Using a smartwatch and smartphone to assess early Parkinson's disease in the WATCH-PD study over 12 months.

Digital measures may provide objective, sensitive, real-world measures of disease progression in Parkinson's disease (PD). However, multicenter longitudinal assessments of such measures are few. We recently demonstrated that baseline assessments of gait, tremor, finger tapping, and speech from a commercially available smartwatch, smartphone, and research-grade wearable sensors differed significantly between 82 individuals with early, untreated PD and 50 age-matched controls.

Transforming Drug Development for Neurological Disorders: Proceedings from a Multidisease Area Workshop.

Neurological disorders represent some of the most challenging therapeutic areas for successful drug approvals. The escalating global burden of death and disability for such diseases represents a significant worldwide public health challenge, and the rate of failure of new therapies for chronic progressive disorders of the nervous system is higher relative to other non-neurological conditions. However, progress is emerging rapidly in advancing the drug development landscape in both rare and common neurodegenerative diseases.

Regional serotonin terminal density in aging human brain: A [C]DASB PET study.

There are conflicting results regarding regional age-related changes in serotonin terminal density in human brain. Some imaging studies suggest age-related declines in serotoninergic terminals and perikarya. Other human imaging studies and post-mortem biochemical studies suggest stable brain regional serotoninergic terminal densities across the adult lifespan.

Mapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early Parkinson's Disease.

Background: Adoption of new digital measures for clinical trials and practice has been hindered by lack of actionable qualitative data demonstrating relevance of these metrics to people with Parkinson's disease.

Objective: This study evaluated of relevance of WATCH-PD digital measures to monitoring meaningful symptoms and impacts of early Parkinson's disease from the patient perspective.

Methods: Participants with early Parkinson's disease (N = 40) completed surveys and 1:1 online-interviews.

Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson's Disease.

Background: Patient perspectives on meaningful symptoms and impacts in early Parkinson's disease (PD) are lacking and are urgently needed to clarify priority areas for monitoring, management, and new therapies.

Objective: To examine experiences of people with early-stage PD, systematically describe meaningful symptoms and impacts, and determine which are most bothersome or important.

Methods: Forty adults with early PD who participated in a study evaluating smartwatch and smartphone digital measures (WATCH-PD study) completed online interviews with symptom mapping to hierarchically delineate symptoms and impacts of disease from "Most bothersome" to "Not present," and to identify which of these were viewed as most important and why.

Leveraging the regulatory framework to facilitate drug development in Parkinson's disease.

There is an exigent need for disease-modifying and symptomatic treatment approaches for Parkinson's disease. A better understanding of Parkinson's disease pathophysiology and new insights in genetics has opened exciting new venues for pharmacological treatment targets. There are, however, many challenges on the path from discovery to drug approval.

Progression of regional cortical cholinergic denervation in Parkinson's disease.

Cortical cholinergic deficits contribute to cognitive decline and other deficits in Parkinson's disease. Cross-sectional imaging studies suggest a stereotyped pattern of posterior-to-anterior cortical cholinergic denervation accompanying disease progression in Parkinson's disease. We used serial acetylcholinesterase PET ligand imaging to characterize the trajectory of regional cholinergic synapse deficits in Parkinson's disease, testing the hypothesis of posterior-to-anterior progression of cortical cholinergic deficits.

Empowering drug development: Leveraging insights from imaging technologies to enable the advancement of digital health technologies.

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.

Identification of cholinergic centro-cingulate topography as main contributor to cognitive functioning in Parkinson's disease: Results from a data-driven approach.

Background: Degeneration of the cholinergic system plays an important role in cognitive impairment in Parkinson's disease (PD). Positron emission tomography (PET) imaging using the presynaptic vesicular acetylcholine transporter (VAChT) tracer [F]Fluoroethoxybenzovesamicol ([F]FEOBV) allows for regional assessment of cholinergic innervation. The purpose of this study was to perform a data-driven analysis to identify co-varying cholinergic regions and to evaluate the relationship of these with cognitive functioning in PD.

