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.

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.

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.

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.

Locations of movement-related cells in the human subthalamic nucleus in Parkinson's disease.

The subthalamic nucleus (STN) is an emerging target for deep brain stimulator (DBS) implantation for the treatment of advanced Parkinson's disease (PD). Understanding the somatotopic organization of the STN is important for surgical navigation within the nucleus. We analyzed intraoperative data obtained during 54 procedures for the implantation of STN stimulators to assess the locations of movement-related cells. Cells were considered movement-related if they exhibited modulation of the cell discharge during passive movement of the contralateral upper or lower extremity. Microelectrode track reconstructions were plotted on a human brain atlas, using the location of the DBS electrode from postoperative magnetic resonance images as a registration mark in reconstructing microelectrode track locations. Movement-related cells were predominantly located in the dorsal part of the nucleus. The majority of the cells were related to proximal joint manipulation. Arm-related cells were located laterally and at the rostral and caudal poles, whereas leg-related cells were located medially and centrally. The finding of three or more leg-related cells on a given microelectrode track was predictive of a medial localization within the motor area. Our findings are consistent with the small number of published studies on STN somatopy in the human and the nonhuman primate.

Implantation of deep brain stimulators into the subthalamic nucleus: technical approach and magnetic resonance imaging-verified lead locations.

OBJECT: Chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a procedure that is rapidly gaining acceptance for the treatment of symptoms in patients with Parkinson disease (PD), but there are few detailed descriptions of the surgical procedure itself. The authors present the technical approach used to implant 76 stimulators into the STNs of patients with PD and the lead locations, which were verified on postoperative magnetic resonance (MR) images. METHODS: Implantation procedures were performed with the aid of stereotactic MR imaging, microelectrode recording (MER) in the region of the stereotactic target to define the motor area of the STN, and intraoperative test stimulation to assess the thresholds for stimulation-induced adverse effects. All patients underwent postoperative MR imaging, which was performed using volumetric gradient-echo and T2-weighted fast-spin echo techniques, computational reformatting of the MR image into standard anatomical planes, and quantitative measurements of lead location with respect to the midcommissural point and the red nucleus. Lead locations were statistically correlated with physiological data obtained during MER and intraoperative test stimulation. CONCLUSIONS: The authors' approach to implantation of DBS leads into the STN was associated with consistent lead placement in the dorsolateral STN, a low rate of morbidity, efficient use of operating room time, and robust improvement in motor function. The mean coordinates of the middle of the electrode array, measured on postoperative MR images, were 11.6 mm lateral, 2.9 mm posterior, and 4.7 mm inferior to the midcommissural point, and 6.5 mm lateral and 3.5 mm anterior to the center of the red nucleus. Voltage thresholds for several types of stimulation-induced adverse effects were predictive of lead location. Technical nuances of the surgery are described in detail.