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The exact cause of Parkinson disease is unknown, but it is assumed to be the result of a combination of environmental influences superimposed on genetic predisposition or susceptibility (Table 2).14-16 There is increasing evidence that the genetic and environmental insults leading to [Jankovic J. Parkinson] disease commonly lead to abnormal forms of a normal protein, α-synuclein, which seems to contribute to cell death.16,23 The onset of Parkinson disease can be categorized as juvenile (age < 21 yr), early onset (21-50 yr) and late onset (generally > 60 yr).24,25 The juvenile form is rare, is often familial (in as many as 50% of cases), is most frequently associated with a parkin gene mutation and has an atypical presentation.25,26 Of patients with Parkinson disease, 10%-16% have an affected first- or second-degree relative; first-degree relatives may have double the risk of Parkinson disease compared with the general population.26-29 In early- and late-onset Parkinson disease, the frequency of a positive family history is not statistically different.24 In advanced Parkinson disease, the efficacy of levodopa can decline and fluctuate throughout the day switching between \"on\" and \"off' medication periods.92 The motor and nonmotor fluctuations mirror those seen in levodopa plasma concentrations resulting from levodopa's short half-life.93 Providing continuous dopaminergic stimulation is the goal of treating fluctuations in patients with advanced Parkinson disease.94-96 We now have surgical options, including deep brain stimulation and levodopacarbidopa intestinal gel, to provide treatment to such patients. Currently, deep brain stimulation has the highest level of evidence with the largest number of randomized controlled trials.97 Emerging therapies currently being studied in Parkinson disease are listed in Appendix 7, available at www.cmaj.ca/lookup/suppl/doi :10.1503/cmaj.151179/-/DC1. The response to deep brain stimulation is equal to the best response on levodopa, but more effective than medical therapy in improving \"on\" time without troublesome dyskinesias.101,102 Deep brain stimulation typically improves levodoparesponsive symptoms (e.g., tremor, bradykinesia, rigidity) and on-off fluctuations and dyskinesias, whereas impairments in gait, balance and speech are less likely to improve. Patients should be considered for deep brain stimulation only if adequate trials of multiple medications for Parkinson disease (e.g., levodopa-carbidopa, dopamine agonists, monoamine oxidase B inhibitors and amantadine) have been unsuccessful.100 Although duration of efficacy is not clearly established, patients who undergo deep brain stimulation may have sustained benefit for at least 10 years.100 A recent study suggests that deep brain stimulation for Parkinson disease may be offered earlier for patients (mean age 52 yr, disease duration 7.5 yr) just beginning to have motor fluctuations.103 Thalamic deep brain stimulation may be considered as an option in patients who predominantly have disabling tremor where subthalamic nucleus stimulation cannot be performed.57

ABSTRACT Background The outcome of levodopa/carbidopa intestinal gel (LCIG) in Parkinson's disease carriers of GBA1 mutations (GBA‐PD) remains uncertain. Objective To evaluate the safety and efficacy of LCIG in a large PD cohort, focusing on GBA1 variants. Methods This multicenter, retrospective, longitudinal “real‐world” study included consecutive patients with advanced PD treated with LCIG at 31 Italian centers; data were collected at baseline, 1‐, 5‐year, and last‐available follow‐up. Results Data from 512 PD patients (59% male, mean age and disease duration at LCIG initiation 67.0 ± 8.0 and 12.9 ± 5.0 years, respectively) were analyzed. GBA1 genotyping was available for 306 patients (60%), of whom 40 (13%) had GBA1 mutations or risk variants. Mean follow‐up on LCIG was 3.9 ± 2.9 years; 5‐year follow‐up data were available for 159 subjects. At baseline, GBA‐PD had a younger age, shorter PD duration, worse cognition, and more hallucinations than noncarriers. At 1‐ and 5‐year follow‐up, LCIG improved motor and non‐motor symptoms, OFF‐time, and dyskinesias in the entire population. In GBA‐PD, MDS‐UPDRS parts I, II, and III scores did not change, while part IV score improved significantly less than in noncarriers; cognition and orthostatic hypotension symptoms worsened more rapidly. Multivariate analysis of predictors for adverse events and LCIG discontinuation found no significant contribution from GBA1 mutation status. Conclusions GBA1 status does not increase the risk of adverse events or LCIG discontinuation. LCIG is a safe option for advanced GBA‐PD, even in patients with cognitive impairment at baseline. However, GBA‐PD experiences lower efficacy on motor disability and complications and faster cognitive decline than noncarriers.

ABSTRACT Background Parkinson's disease (PD) treatments, such as apomorphine (APO) and levodopa–carbidopa intestinal gel (LCIG), represent advanced therapeutic options for managing motor symptoms. However, clear selection criteria and well‐defined cognitive outcomes are lacking. This systematic review specifically aimed to address these gaps by assessing the cognitive impact of APO and LCIG in PD patients. Methods A systematic review was conducted following PRISMA guidelines, with searches in PubMed, Web of Science, Scopus, and Embase. Two authors screened studies based on key inclusion criteria, including at least two cognitive tests, and a follow‐up of 6 months or more. The risk of bias was evaluated using the Newcastle–Ottawa Scale (NOS). Results Fifteen studies were identified (7 APO and 8 LCIG). APO generally preserved cognitive function over a 12‐month follow‐up, with some decreases in visuospatial memory and executive functions. LCIG, with a 28‐month follow‐up, showed more extensive cognitive decline, particularly in patients with pre‐existing impairments. Variability in cognitive tests made direct comparisons difficult. Discussion APO may have a more favorable cognitive profile than LCIG. However, differences in follow‐up duration, moderate risk of bias, and inconsistent cognitive assessments warrant cautious interpretation. Improved patient selection and comprehensive cognitive evaluations are recommended for future practice.

Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke. This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5–42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45–60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613. Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53–1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]). Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therapy. Medical Research Council.

Device-aided therapies (DATs) are treatments indicated for people with Parkinson´s disease (PwP) experiencing clinical fluctuations that remain suboptimal despite conventional medication. New DATs have recently emerged such as levodopa-entacapone-carbidopa intestinal gel infusion (LECIG) and subcutaneous infusion of foslevodopa/foscarbidopa (fLD/fCD). Understanding the differences between various DATs is essential. We present here the protocol study of the DATs-PD GETM Spanish Registry. This is a descriptive, observational, prospective, multicenter, open study that is proposed as a clinical registry with progressive inclusion of PwP treated with a DAT in daily clinical practice conditions in more 40 centers from Spain for 10 years. The principal aim is to know the type of DAT that PwP in our country (Spain) receive. Specific objectives are to compare the clinical characteristics of the patients, the effectiveness, safety and tolerability, to identify predictors of a good response and to analyze the response by groups (gender, disease duration, phenotype, etc.). There is a baseline visit (V1; indication of the therapy), start visit (V2; initiation of the therapy) and follow-up visits at 6 months ±  3 months (V3_6M) and after this annually ±  3 months for 10 years (V3_12M, V3_24M, etc.). The registry is on going. The first patient was included on April 10, 2024. Patient recruitment and follow-up will be conducted until 31/DEC/2033. It is estimated that the registry will include a minimum of 3,000 patients. The present study will help improve the care of PD patients treated with a DAT.

INTRODUCTION This retrospective study investigates whether exposure to levodopa/carbidopa (LA/CA) medication is associated with modified Alzheimer's disease (AD) trajectories. METHODS Multivariate analysis used cerebrospinal fluid (CSF) biomarker information included in the National Alzheimer's Coordinating Center Uniform Data Set for subjects with normal cognition (NC), mild cognitive impairment (MCI), and dementia (DE). Survival analyses examined the progression to MCI/DE and death events. RESULTS LA/CA use is associated with lower levels of CSF amyloid beta, phosphorylated‐tau (p‐tau) and total‐tau. After adjusting for age, sex, and apolipoprotein E (APOE) ε4 allele presence, that effect was quantified by negative coefficients of the fitted linear mixed models: p‐values < 0.01 in all cases except for p‐tau in the MCI subgroup (p = 0.02). No similar effects were identified for other antiparkinsonians. Exposure to LA/CA decreased the progression from MCI to DE (p = 0.03). DISCUSSION The identified association between LA/CA exposure, AD biomarkers, and progression deserves further investigation in controlled clinical trials. Highlights LA/CA is associated with lower levels of CSF biomarkers for AD. This effect is not observed when other antiparkinsonian drugs are used. LA/CA is also associated with delayed progression to dementia by AD patients with MCI.

Background Levodopa–carbidopa intestinal gel (LCIG) is available in several countries for the treatment of advanced levodopa-responsive Parkinson’s disease (PD) with severe motor fluctuations and dyskinesia when other treatments have not given satisfactory results. Objective Our objective was to summarize the present evidence base for LCIG therapy through a systematic review of the literature. Methods Studies were identified from the PubMed and EMBASE databases up to 12 March 2016 using the following search terms: Parkinson disease, duodopa, levodopa/carbidopa intestinal gel, levodopa–carbidopa intestinal gel, LCIG, l-dopa infusion, levodopa infusion, duodenal l-dopa infusion, and duodenal levodopa infusion. Data extraction focused on whether LCIG therapy improves motor and non-motor outcomes as well as quality of life in PD patients compared with conventional therapy, apomorphine infusion, or deep brain stimulation. Randomized controlled trials (RCTs) and observational studies, with or without a control group, that included more than ten patients were included. The search was limited to peer-reviewed articles published in full in the English language and involving humans. Results Infusion of LCIG reduced “off” time, increased “on” time without increasing troublesome dyskinesias, and improved quality of life in three RCTs (one double-blind). Open-label follow-ups confirm these findings. The data evaluating long-term efficacy and safety are still limited. Conclusions The quality of evidence that LCIG is effective in reducing fluctuating motor symptoms and improving quality of life is moderate. Quality of evidence for reduction of non-motor symptoms is very low. Safety issues mainly relate to the intestinal infusion system. LCIG might be a useful treatment option in PD patients with severe motor fluctuations.

Levodopa inhalation powder (Inbrija ® ) is approved for the intermittent treatment of OFF episodes in patients with Parkinson’s disease (PD) treated with levodopa/dopa-decarboxylase inhibitor (LD-DCI) in the EU and specifically with carbidopa/levodopa in the USA. The approved dosage is 84 mg taken as needed up to five times a day. Administered via a breath-actuated inhaler, this formulation enables levodopa to bypass the gastrointestinal (GI) tract and, instead, rapidly enter the bloodstream through the pulmonary system. In the 12-week, double-blind, placebo-controlled, phase III SPAN-PD trial, as-needed levodopa inhalation powder 84 mg improved motor symptoms during OFF periods in PD patients (aged 30–86 years) treated with levodopa and carbidopa or benserazide. The likelihood of achieving an ON state 60 min postdose was significantly higher in the levodopa inhalation powder than the placebo group, with most patients in the levodopa inhalation powder group experiencing improvements in PD symptoms. Findings from longer-term, 52-week phase III studies were consistent with those from the SPAN-PD trial with regards to the treatment of OFF episodes. Levodopa inhalation powder was generally well tolerated and did not noticeably affect pulmonary function in PD patients. Providing a nonintrusive, convenient treatment method, levodopa inhalation powder is a promising option for the intermittent treatment of OFF episodes in patients with PD treated with a LD-DCI.

