Progress towards therapies for disease modification in Parkinson's disease

The development of interventions to slow or halt the progression of Parkinson's disease remains a priority for patients and researchers alike. To date, no agents have been shown to have unequivocal evidence of disease-modifying effects in Parkinson's disease. The absence of disease-modifying treatments might relate not only to inadequate approaches for the selection of therapeutic candidates but also to insufficient attention to detail in clinical trial design. Better understanding of Parkinson's disease pathogenesis associated with advances in laboratory models, the use of objective biomarkers of disease progression and target engagement, and a focus on agents known to be safe for human use, alongside the use of precision medicine approaches, should together greatly increase the likelihood for successful identification of disease-modifying treatments for Parkinson's disease

Pioglitazone in early Parkinson\u27s disease: a phase 2, multicentre, double-blind, randomised trial

Background A systematic assessment of potential disease-modifying compounds for Parkinson\u27s disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson\u27s disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson\u27s disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson\u27s Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0.10. The study is registered at ClinicalTrials.gov, number NCT01280123. Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4.42 (95% CI 2.55-6.28) for 15 mg pioglitazone, 5.13 (95% CI 3.17-7.08) for 45 mg pioglitazone, and 6.25 (95% CI 4.35-8.15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was -1.83 (80% CI -3.56 to -0.10) and the null hypothesis could not be rejected (p=0.19). The mean difference between the 45 mg and placebo groups was -1.12 (80% CI -2.93 to 0.69)and the null hypothesis was rejected in favour of futility (p=0.09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers\u27 only sample, suggested that the 15 mg dose is also futile (p=0.09 for LVCF, p= 0.09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0.12 for LVCF, p=0.19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson\u27s disease. Further study of pioglitazone in a larger trial in patients with Parkinson\u27s disease is not recommended

Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson\u27s disease

\ua9 The Author(s) 2024. Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson’s disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab’s potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic–rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson’s disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression

Background: The objective of this study was to assess neurofilament light chain as a Parkinson’s disease biomarker. Methods: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson’s disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson’s disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. Results: In the Parkinson’s Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson’s disease patients (13 � 7.2 pg/mL) than in controls (12 � 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson’s disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. Conclusions: Neurofilament light chain in serum samples is increased in Parkinson’s disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson’s disease severity. Although the specificity of neurofilament light chain for Parkinson’s disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson’s disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed

Long-term dementia prevalence in Parkinson Disease: Glass half-full?

Introduction: Dementia occurs in up to 80% of Parkinson’s disease (PD) patients long-term, but studies reporting such high rates were published years ago and had relatively small sample sizes and other limitations. Objective: To determine long-term, cumulative dementia prevalence rates in PD using data from two large, ongoing, prospective observational studies. Design: Analyses of data from the Parkinson’s Progression Markers Initiative (PPMI) and a longstanding PD research clinical core at the University of Pennsylvania (Penn). Setting: PPMI is a multi-site international study, and Penn is a single site study at a tertiary movement disorders center. Participants: PPMI enrolls de novo, untreated PD participants at baseline, and Penn enrolls a convenience cohort from a large clinical center. Methods: For PPMI a cognitive battery and MDS-UPDRS Part I are administered annually, and the site investigator assigns a cognitive diagnosis annually. At Penn a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Main Outcomes: Kaplan-Meier (KM) survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using assigned cognitive diagnosis of dementia as the primary endpoint (for both PPMI and Penn), and MoCA score <21 and MDS-UPDRS Part I cognition score ≥3 as secondary endpoints (for PPMI). In addition, cumulative dementia prevalence by PD disease duration was tabulated for each study and endpoint. Results: For the PPMI cohort, 417 PD participants were seen at baseline; estimated cumulative probability of dementia at year 10 disease duration were: 7% (site investigator diagnosis), 9% (MoCA) or 7.4% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 PD participants were followed over time, with 184 participants (47% of cohort) eventually diagnosed with dementia. The KM curve for the Penn cohort had median time to dementia diagnosis =15 years (95% CI: 13-15) disease duration; the estimated cumulative probability of dementia was 27% at year 10, 50% at year 15, and 74% at year 20. Conclusions and Relevance: Results from two large, prospective studies suggest that dementia in Parkinson disease occurs less frequently, or later in the disease course, than often-cited previous research studies have reported

Early Presymptomatic and Long-Term Changes of Rest Activity Cycles and Cognitive Behavior in a MPTP-Monkey Model of Parkinson's Disease

It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms.Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested.Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits

The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort

Objective The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials. Methods A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org. Results Approximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t-tau (45/53) and p-tau (16/18) were reduced in PD versus HC (P < 0.01), Interpretation PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease

BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. CONCLUSION: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD

Precompetitive consensus building to facilitate the use of digital health technologies to support Parkinson Disease drug development through regulatory science

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson’s Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder