Novel therapies with the ability to delay disease progression are a gap in the care of people living with Parkinson disease (PD) today. Clinical outcomes assessments (COAs) that are sensitive to the ...earliest clinical changes in PD are deemed essential for a successful therapeutic development. To understand the current landscape of COAs use in clinical trials in PD and define priorities for future research in the field, a stakeholder roundtable meeting was held in November 2022. The current paper 1) proposes the collaborative development of patient-centric COAs that can adequately document the effectiveness of disease modification therapies in PD based on key priorities identified during this initial meeting, 2) summarizes the progress made in the subsequent 12 months, and 3) presents the deliverables expected in the near future. Key priorities include 1) the development of a consensus conceptual model of early PD experiences, 2) the adaptation of existing patient-reported outcomes (PROs), 3) the investigation of the role of observer-reported outcomes in addition to 4) enabling diversity in PD research and advocacy, 5) fostering data sharing, and 6) reaching consensus on a biological staging system for PD to drive the development of appropriate PROs for biologically defined populations.
We quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in the urine of deeply phenotyped cohorts in the Parkinson's Progression Markers ...Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S+ NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G+ NMC (N = 15), GBA1 N409S PD (N = 76) and N409S+ NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). The effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3-7× higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~30-40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off, or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.
Previous studies have used paired‐pulse transcranial magnetic stimulation to show that short‐interval intracortical inhibition (SICI) is reduced in patients with Parkinson's disease (PD). This study ...examined whether reduced SICI in PD is caused by an increase in the threshold of inhibitory pathways or a reduction in the threshold of excitatory pathways. Motor‐evoked potentials were recorded from a hand muscle in 12 patients with PD (7 patients were tested off and on antiparkinsonian medications) and 12 control subjects. SICI was tested at seven conditioning stimulus intensities (CSIs; 40–100% of resting motor threshold) and at interstimulus intervals (ISIs) of 2, 3, and 4 milliseconds. No differences were found between groups in resting or active motor threshold, SICI threshold, or the extent of SICI at CSIs at or below 80% of resting motor threshold. Significant differences between groups were observed at CSIs of 90% and 100% with an ISI of 3 milliseconds. Antiparkinsonian medication had no effect on SICI. These findings show that the low threshold inhibitory pathways mediating SICI are normal in PD. The suppression of SICI observed at higher CSIs suggests that the threshold of intracortical facilitatory pathways is decreased in PD. Ann Neurol 2005;58:516–524
Introduction. Levodopa is the gold-standard for treatment of Parkinson's disease (PD) related motor symptoms. In this study, we used pseudo-continuous arterial spin labeling (pCASL) to quantify ...changes in cerebral blood flow (CBF) after acute oral administration of levodopa in PD patients. Materials and Methods. Thirteen patients (3 females, age 66.2 ± 8.7 years) with moderately advanced PD (Hoehn and Yahr stage >2 (median 2.5), disease duration >3 years) were scanned on a 3T Siemens MR scanner before and after oral levodopa administration. Statistical parametric mapping was used to detect drug-induced changes in CBF and its correlation to clinical severity scales. Images were normalized and flipped in order to examine effects on the more affected (left) and less affected (right) cerebral hemispheres across the cohort. Results. Levodopa did not change global CBF but increased regional CBF in dorsal midbrain, precuneus/cuneus, more affected inferior frontal pars opercularis and triangularis, bilateral pre- and postcentral gyri, more affected inferior parietal areas, as well as less affected putamen/globus pallidus by 27-74% (p < 0.05, FWE corrected for multiple comparisons). CBF change was negatively correlated with improvement in bradykinesia UPDRS-III subscore in the more affected precentral gyrus, and total predrug UPDRS-III score in the mid-cingulate region. Drug-induced CBF change in a widespread network of regions including parietal and postcentral areas was also negatively correlated with the predrug rigidity UPDRS-III subscore. Conclusion. These findings are in line with prior reports of abnormal activity in the nigrostriatal pathway of PD patients and demonstrate the feasibility of pCASL as a neuroimaging tool for investigating in vivo physiological effects of acute drug administration in PD.
