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The entry of Levodopa into the brain is limited by competition with large neutral amino acids (LNAA). A strict low protein diet improves motor fluctuations but might lead to protein malnutrition. Because insulin secretion lowers plasma LNAA, a stable dietary ratio of carbohydrate:protein might be as effective as protein restriction. This double blind crossover study compared the effects of three proportioned diets: (A) a 7:1 carbohydrate: protein ratio; (B) a 30:1 carbohydrate: protein ratio; and (C) a 1:1.5 carbohydrate:protein ratio, on motor fluctuations, plasma LNAA and levodopa in 12 Parkinson patients. After random assignments to each diet, patients were observed for 11 hours. Serum levodopa and LNAA levels and motor component of the UPDRS were measured hourly. The 7:1 and high carbohydrate diets were both effective at stabilizing plasma LNAA levels. Mean hourly sum of LNAA was significantly different on each of the diets, being highest on the high protein diet and lowest on the high carbohydrate diet. There was a significant correlation between plasma LNAA and amount of ''off'' time, and a significant inverse correlation between plasma LNAA and amount of time ''on with dyskinesias.'' A fixed dietary carbohydrate:protein ratio stabilizes plasma LNAA levels and may optimize response to levodopa without the risk of malnutrition. [ABSTRACT FROM PUBLISHER]

Abstract Background We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. Methods A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. Results Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. Conclusion Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Abstract Background Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD. Methods In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs. Results Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci. Conclusion In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

Until 1993, chlordecone (CLD) was extensively used in banana fields in French West Indies. In a previous study, CLD was detected in 90 % of Martinican and Guadeloupean adult's serum. In order to simplify the analyses of CLD in the serum, a new QuEChERS-HPLC-MS/MS method was implemented and validated by the Pasteur Institute of Guadeloupe (IPG). This method was validated with accuracy profiles according to the French Standard NF V03-110 plus the ISO 15189 and European guidelines. Linearity, repeatability, accuracy, intermediate precision, specificity, limit of detection (LOD), limit of quantification (LOQ) and uncertainty were determined. The accuracy profile allowed the method to be validated between 0.06  µg L -1 and 1.00  µg L -1 of serum. The LOD was 0.02  µg L -1 , the LOQ was 0.06  µg L -1 and the uncertainty of the method was 21 %. A comparison of 49 serum samples between the IPG (LC-MS/MS) and the LEAE-CART (GC-HRMS) laboratories demonstrated that this new method can reliably determine CLD in human serum. Stability tests were performed and duration of the storage of raw samples and extracts before analysis by HPLC-MS/MS. Raw samples were stable after collection for at least one week at 5 °C or 25 °C and for at least 3 months at -20 °C. Extracts in acetonitrile were stable for at least 1 month at -20 °C. These stability results facilitate the daily use of the method. This method should help the entire population of Guadeloupe and Martinique by allowing a routinely analyzed for CLD and will be useful for future projects aimed at improving population health monitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

On-demand therapies for Parkinson's disease (PD) provide rapid, reliable relief for patients experiencing OFF periods; however, practical guidelines on the use of these therapies are not generally available. This paper reviews the use of on-demand treatments. Motor fluctuations occur in nearly all patients with PD after long-term use of levodopa. As the goal of PD treatment is to provide good ON time, on-demand treatments that have a more rapid reliable onset than the slower-acting oral medications provide rapid relief for OFF periods. All current on-demand treatments bypass the gastrointestinal tract, providing dopaminergic therapy directly into the blood stream by subcutaneous injection, through the buccal mucosa, or by inhalation into the pulmonary circulation. On-demand treatments are fast acting (10- to 20-min onset), with maximum, reliable, and significant responses reached within 30 min after administration. Oral medications pass through the gastrointestinal tract and thus have slower absorption owing to gastroparesis and competition with food. On-demand therapies, by providing fast-acting relief, can have a positive impact on a patient's quality of life when patients are experiencing OFF periods., (© 2023. The Author(s).)

