The ultimate goal in Parkinson's disease (PD) research remains the identification of treatments that are capable of slowing or even halting the progression of the disease. The failure of numerous ...past disease-modification trials in PD has been attributed to a variety of factors related not only to choosing wrong interventions, but also to using inadequate trial designs and target populations. In patients with clinically established PD, neuronal pathology may already have advanced too far to be modified by any intervention. Based on such reasoning, individuals in yet prediagnostic or prodromal disease stages, may provide a window of opportunity to test disease-modifying strategies. There is now sufficient evidence from prospective studies to define diagnostic criteria for prodromal PD and several approaches have been studied in observational cohorts. These include the use of PD-risk algorithms derived from multiple established risk factors for disease as well as follow-up of cohorts with single defined prodromal markers like hyposmia, rapid eye movement sleep behavior disorders, or PD gene carriers. In this review, we discuss recruitment strategies for disease-modification trials in various prodromal PD cohorts, as well as potential trial designs, required trial durations, and estimated sample sizes. We offer a concluding outlook on how the goal of implementing disease-modification trials in prodromal cohorts might be achieved in the future.
Abstract
Study Objectives
To evaluate macro sleep architecture and characterize rapid eye movement (REM) sleep without atonia (RWA) by using the SINBAR excessive electromyographic (EMG) montage ...including mentalis and upper extremity muscles in early and advanced Parkinson’s disease (PD).
Methods
We recruited 30 patients with early- and advanced-stage of PD according to Movement Disorder Society (MDS) Clinical Diagnostic Criteria. Participants were classified as early-stage PD if they were treatment-naïve or had no motor complications and had been diagnosed with PD within the previous 6 years. Advanced PD was defined as a disease duration equal to or >6 years with or without motor complications.
Results
There was significantly shorter REM sleep latency in early as compared to the advanced stage of PD. We found that the sleep Innsbruck Barcelona (SINBAR) EMG index and tonic EMG activity of the mentalis muscle in advanced-stage PD were significantly higher than in early-stage PD with a trend in phasic EMG activity of the flexor digitorum superficialis muscles. The SINBAR EMG index, tonic and any EMG activity of the mentalis muscle, and phasic EMG activity of flexor digitorum superficialis muscles significantly correlated with disease duration.
Conclusions
This study analyzed RWA using the SINBAR EMG montage in early- and advanced-stage of PD and showed higher RWA in mentalis and flexor digitorum superficialis muscles and SINBAR EMG index in advanced-PD patients compared to patients in the early stage. Also, polysomnography-confirmed REM sleep behavior disorder was more common in advanced versus early-stage patients. Our findings suggest that RWA worsens or is more intense or more frequent with disease progression.
Sarcopenia and frailty are found in up to one-third of the general elderly population. Both are associated with major adverse health outcomes such as nursing home placement, disability, decreased ...quality of life, and death. Data on the frequency of both syndromes in Parkinson's disease (PD), however, are very limited.
We aimed to screen for sarcopenia and frailty in PD patients and to assess potential associations of both geriatric syndromes with demographic and clinical parameters as well as quality of life.
In this observational, cross-sectional study, we included 104 PD patients from a tertiary center and 330 non-PD controls from a population-based cohort aged > 65 years. All groups were screened for sarcopenia using the SARC-F score and for frailty using the Clinical Frailty Scale of the Canadian Study of Health and Aging (CSHA CFS). Prevalence rates of sarcopenia and frailty were also assessed in 18 PD patients from a population-based cohort aged > 65 years. Moreover, PD patients from the tertiary center were evaluated for motor and non-motor symptoms, quality of life, and dependency.
The prevalence of sarcopenia was 55.8% (95% CI: 46.2-64.9%) in PD patients from the tertiary center and 8.2% (5.7-11.7%; p < 0.001) in non-PD controls. Frailty was detected in 35.6% (27.0-45.2%) and 5.2% (3.2-8.1%; p < 0.001). Prevalence rates for sarcopenia and frailty were 33.3% (16.1-56.4%; p = 0.004) and 22.2% (8.5-45.8%; p = 0.017) in the community-based PD sample. Both sarcopenia and frailty were significantly associated with longer disease duration, higher motor impairment, higher Hoehn and Yahr stages, decreased quality of life, higher frequency of falls, a higher non-motor symptom burden, institutionalization, and higher care levels in PD patients from a tertiary center compared to not affected PD patients (all p < 0.05).
Both frailty and sarcopenia are more common in PD patients than in the general community and are associated with a more adverse course of the disease. Future studies should look into underlying risk factors for the occurrence of sarcopenia and frailty in PD patients and into adequate management to prevent and mitigate them.
Background
Gait impairment is a pivotal feature of parkinsonian syndromes and increased gait variability is associated with postural instability and a higher risk of falls.
Objectives
We compared ...gait variability at different walking velocities between and within groups of patients with Parkinson-variant multiple system atrophy, idiopathic Parkinson’s disease, and a control group of older adults.
