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A rich pipeline of therapeutic candidates is advancing for Parkinson's disease, many of which are targeting the underlying pathophysiology of disease. Emerging evidence grounded in novel genetics and biomarker discoveries is illuminating the true promise of precision medicine-based therapeutic strategies for PD. There has been a growing effort to investigate disease-modifying therapies by designing clinical trials for genetic forms of PD - providing a clearer link to underlying pathophysiology. Leading candidate genes based on human genetic findings that are under active investigation in an array of basic and translational models include SNCA, LRRK2, and GBA. Broad investigations across mechanistic models show that these genes signal through common molecular pathways, namely, autosomal lysosomal pathways, inflammation and mitochondrial function. Therapeutic clinical trials to date based on genetically defined targets have not yet achieved approvals; however, much is to be learned from such pioneering trials. Fundamental principles of drug development that include proof of pharmacology in target tissue are critical to have confidence in advancing such precision-based therapies. There is a clear need for downstream biomarkers of leading candidate therapies to demonstrate proof of mechanism. The current regulatory landscape is poised and primed to support translational modeling strategies for the effective advancement of PD diseasemodifying therapeutic candidates. A convergence of rich complex data that is available, the regulatory framework of model informed drug development (MIDD), and the new biological integrated staging frameworks when combined are collectively setting the stage for advancing new approaches in PD to accelerate progress. This perspective review highlights the potential of quantitative systems pharmacology (QSP) modeling in contributing to the field and hastening the pace of progress in advancing collaborative approaches for urgently needed PD disease-modifying treatments. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) has publicly recognized the importance of improving drug development efficiency, deeming translational biomarkers a top priority. The use of imaging biomarkers has been associated with increased rates of drug approvals. An appropriate level of validation provides a pragmatic way to choose and implement these biomarkers. Standardizing imaging modality selection, data acquisition protocols, and image analysis (in ways that are agnostic to equipment and algorithms) have been key to imaging biomarker deployment. The best known examples come from studies done via precompetitive collaboration efforts, which enable input from multiple stakeholders and data sharing. Digital health technologies (DHTs) provide an opportunity to measure meaningful aspects of patient health, including patient function, for extended periods of time outside of the hospital walls, with objective, sensor‐based measures. We identified the areas where learnings from the imaging biomarker field can accelerate the adoption and widespread use of DHTs to develop novel treatments. As with imaging, technical validation parameters and performance acceptance thresholds need to be established. Approaches amenable to multiple hardware options and data processing algorithms can be enabled by sharing DHT data and by cross‐validating algorithms. Data standardization and creation of shared databases will be vital. Pre‐competitive consortia (public‐private partnerships and professional societies that bring together all stakeholders, including patient organizations, industry, academic experts, and regulators) will advance the regulatory maturity of DHTs in clinical trials. [ABSTRACT FROM AUTHOR]

Objective: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4β2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4β2* nAChR partial agonist varenicline.Methods: Nondemented PD participants with cholinergic deficits were identified with [18 F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4β2* nAChR occupancy after subacute oral varenicline treatment was measured with [18 F]flubatine PET. With a dose selected from the nAChR occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability.Results: Varenicline doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three participants completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements.Interpretation: Varenicline occupied α4β2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4β2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142. [ABSTRACT FROM AUTHOR]

Successful behavior depends on the ability to detect and respond to relevant cues, especially under challenging conditions. This essential component of attention has been hypothesized to be mediated by multiple neuromodulator systems, but the contributions of individual systems (e.g., cholinergic, dopaminergic) have remained unclear. The present study addresses this issue by leveraging individual variation in regionally-specific cholinergic denervation in Parkinson's disease (PD) patients, while controlling for variation in dopaminergic denervation. Patients whose dopaminergic and cholinergic nerve terminal integrity had been previously assessed using Positron Emission Tomography (Bohnen et al., 2012) and controls were tested in a signal detection task that manipulates attentional-perceptual challenge and has been used extensively in both rodents and humans to investigate the cholinergic system's role in responding to such challenges (Demeter et al., 2008; McGaughy and Sarter, 1995; see Hasselmo and Sarter 2011 for review). In simple correlation analyses, measures of midbrain dopaminergic, and both cortical and thalamic cholinergic innervation all predicted preserved signal detection under challenge. However, regression analyses also controlling for age, disease severity, and other variables showed that the only significant independent neurotransmitter-related predictor over and above the other variables in the model was thalamic cholinergic integrity. Furthermore, thalamic cholinergic innervation exclusively predicted hits, not correct rejections, indicating a specific contribution to bottom-up salience processing. These results help define regionally-specific contributions of cholinergic function to different aspects of attention and behavior. [ABSTRACT FROM AUTHOR]

Background: Progression to Hoehn and Yahr (HY) stage 3 marks the transition to advanced disease staging and disability in Parkinson disease (PD). Objective/Methods: We conducted a case-control study of 36 PD subjects at HY stage 2.5 or 3, with groups matched for gender, age, and disease duration. Positron Emission tomography (PET) imaging included dihydrotetrabenazine [11C]DTBZ and Pittsburgh Compound B [11C]PiB. Results: Subjects with HY 2.5 differed from HY 3.0 in mean cortical PiB distribution volume ratio (1.14 vs. 1.23;Wilcoxon two-sample Z = 2.36, p = 0.024) but not striatal DTBZ PET. Conclusion: Cortical amyloid burden differentiates subjects below and at HY stage 3. These results suggest that cortical amyloid accumulation influences the transition from HY2.5 to HY3 and that cortical amyloidopathy may be a therapeutic target in PD. [ABSTRACT FROM AUTHOR]