Journal of Parkinson's disease最新文献

Slowing or halting progression continues to be a major unmet medical need in Parkinson's disease (PD). Numerous trials over the past decades have tested a broad range of interventions without ultimate success. There are many potential reasons for this failure and much debate has focused on the need to test 'disease-modifying' candidate drugs in the earliest stages of disease. While generally accepted as a rational approach, it is also associated with significant challenges around the selection of trial populations as well as trial outcomes and durations. From a health care perspective, intervening even earlier and before at-risk subjects have gone on to develop overt clinical disease is at the heart of preventive medicine. Recent attempts to develop a framework for a biological definition of PD are aiming to enable 'preclinical' and subtype-specific diagnostic approaches. The present review addresses past efforts towards disease-modification, including drug targets and reasons for failure, as well as novel targets that are currently being explored in disease-modification trials in early established PD. The new biological definitions of PD may offer new opportunities to intervene even earlier. We critically discuss the potential and challenges around planning 'disease-prevention' trials in subjects with biologically defined 'preclinical' or prodromal PD.

The ability to identify individuals in the prodromal phase of Parkinson's disease has improved in recent years, raising the question of whether and how those affected should be informed about the risk of future disease. Several studies investigated prognostic counselling for individuals with isolated REM sleep behavior disorder and have shown that most patients want to receive information about prognosis, but autonomy and individual preferences must be respected. However, there are still many unanswered questions about risk disclosure or early diagnosis of PD, including the impact on personal circumstances, cultural preferences and specific challenges associated with different profiles of prodromal symptoms, genetic testing or biomarker assessments. This narrative review aims to summarize the current literature on prognostic counselling and risk disclosure in PD, as well as highlight future perspectives that may emerge with the development of new biomarkers and their anticipated impact on the definition of PD.

There is increasing evidence that microbial-based therapies can be useful in people with Parkinson's disease (PD). In this viewpoint, we provide a state-of-the-art review of the clinical and pre-clinical evidence for probiotics and prebiotics in PD. Currently, short-term clinical studies, including double-blind placebo-controlled randomized clinical trials, have demonstrated safety, and efficacy primarily in improving constipation-related symptoms. Pre-clinical studies consistently reported improvements in a range of biological markers and outcomes, including evidence for attenuation of gut dysfunction and neuroprotection. Bacteria from the genus Lactobacillus and Bifidobacterium have been the most frequently studied both in clinical and pre-clinical probiotics studies, while research into prebiotics is still limited and primarily involved resistant starch and fructooligosaccharides. We provide practical suggestions for clinicians on how to advise patients in the clinic regarding these popular treatments, and important caveats to be aware of. Finally, areas for further advancements are highlighted. It is envisaged that in the future, microbial-based therapies may benefit from personalization based on an enhanced understanding of a whole range of host factors and host-microbiome interactions.

Background: Visual biomarkers of Parkinson's disease (PD) are attractive as the retina is an outpouching of the brain. Although inner retinal neurodegeneration in PD is well-established this has overlap with other neurodegenerative diseases and thus outer retinal (photoreceptor) measures warrant further investigation.

Objective: To examine in a cross-sectional study whether clinically implementable measures targeting outer retinal function and structure can differentiate PD from healthy ageing and whether these are sensitive to intraday levodopa (L-DOPA) dosing.

Methods: Centre-surround perceptual contrast suppression, macular visual field sensitivity, colour discrimination, light-adapted electroretinography and optical coherence tomography (OCT) were tested in PD participants (n = 16) and controls (n = 21). Electroretinography and OCT were conducted before and after midday L-DOPA in PD participants, or repeated after ∼2 hours in controls.

Results: PD participants had decreased center-surround contrast suppression (p < 0.01), reduced macular visual field sensitivity (p < 0.05), color vision impairment (p < 0.01) photoreceptor dysfunction (a-wave, p < 0.01) and photoreceptor neurodegeneration (outer nuclear layer thinning, p < 0.05), relative to controls. Effect size comparison between inner and outer retinal parameters showed that photoreceptor metrics were similarly robust in differentiating the PD group from age-matched controls as inner retinal changes. Electroretinography and OCT were unaffected by L-DOPA treatment or time.

Conclusions: We show that outer retinal outcomes of photoreceptoral dysfunction (decreased cone function and impaired color vision) and degeneration (i.e., outer nuclear layer thinning) were equivalent to inner retinal metrics at differentiating PD from healthy age-matched adults. These findings suggest outer retinal metrics may serve as useful biomarkers for PD.

