activation.

NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62.

NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.

Development of Parkinson's disease in patients with Narcolepsy.

Although amphetamine drugs can damage dopaminergic axons, it is unknown whether chronic treatment with amphetamine increases the risk of developing Parkinson's disease (PD). Of 1,152 consecutive PD patients, 3 had a prior diagnosis of narcolepsy. This rate is five times higher than expected (p = 0.02). These patients had typical onset of narcolepsy and underwent treatment with amphetamine. Although preliminary, this observation raises the possibility that some factors intrinsic to narcolepsy or its treatment may be a risk factor for PD.

Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial.

BACKGROUND AND OBJECTIVES: To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations. METHODS: PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg. RESULTS: No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts. DISCUSSIONS: VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years. TRIAL REGISTRATION INFORMATION: NCT01973543. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Parkinsonism in patients with a history of amphetamine exposure.

We recently found a higher rate of prolonged amphetamine exposure in patients diagnosed with Parkinson's disease (PD) than in spouse/caregiver controls. Since distinguishing features have been described in some patients with parkinsonism due to environment exposures (e.g., manganese), we sought to compare the clinical features of patients with PD with prolonged amphetamine exposure with unexposed patients with PD. Prolonged exposure was defined as a minimum of twice a week for >or=3 months, or weekly use >or=1 year. We reviewed the clinical records of patients with PD who had participated in a telephone survey of drug and environmental exposures and compared the clinical features of patients with a history of prolonged amphetamine exposure to patients who had no such exposure. Records were available for 16 of 17 (94%) patients with prior amphetamine exposure and 127 of 137 (92%) of those unexposed. Age at diagnosis was younger in the amphetamine-exposed group (49.8 +/- 8.2 years vs. 53.1 +/- 7.4 years; P < 0.05), but other features, including presenting symptoms, initial and later treatments, development of motor fluctuations, and MRI findings were similar between these groups. Because we did not detect clinical features that differentiate parkinsonism in patients with prolonged amphetamine exposure, research to determine whether amphetamine exposure is a risk factor for parkinsonism will require detailed histories of medication and recreational drug use.

Pedunculopontine nucleus deep brain stimulation in a patient with primary progressive freezing gait disorder.

BACKGROUND: Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) has recently been suggested for treatment of medication-unresponsive gait and axial symptoms in Parkinson's disease. Patients with the rare primary progressive freezing gait disorder (PPFG) have similar disabling symptoms and few therapeutic options. We report here on our experience with PPN DBS in treating a 76-year-old man with medication-refractory PPFG. METHODS: The patient was treated with staged PPN DBS and underwent careful pre- and postoperative clinical evaluations up to 12 months after surgery. RESULTS: PPN DBS resulted in only mild improvement in symptoms after 12 months of stimulation. CONCLUSION: In this single case of a patient with PPFG, PPN DBS served only a limited role in treating his symptoms and adds to the very limited published literature describing patients treated with DBS at this brain target.

Vitamin B12 measurements across neurodegenerative disorders.

BACKGROUND: Vitamin B12 deficiency causes a number of neurological features including cognitive and psychiatric disturbances, gait instability, neuropathy, and autonomic dysfunction. Clinical recognition of B12 deficiency in neurodegenerative disorders is more challenging because it causes defects that overlap with expected disease progression. We sought to determine whether B12 levels at the time of diagnosis in patients with Parkinson's disease (PD) differed from those in patients with other neurodegenerative disorders. METHODS: We performed a cross-sectional analysis of B12 levels obtained around the time of diagnosis in patients with PD, Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), or Mild Cognitive Impairment (MCI). We also evaluated the rate of B12 decline in PD, AD, and MCI. RESULTS: In multivariable analysis adjusted for age, sex, and B12 supplementation, we found that B12 levels were significantly lower at time of diagnosis in patients with PD than in patients with PSP, FTD, and DLB. In PD, AD, and MCI, the rate of B12 decline ranged from - 17 to - 47 pg/ml/year, much greater than that reported for the elderly population. CONCLUSIONS: Further studies are needed to determine whether comorbid B12 deficiency affects progression of these disorders.

Cognitive and neuropsychiatric profile of the synucleinopathies: Parkinson disease, dementia with Lewy bodies, and multiple system atrophy.