Methods
Gait metrics were recorded in 11 multiple system atrophy, 12 Parkinson’s disease patients, and 18 controls using sensor-based gait analysis. Gait variability was analyzed for stride, swing and stance time, stride length and gait velocity. Values were compared between and within the groups at self-paced comfortable, fast and slow walking speed.
Results
Multiple system atrophy patients displayed higher gait variability except for stride time at all velocities compared with controls, while Parkinson’s patients did not. Compared with Parkinson’s disease, multiple system atrophy patients displayed higher variability of swing time, stride length and gait velocity at comfortable speed and at slow speed for swing and stance time, stride length and gait velocity (all
P
< 0.05). Stride time variability was significantly higher in slow compared to comfortable walking in patients with multiple system atrophy (
P
= 0.014). Variability parameters significantly correlated with the postural instability/gait difficulty subscore in both disease groups. Conversely, significant correlations between variability parameters and MDS-UPDRS III score was observed only for multiple system atrophy patients.
Conclusion
This analysis suggests that gait variability parameters reflect the major axial impairment and postural instability displayed by multiple system atrophy patients compared with Parkinson’s disease patients and controls.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Associations of substantia nigra (SN) hyperechogenicity on transcranial sonography, olfactory dysfunction, and mild parkinsonian signs (MPS) with incident Parkinson's disease (PD) have only been ...studied over limited periods of follow-up and their long-term predictive properties are unclear. We aimed to prospectively assess the risk for incident PD over 10 years in community-dwelling elderly individuals with these risk markers.
SN-hyperechogenicity, olfactory function, and MPS were assessed in the prospective population-based Bruneck Study (2005 in-person assessment; n = 574, aged 55–94 years). Cases of incident PD were identified at 5-year and 10-year follow-up visits. We estimated relative risks of baseline markers for incident cases.
After excluding 35 cases with PD or secondary parkinsonism at baseline, a total of 20 cases of incident PD were identified from the remaining 539 participants (11 at 5 years and 9 at 10 years). Relative risks for incident PD over the 10-year follow-up period were 7.43 (2.71–20.39), 3.60 (1.48–8.78), and 5.52 (2.43–12.57) for baseline SN-hyperechogenicity, hyposmia, and mild parkinsonian signs, respectively. While risk of hyposmia for incident PD was similar for the two sequential 5-year periods studied, relative risks of SN-hyperechogenicity and MPS were higher for the first five years as compared to later.
Our findings extend the established risk relationship of SN-hyperechogenicity, hyposmia, and MPS with incident PD beyond 5 years of follow-up.
•We assessed substantia nigra hyperechogenicity, hyposmia, and mild parkinsonian signs as long term risk markers for Parkinson's disease.•All three markers were associated to a significantly increased risk over 10 years.•Hyposmia was the only marker with similar risk short- and long term risk (<5 and 5–10 years).•The risk related to substantia nigra hyperechogenicity and mild parkinsonian signs was higher for the first 5 years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The synthetic tetrahydrocannabinol-analog nabilone improved non-motor symptoms (NMS) in Parkinson's disease (PD) patients in a placebo-controlled, double-blind, parallel-group, randomized withdrawal ...trial with enriched enrollment (NMS-Nab-study). This was a single-center open-label extension study to assess the long-term safety and efficacy of nabilone for NMS in PD. To be eligible for this study, patients had to be treatment responders during the previous NMS-Nab-trial and complete its double-blind phase without experiencing a drug-related serious/severe/moderate adverse event (AE). Patients were re-introduced to nabilone during an up-titration phase until their overall NMS burden improved. Nabilone was continued for six months with clinic visits every 3 months. Evaluation of AEs was based on self-report and clinical assessment. Twenty-two patients participated in the NMS-Nab2-study (age-median 68.33 y, 52% females, disease duration-median 7.42 y). Nabilone was well tolerated with concentration difficulties as the most common treatment-related AE (possibly/not related n = 1 each). One in two drop-outs discontinued because of an AE for which a prohibited concomitant medication needed to be introduced (night-time sleep problems). Efficacy evaluation showed a significant and lasting improvement in NMS burden according to the CGI-I (79% at V3). Nabilone improved overall sleep (NMSS Domain-2: -8.26 points; 95%CI -13.82 to -2.71; p = 0.004; ES = -0.72), night-time sleep problems (MDS-UPDRS-1.7: -1.42 points; 95 CI -2.16 to -0.68; p = 0.002; ES = -0.92), and overall pain (KPPS Total Score: -8.00 points; 95%CI -15.05 to -0.95; p = 0.046; ES -0.55 and MDS-UPDRS-1.9: -0.74 points; 95%CI -1.21 to -0.26; p = 0.008; ES = -0.74). This study demonstrates continuous long-term safety and efficacy in PD patients responding early to nabilone without intolerable side effects.