Background and Purpose: Few persons with Parkinson disease (PD) appear to engage in moderate-intensity walking associated with disease-modifying health benefits. How much time is spent walking at lower, yet still potentially beneficial, intensities is poorly understood. The purpose of this exploratory, observational study was to describe natural walking intensity in ambulatory persons with PD., Methods: Accelerometer-derived real-world walking data were collected for more than 7 days at baseline from 82 participants enrolled in a PD clinical trial. Walking intensity was defined according to the number of steps in each active minute (1-19, 20-39, 40-59, 60-79, 80-99, or ≥100 steps). Daily minutes of walking and duration of the longest sustained walking bout were calculated at each intensity. Number of sustained 10 to 19, 20 to 29, and 30-minute bouts and greater at any intensity also were calculated. Values were analyzed in the context of physical activity guidelines., Results: Most daily walking occurred at lower intensities (157.3 ± 58.1 min of 1-19 steps; 81.3 ± 32.6 min of 20-39 steps; 38.2 ± 21.3 min of 40-59 steps; 15.1 ± 11.5 min of 60-79 steps; 7.4 ± 7.0 min of 80-99 steps; 7.3 ± 9.6 min of ≥100 steps). The longest daily sustained walking bout occurred at the lowest intensity level (15.9 ± 5.2 min of 1-19 steps). Few bouts lasting 20 minutes and greater occurred at any intensity., Discussion and Conclusions: Despite relatively high daily step counts, participants tended to walk at remarkably low intensity, in bouts of generally short duration, with relatively few instances of sustained walking. The findings reinforced the need for health promotion interventions designed specifically to increase walking intensity.Video Abstract available for more insight from authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A426 )., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Academy of Neurologic Physical Therapy, APTA.)

Objective: The study examined how clinically measured walking capacity contributes to real-world walking performance in persons with Parkinson's disease (PD)., Methods: Cross-sectional baseline data (n = 82) from a PD clinical trial were analyzed. The 6-Minute Walk Test (6MWT) and 10-Meter Walk Test (10MWT) were used to generate capacity metrics of walking endurance and fast gait speed, respectively. An activity monitor worn for seven days was used to generate performance metrics of mean daily steps and weekly moderate intensity walking minutes. Univariate linear regression analyses were used to examine associations between each capacity and performance measure in the full sample and less and more active subgroups., Results: Walking capacity significantly contributed to daily steps in the full sample (endurance: R 2 =.13, p < .001; fast gait speed: R 2 =.07, p = .017) and in the less active subgroup (endurance: R 2 =.09, p = .045). Similarly, walking capacity significantly contributed to weekly moderate intensity minutes in the full sample (endurance: R 2 =.13, p < .001; fast gait speed: R 2 =.09, p = .007) and less active subgroup (endurance: R 2 = .25, p < .001; fast gait speed: R 2 =.21, p = .007). Walking capacity did not significantly contribute to daily steps or moderate intensity minutes in the more active subgroup., Conclusions: Walking capacity contributed to, but explained a relatively small portion of the variance in, real-world walking performance. The contribution was somewhat greater in less active individuals. The study adds support to the idea that clinically measured walking capacity may have limited benefit for understanding real-world walking performance in PD. Factors beyond walking capacity may better account for actual walking behavior., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Social participation is a key determinant of healthy aging, yet little is known about how people with Parkinson's disease manage social living. This study describes individual differences in social self-management practices and their association with symptom severity and health quality of life., Methods: People with Parkinson's disease ( N  = 90) completed measures of healthy routines, activities and relationships, symptom severity, and health related quality of life. Cluster analysis identified profiles of social self-management practices. Analysis of variance tested differences between profiles in symptom severity and health quality of life., Results: Participants clustered into one of seven groups according to different combinations of three practices: health resources utilization , activities in home and community , and social support relationships . The healthiest cluster engaged equally in all three practices at above sample average degree of engagement. Four clusters that engaged at or above sample average in activities in home and community experienced less health problems than three clusters that engaged below average. Variation in aspects of social lifestyle unrelated to health appeared also to contribute to profile diversity., Conclusion: Findings provide insight into similarity and variation in how people with Parkinson's disease engage with social self-management resources and point to person-centered interventions.Implications for RehabilitationSocial self-management is a biopsychosocial construct to identify and describe self-care practices that engage one's social resources for managing healthful daily living.People with Parkinson's disease vary in their profiles of engaging in social self-management practices in daily living, and this variability relates to severity of symptoms and health quality of life.Learning how to identify health-centered social self-management practices may help people with Parkinson's disease to focus on the healthfulness of their own practices.Learning how to strategically engage one's social resources as part of self-care may help people with Parkinson's disease to master managing their health and well-being in daily life.