Parkinson disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) share alpha-synuclein immunoreactivity. These "synucleinopathies" have overlapping signs and symptoms, but less is known about similarities and differences in their cognitive and neuropsychiatric profiles. We compared the cognitive and neuropsychiatric profiles of individuals with PD, MSA, and DLB. Overall, the DLB group showed the most cognitive impairment, the MSA group demonstrated milder impairment, and the PD group was the least cognitively impaired. The DLB and MSA groups showed worse executive function and visuospatial skills than PD, whereas DLB showed impaired memory relative to both PD and MSA. On the neuropsychiatric screening, all groups endorsed depression and anxiety; the DLB group alone endorsed delusions and disinhibition. Consistent with their greater level of cognitive and neuropsychiatric impairment, the DLB group showed the greatest amount of functional impairment on a measure of instrumental activities of daily living (Functional Activities Questionnaire). We found that MSA subjects had cognitive difficulties that fell between the mild deficits of the PD group and the more severe deficits of the DLB group. PD, MSA, and DLB groups have similar neuropsychiatric profiles of increased depression and anxiety. Similar underlying alpha-synuclein pathology may contribute to these shared features.

The neurophysiology and effect of deep brain stimulation in a patient with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism.

Parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure was first identified in intravenous drug users. This neurotoxicant has since been used extensively in nonhuman primates to induce an experimental model of Parkinson disease (PD). In this study, the authors examined the intraoperative physiological characteristics and efficacy of subthalamic nucleus deep brain stimulation (DBS) in 1 of only 4 known living patients with MPTP-induced parkinsonism. The physiological recordings were consistent with recordings from MPTP-treated primates and humans with PD, thus providing further validation for the MPTP model in the study of the neurophysiology of the nigrostriatal dopaminergic deficit in PD. Furthermore, DBS produced a significant clinical improvement in this patient similar to the improvement seen after DBS in patients with idiopathic PD. This unique case has important implications for translational research that employs the MPTP-primate model for symptomatic therapy in PD.

Characterization of Vitamin B12 Supplementation and Correlation with Clinical Outcomes in a Large Longitudinal Study of Early Parkinson's Disease.

OBJECTIVE: In Parkinson's disease (PD), vitamin B12 levels are lower, and comorbid B12 deficiency has been associated with the development of neuropathy and early gait instability. Because little is known about B12 supplement use in PD, we sought to evaluate its use in a large PD cohort and, as an exploratory analysis, to determine whether baseline characteristics or disease progression differed according to B12 supplementation. METHODS: We utilized data collected as part of the National Institutes of Health Exploratory Trials in PD (NET-PD) Long-term Study (LS-1), a longitudinal study of 1,741 participants. We stratified subjects into 4 groups according to daily supplement use: no B12, multivitamin (MVI) containing < 100 µg B12, B12 ≥ 100 µg, and MVI + B12 ≥ 100 µg. Clinical outcomes were assessed at 3 years for each group using the Unified Parkinson's Disease Rating Scale (UPDRS), its subscores, and selected individual questions. RESULTS: Of the 1,147 participants who completed the 3-year visit, 41% took an MVI, 2% took B12, 3% took MVI + B12, and 54% reported taking no supplements. At 3 years, no significant differences in clinical outcomes were observed. However, there was a trend toward lower hazard ratios for developing sensory symptoms (UPDRS Item 17) in the MVI (p = 0.08) and B12 + MVI (p = 0.08) groups compared to that in the no supplement group. CONCLUSION: These results show that supplementation with vitamin B12 ≥ 100 µg is uncommon in early PD. The finding of a trend toward a lower hazard ratio for the development of sensory symptoms in those taking an MVI or B12 + MVI warrants further study.

Characterization of vitamin D supplementation and clinical outcomes in a large cohort of early Parkinson's disease.

BACKGROUND: Vitamin D (VitD) deficiency is common in Parkinson's disease (PD) and has been raised as a possible PD risk factor. In the past decade, VitD supplementation for potential prevention of age related conditions has become more common. In this study, we sought to characterize VitD supplementation in early PD and determine as an exploratory analysis whether baseline characteristics or disease progression differed according to reported VitD use. METHODS: We analyzed data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term study (LS-1), a longitudinal study of 1741 participants. Subjects were divided into following supplement groups according to subject exposure (6 months prior to baseline and during the study): no VitD supplement, multivitamin (MVI), VitD ≥400 IU/day, and VitD + multivitamin (VitD+MVI). Clinical status was followed using the Unified Parkinson's Disease Rating Scale, Symbol Digit Modalities Test, total daily levodopa equivalent dose, and Parkinson's Disease Questionnaire. RESULTS: About 5% of subjects took VitD alone, 7% took VitD+MVI, 34% took MVI alone, while 54% took no supplement. Clinical outcomes at 3 years were similar across all groups. CONCLUSION: This study shows VitD supplementation ≥400 IU/day was not common in early PD and that its use was similar to that seen in the US population. At 3 years, there was no difference in disease progression according to vitamin D supplement use.