The topic of the therapeutic use of cannabinoids in Parkinson's disease (PD) is broadly discussed and frequently comes up in the outpatient clinic. So far, there are only a few randomized clinical ...trials assessing the effects of cannabinoids in PD. We are able to demonstrate a reduction in non-motor symptom (NMS) burden after the administration of nabilone. As impairment of attention and working memory have been described earlier as possible side effects, we assess cognitive performance using saccadic paradigms measured by an eye tracker. We do not observe a significant difference in any of the saccadic paradigms between PD patients on placebo versus those treated with nabilone. We, therefore, conclude that top-down inhibitory control is not affected by the tetrahydrocannabinol analogue. Nabilone did not significantly worsen cognitive performance and appears to be safe to use in selected PD patients who suffer from disabling NMS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To date, despite numerous clinical trials, no intervention has been demonstrated to modify the progression of Parkinson's disease (PD). However, over the past decades encouraging progress has been ...made towards a better understanding of molecular pathways relevant for the neurodegenerative process in PD. This is also based on new insights into the genetic architecture of the disease, revealing multiple novel targets for potentially disease-modifying interventions. Important achievements have also been made in the field of risk markers and combinations thereof, in the form of risk algorithms, will hopefully soon provide the possibility to identify affected individuals at yet prediagnostic or prodromal stages of the illness. Such phases of the disease would provide an ideal window for neuroprotection trials. Taken together, these developments offer hope that a breakthrough towards modifying the course of PD might be reached. In this article we summarize various approaches currently pursued in this quest.
This article is part of the special issue entitled ‘The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders’.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, SAZU, SBCE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Different algorithms aiming to identify individuals at risk of Parkinson disease (PD) have been proposed. Comparative studies of these scores and their recent updates in the general elder population ...are needed.
We have previously applied the "basic" PREDICT-PD algorithm, designed for remote screening, and the original and updated Movement Disorder Society (MDS) criteria for prodromal PD to the longitudinal population-based Bruneck study cohort. We have now additionally employed the "enhanced" PREDICT-PD algorithm (which includes motor assessment, olfaction, probable rapid eye movement sleep behaviour disorder status, pesticide exposure, and diabetes as additional factors). Risk scores were calculated based on comprehensive baseline assessments (2005) in 574 subjects aged 55-94 years (290 females), and cases of incident PD were identified at 5-year (n = 11) and 10-year follow-up (n = 9). We analysed the association of the different log-transformed risk scores with incident PD at follow-up (calculated per 1-SD unit change).
The enhanced PREDICT-PD algorithm was associated with incident PD over 10-years of follow-up, yielding higher odds for incident PD (odds ratio OR = 4.61, 95% confidence interval CI = 2.68-7.93, p < 0.001) compared with the basic PREDICT-PD score (OR = 2.38, 95% CI = 1.49-3.79, p < 0.001). The updated MDS prodromal criteria yielded a numerically higher OR of 7.13 (95% CI = 3.49-14.54, p < 0.001) in comparison with the original criteria as well as the enhanced PREDICT-PD algorithm, with overlapping 95% CIs.
The enhanced PREDICT-PD algorithm was significantly associated with incident PD. The consistent performance of both the enhanced PREDICT-PD algorithm and the updated MDS prodromal criteria compared to their original versions supports their use in PD risk screening.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
The objective of this study was to assess the efficacy and safety of nabilone, a synthetic tetrahydrocannabinol analogue, as a treatment for non‐motor symptoms (NMS) in Parkinson's disease ...(PD).
Methods
This was a phase II placebo‐controlled, double‐blind, parallel‐group, enriched enrollment randomized withdrawal trial conducted at the Medical University Innsbruck. A random sample of 47 patients with PD with stable motor disease and disturbing NMS defined by a score of ≥4 points on the Movement Disorder Society ‐ Unified PD Rating Scale‐I (MDS‐UPDRS‐I) underwent open‐label nabilone titration (0.25 mg once daily to 1 mg twice daily, phase I). Responders were randomized 1:1 to continue with nabilone or switch to placebo for 4 weeks (phase II). The primary efficacy criterion was the change of the MDS‐UPDRS‐I between randomization and week 4. Safety was analyzed in all patients who received at least one nabilone dose.
Results
Between October 2017 and July 2019, 19 patients received either nabilone (median dose = 0.75 mg) or placebo. At week 4, mean change of the MDS‐UPDRS‐I was 2.63 (95% confidence interval CI 1.53 to 3.74, p = 0.002, effect size = 1.15) in the placebo versus 1.00 (95% CI −0.16 to 2.16, p = 0.280, effect size = 0.42) in the nabilone‐group (difference: 1.63, 95% CI 0.09 to 3.18, p = 0.030, effect size = 0.66). Seventy‐seven percent of patients had adverse events (AEs) during open‐label titration, most of them were transient. In the double‐blind phase, similar proportions of patients in each group had AEs (42% in the placebo group and 32% in the nabilone group). There were no serious AEs.
Interpretation
Our results highlight the potential efficacy of nabilone for patients with PD with disturbing NMS, which appears to be driven by positive effects on anxious mood and night‐time sleep problems.
Trial registry: ClinicalTrials.gov (NCT03769896) and EudraCT (2017‐000192‐86). ANN NEUROL 2020;88:712–722
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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