Exenatide, a glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes, has been shown to have neuroprotective benefits in animal models of Parkinson's disease and to be safe ...in a phase 1 study.4 Athauda and colleagues5 reported results of the phase 2 study of exenatide as a potential disease-modifying intervention in Parkinson's disease. ...we would like to highlight a multicentre study of telemedicine care delivery for patients with Parkinson's disease by Beck and colleagues.6 Participants were enrolled in a 12-month randomised study of televisits versus traditional care, showing the feasibility and similar effects of televisits on the quality of life and clinical outcome measures in patients with Parkinson's disease. Amelie-Benoist/BSIP/Science Photo Library TS has received grants from GE Medical and Teva, consulting fees from Acadia, Abbvie, Allergan, GE Medical, Eli Lilly, Harbor, Ibsen, IMPAX, Lundbeck, Merz Inc, Navidea, Pfizer, Teva, UCB Pharma, and US World Meds, and research funding from Auspex, Biotie, Civitas, the US National Institutes of Health, and the Michael J Fox Foundation, and is on the advisory board for IMPAX.
Objective
The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site‐centric therapeutic trials in Parkinson’s ...disease and generate novel insights. The value of this approach has never been more evident than during the current COVID‐19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow‐up of clinical trial participants, (2) compare changes in smartphone‐based assessments, online patient‐reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson’s disease disability and progression.
Methods
Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele‐Health Outcomes in Multiyear Extensions of Parkinson’s Disease trials (AT‐HOME PD), a two‐year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone‐based assessments of motor function and socialization, and patient‐reported outcomes online.
Results
From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study’s smartphone application and 161 (71%) have completed patient‐reported outcomes on the online platform.
Interpretation
It is feasible to conduct a large‐scale, international virtual observational study following the completion of participation in brick‐and‐mortar clinical trials in Parkinson’s disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow‐up of clinical trial participants and design of future clinical trials.
To describe the characteristics of people with Parkinson disease and movement disorders (PDMDs) referred by neurologist to a physiatrist-led interdisciplinary rehabilitation screening program.
...Retrospective data analysis of electronic health records (EMRs).
Outpatient PDMD neurology clinic and an interdisciplinary rehabilitation hospital’s PDMD screening program.
People with PDMDs referred by neurologists to the interdisciplinary rehabilitation screening program from 2009-2017 (n=934), with early referrals from 2009-2015 (n=449) and recently referred from 2015-2017 (n=485), and patients who had new interdisciplinary rehabilitation screening program evaluations from 2015-2017 (n=183).
Participation in the physiatrist-led PDMD screening clinic.
Demographics, disease-related features, timed Up and Go, conversational voice volume, recommended therapy services, and number of therapies completed 90 days following interdisciplinary rehabilitation screening program.
People referred from the neurologists to the interdisciplinary rehabilitation screening program from 2009-2017 were 72±12.9 years old, male (56%), white (65%), and with 1 or more comorbidities (62%). Compared with early referrals from 2009-2015, more recently referred participants from 2015-2017 were younger (P<.001) and earlier in disease duration (P=.036). The interdisciplinary rehabilitation screening program participants from 2015-2017 had mean timed Up and Go time of 15.4±10.1 seconds and a mean conversational voice volume of 68.98±4.7 dB.
The interdisciplinary rehabilitation screening program was sustained with increased number of referrals over time, occurring earlier in the disease in more recent years. Key strategies used to sustain the program over time include development of a unique referral order set for the neurologists, implementation of a comprehensive screen tool in the rehabilitation hospital EMR, and centralized communication through social workers at both facilities.
Introduction: Parkinson's disease psychosis (PDP) may develop in up to 60% of Parkinson's patients and is associated with increased morbidity and mortality. It also correlates with depression and ...dementia, and can contribute to caregiver stress and burnout. Pimavanserin is the first FDA approved drug for the treatment of hallucinations and delusions associated with PDP.
Areas covered: For this review, a MEDLINE literature search (via PubMed) and information provided by ACADIA Pharmaceuticals were used. This review will discuss the pathophysiology and current management of PDP. In addition, this review will focus on the rationales behind the development of pimavanserin, mechanism of action, pharmacokinetics, pharmacodynamics, and the clinical trials evaluating the efficacy and safety of pimavanserin. Last, the review will address the drug's package insert warning.
Expert commentary: Pimavanserin, a 5HT2A receptor inverse agonist, is the first FDA approved drug for the treatment of PDP which has been shown to reduce psychosis in PD through its unique mechanism of action. Pimavanserin, does not worsen PD motor symptoms and has an acceptable safety profile. The development of pimavanserin as an antipsychotic opened a new therapeutic avenue in the treatment of PDP as well as targeting psychosis in other disorders such as Alzheimer's disease.
PDF