To reduce the exposure of the French West Indies population to the organochlorine insecticide chlordecone (Kepone; CLD), the contamination of currently consumed foodstuffs must be reduced. Depuration of contaminated animals before slaughter could be a strategy to obtain safe animal products. The aim of this study was to characterize and quantify CLD elimination in contaminated ewes during depuration process. Experiments A and B consisted in a single intravenous (i.v.) administration of CLD (n = 5) and CLDOH (chlordecol; n = 3) followed by a 84-d and 3-d depuration period respectively with collection of blood, faeces and urine samples. After CLD administration, CLD and conjugated-CLDOH (CLDOH-C) were quantified in serum and urine and CLD and CLDOH were quantified in faeces. Based on calculations of faecal, urinary and body clearances of CLD and CLDOH-C, faeces appeared as the major route of CLD excretion with 86 % of the CLD administered dose eliminated in faeces, either as CLD (51 %) or as CLDOH (35 %)., (Copyright © 2021. Published by Elsevier B.V.)

Background and Purpose: Walking activity in persons with Parkinson disease (PD) is important for preventing functional decline. The contribution of walking activity to home and community mobility in PD is poorly understood., Methods: Cross-sectional baseline data (N = 69) were analyzed from a randomized controlled PD trial. The Life-Space Assessment (LSA) quantified the extent, frequency, and independence across 5 expanding levels of home and community mobility, producing individual subscores and a total score. Two additional summed scores were used to represent mobility within (Levels 1-3) and beyond (Levels 4-5) neighborhood limits. An accelerometer measured walking activity for 7 days. Regression and correlation analyses evaluated relationships between daily steps and mobility scores. Mann-Whitney U tests secondarily compared differences in mobility scores between the active and sedentary groups., Results: Walking activity contributed significantly to the summed Level 1-3 score (β = 0.001, P = 0.004) but not to the summed Level 4-5 (β = 0.001, P = 0.33) or total (β = 0.002, P = 0.07) scores. Walking activity was significantly related to Level 1 (ρ = 0.336, P = 0.005), Level 2 (ρ = 0.307, P = 0.010), and Level 3 (ρ = 0.314, P = 0.009) subscores. Only the summed Level 1-3 score (P = 0.030) was significantly different between the active and sedentary groups., Discussion and Conclusions: Persons with PD who demonstrated greater mobility beyond the neighborhood were not necessarily more active; walking activity contributed more so to home and neighborhood mobility. Compared with LSA total score, the Level 1-3 summed score may be a more useful participation-level measure for assessing the impact of changes in walking activity.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A349)., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Academy of Neurologic Physical Therapy, APTA.)

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.

Chlordecone (CLD) is an organochlorine pesticide used in banana fields of the French West Indies between 1972 and 1993. This use resulted in a long-term pollution of soils and the possible contamination of farm animals. Indeed, after involuntary ingestion of soil, CLD is absorbed and consequently leads to contaminated animals. The aim of this study was the determination of CLD half-life and the establishment of the linearity of CLD disappearance kinetics in non-lactating adult's ewes. Chlordecone diluted in cremophor was intravenously administrated to ewes at different doses: 0.04, 0.2, or 1 mg kg -1 body weight (n = 5 for each dose). Blood samples were collected from time t = 0 to time t = 84 days. Serum samples were extracted with a solid-phase extraction and analyzed by electron capture detection gas chromatography. A two-compartmental model was applied to the serum CLD kinetics. An additional statistical analysis was applied to the observed elimination parameters in serum according to the administrated dose, and no significant differences were detected. The linear elimination of CLD between 0.04 and 1 mg kg -1 body weight allowed the possibility of ewe's extrapolation half-life in this dose range. The estimated mean CLD half-life in ewes was 24 days. Overall, the results of this study will be useful to establish decontamination strategies in small ruminants reared in contaminated CLD areas. Graphical abstract Experimental design of the CLD toxicokinetic study in ewes.