Background: A possible genetic contribution of dopamine D3 receptor (DRD3) to cognitive impairment in Parkinson's disease (PD) has yet to be investigated.

Objective: To explore the effects of rs6280 (Ser9Gly) genotype on PD patients' cognitive performance and to clarify possible interactions with psychopathology.

Methods: Two hundred and fifty-three consecutive PD patients underwent neurological and neuropsychological evaluations, which included: Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Dementia Rating Scale-2 (DRS-2), and Hospital Anxiety and Depression Scale (HADS). rs6280 polymorphism was genotyped for all PD patients and for 270 ethnically matched healthy volunteers (HC). Non-parametric group comparisons and logistic regressions were used for data analyses.

Results: rs6280 genotype did not differ between PD and HC groups. PD patients with rs6280 CC genotype had more impaired cognitive performance (i.e., <1st percentile of demographically adjusted norms) on DRS-2 subscales Initiation/Perseveration and Construction than those with TT genotype. These associations remained statistically significant when other covariates (e.g., demographic features, disease duration, severity of motor symptoms in OFF and ON states, anti-parkinsonian medication, and psychopathology symptoms) were taken into consideration. PD patients with rs6280 TC had less anxiety (i.e., HADS Anxiety≥11) than those with TT (p = 0.012). This association was also independent of other covariates.

Conclusions: Study findings suggest that rs6280 CC genotype predisposes to executive dysfunction and visuoconstructional deficits, whereas the heterozygous genotype protects from anxiety in PD. These effects do not appear to be dependent of one another. rs6280 is not a genotypic susceptibility factor for PD.

Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release.

Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia.

Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats.

Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats.

Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

Background: Patient and public involvement and engagement (PPIE) in the design of trials is important, as participant experience critically impacts delivery. The Edmond J Safra Accelerating Clinical Trials in PD (EJS ACT-PD) initiative is a UK consortium designing a platform trial for disease modifying therapies in PD.

Objective: The integration of PPIE in all aspects of trial design and its evaluation throughout the project.

Methods: PwP and care partners were recruited to a PPIE working group (WG) via UK Parkinson's charities, investigator patient groups and participants of a Delphi study on trial design. They are supported by charity representatives, trial delivery experts, researchers and core project team members. PPIE is fully embedded within the consortium's five other WGs and steering group. The group's terms of reference, processes for effective working and PPIE evaluation were co-developed with PPIE contributors.

Results: 11 PwP and 4 care partners have supported the PPIE WG and contributed to the development of processes for effective working. A mixed methods research-in-action study is ongoing to evaluate PPIE within the consortium. This includes the Patient Engagement in Research Scale -a quantitative PPIE quality measure; semi-structured interviews -identifying areas for improvement and overall impressions of involvement; process fidelity- recording adherence; project documentation review - identifying impact of PPIE on project outputs.

Conclusions: We provide a practical example of PPIE in complex projects. Evaluating feasibility, experiences and impact of PPIE involvement in EJS ACT-PD will inform similar programs on effective strategies. This will help enable future patient-centered research.

Background: Measurement of freezing of gait (FOG) relies on the sensitivity and reliability of tasks to provoke FOG. It is currently unclear which tasks provide the best outcomes and how medication state plays into this.

Objective: To establish the sensitivity and test-retest reliability of various FOG-provoking tasks for presence and severity of FOG, with (ON) and without (OFF) dopaminergic medication.

Methods: FOG-presence and percentage time frozen (% TF) were derived from video annotations of a home-based FOG-provoking protocol performed in OFF and ON. This included: the four meter walk (4MW), Timed Up and Go (TUG) single (ST) and dual task (DT), 360° turns in ST and DT, a doorway condition, and a personalized condition. Sensitivity was tested at baseline in 63 definite freezers. Test-retest reliability was evaluated over 5 weeks in 26 freezers.

Results: Sensitivity and test-retest reliability were highest for 360° turns and higher in OFF than ON. Test-retest intra-class correlation coefficients of % TF varied between 0.63-0.90 in OFF and 0.18-0.87 in ON, and minimal detectable changes (MDCs) were high. The optimal protocol included TUG ST, 360° turns ST, 360° turns DT and a doorway condition, provoking FOG in all freezers in OFF and 91.9% in ON and this could be done reliably in 95.8% (OFF) and 84.0% (ON) of the sample. Combining OFF and ON further improved outcomes.

Conclusions: The highest sensitivity and reliability was achieved with a multi-trigger protocol performed in OFF + ON. However, the high MDCs for % TF underscore the need for further optimization of FOG measurement.