Introduction Research comparing levodopa/carbidopa intestinal gel (LCIG), deep brain stimulation (DBS), and continuous subcutaneous apomorphine infusion (CSAI) for advanced Parkinson’s disease (PD) is lacking. This network meta-analysis (NMA) assessed the comparative effectiveness of LCIG, DBS, CSAI and best medical therapy (BMT) in reducing off-time and improving quality of life (QoL) in patients with advanced PD. Methods A systematic literature review was conducted for randomized controlled trials (RCTs), observational and interventional studies from January 2003 to September 2019. Data extracted at baseline and 6 months were off-time, as reported by diary or Unified Parkinson’s Disease Rating Scale Part IV item 39, and QoL, as reported by Parkinson’s Disease Questionnaire (PDQ-39/PDQ-8). Bayesian NMA was performed to estimate pooled treatment effect sizes and to rank treatments in order of effectiveness. Results A total of 22 studies fulfilled the inclusion criteria ( n = 2063 patients): four RCTs, and 16 single-armed, one 2-armed and one 3-armed prospective studies. Baseline mean age was between 55.5–70.9 years, duration of PD was 9.1–15.3 years, off-time ranged from 5.4 to 8.7 h/day in 9 studies, and PDQ scores ranged from 28.8 to 67.0 in 19 studies. Levodopa/carbidopa intestinal gel and DBS demonstrated significantly greater improvement in off-time and QoL at 6 months compared with CSAI and BMT ( p < 0.05). There was no significant difference in the effects of LCIG and DBS, but DBS was ranked first for reduction in off-time, and LCIG was ranked first for improvement in QoL. Conclusions This NMA found that LCIG and DBS were associated with superior improvement in off-time and PD-related QoL compared with CSAI and BMT at 6 months after treatment initiation. This comparative effectiveness research may assist providers, patients, and caregivers in the selection of the optimal device-aided therapy.

Background Entacapone has been widely used in the treatment of moderate to advanced Parkinson’s disease (PD), and its efficacy for motor symptoms has been well-known from several clinical trials and long-term clinical use. The efficacy of Levodopa/Carbidopa/Entacapone (LCE) on neuropsychological functions in moderate to advanced PD has not been validated yet, and little is known about the effect of LCE on peripheral inflammatory cytokines. Objectives The aim of this study was to investigate the efficacy of LCE on neuropsychological functions in moderate to advanced PD and to explore its relationship with the changes in peripheral inflammatory cytokine levels. Methods All patients were randomly assigned to the experimental group receiving treatment of LCE or the control group receiving treatment of Levodopa/Carbidopa (LC). All patients were clinically evaluated using the Unified Parkinson’s Disease Rating Scale part III (UPDRS III), the total score of the Parkinson’s Disease Questionnaire-39 (PDQ-39), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Hamilton Anxiety Scale (HAMA), and the Hamilton Depression Scale (HAMD), and serum homocysteine (HCY) as well as serum inflammatory cytokines were measured at baseline and after 8 weeks. Results The moderate to advanced PD patients treated with LCE had more significant improvement in MMSE scores ( P  = 0.004) and MoCA scores ( P  = 0.001), as well as a greater decline in IL-6 levels ( P  = 0.002) than those treated with LC. There were no significant differences in the changes of the UPDRS III, PDQ39, HAMA, and HAMD scores between the two treatment groups. Linear correlation analysis revealed that there was a significant negative correlation between the improvement of MoCA scores (ΔMoCA) and the reduction of IL-6 levels (ΔIL-6) (correlation coefficient: -0.252; P  = 0.024). Conclusions The ability of LCE to improve cognitive function and to downregulate the peripheral inflammatory cytokine IL-6 levels in moderate to advanced PD is superior to the traditional dopamine preparation—LC. LCE may improve cognitive function by suppressing the levels of inflammatory cytokines like IL-6. Trial registration The full name of the registry: Dongyang People’s Hospital, Affiliated to Wenzhou Medical University. The trial registration number (TRN): ChiCTR2400091631. The date of registration: October 31, 2024 (Retrospectively registered).