Decreased vestibular efficacy contributes to abnormal balance in Parkinson's disease.

Background And Purpose: Abnormal balance is poorly responsive to dopaminergic therapy in Parkinson's disease (PD). Decreased vestibular efficacy may contribute to imbalance in PD. The purpose of this study was to investigate the relationship between vestibular measures of dynamic posturography and imbalance in PD while accounting for confounder variables.

Application of longitudinal item response theory models to modeling Parkinson's disease progression.

The Movement Disorder Society revised version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts 2 and 3 reflect patient-reported functional impact and clinician-reported severity of motor signs of Parkinson's disease (PD), respectively. Total scores are common clinical outcomes but may obscure important time-based changes in items. We aim to analyze longitudinal disease progression based on MDS-UPRDS parts 2 and 3 item-level responses over time and as functions of Hoehn & Yahr (H&Y) stages 1 and 2 for subjects with early PD.

Identifying and characterising sources of variability in digital outcome measures in Parkinson's disease.

Smartphones and wearables are widely recognised as the foundation for novel Digital Health Technologies (DHTs) for the clinical assessment of Parkinson's disease. Yet, only limited progress has been made towards their regulatory acceptability as effective drug development tools. A key barrier in achieving this goal relates to the influence of a wide range of sources of variability (SoVs) introduced by measurement processes incorporating DHTs, on their ability to detect relevant changes to PD.

Cholinergic brain network deficits associated with vestibular sensory conflict deficits in Parkinson's disease: correlation with postural and gait deficits.

To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [F]fluoroethoxybenzovesamicol ([F]-FEOBV) PET binding in Parkinson' disease (PD) patients with and without vestibular sensory conflict deficits (VSCD). To examine associations between VSCD-associated cholinergic brain deficits and postural instability and gait difficulties (PIGD). PD persons (M70/F22; mean age 67.

Metadata Framework to Support Deployment of Digital Health Technologies in Clinical Trials in Parkinson's Disease.

Sensor data from digital health technologies (DHTs) used in clinical trials provides a valuable source of information, because of the possibility to combine datasets from different studies, to combine it with other data types, and to reuse it multiple times for various purposes. To date, there exist no standards for capturing or storing DHT biosensor data applicable across modalities and disease areas, and which can also capture the clinical trial and environment-specific aspects, so-called metadata. In this perspectives paper, we propose a metadata framework that divides the DHT metadata into metadata that is independent of the therapeutic area or clinical trial design (concept of interest and context of use), and metadata that is dependent on these factors.

Cholinergic systems, attentional-motor integration, and cognitive control in Parkinson's disease.

Dysfunction and degeneration of CNS cholinergic systems is a significant component of multi-system pathology in Parkinson's disease (PD). We review the basic architecture of human CNS cholinergic systems and the tools available for studying changes in human cholinergic systems. Earlier post-mortem studies implicated abnormalities of basal forebrain corticopetal cholinergic (BFCC) and pedunculopontine-laterodorsal tegmental (PPN-LDT) cholinergic projections in cognitive deficits and gait-balance deficits, respectively.

Altered Cholinergic Innervation in De Novo Parkinson's Disease with and Without Cognitive Impairment.

Background: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention.

Objective: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment.

Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson's disease.

Clinical effects of anti-cholinergic drugs implicate cholinergic systems alterations in the pathophysiology of some cardinal motor impairments in Parkinson's disease. The topography of affected cholinergic systems deficits and motor domain specificity are poorly understood. Parkinson's disease patients ( = 108) underwent clinical and motor assessment and vesicular acetylcholine transporter [F]-fluoroethoxybenzovesamicol PET imaging.

Striatal Acetylcholine-Dopamine Imbalance in Parkinson Disease: In Vivo Neuroimaging Study with Dual-Tracer PET and Dopaminergic PET-Informed Correlational Tractography.

Previous studies of animal models of Parkinson disease (PD) suggest an imbalance between striatal acetylcholine and dopamine, although other studies have questioned this. To our knowledge, there are no previous in vivo neuroimaging studies examining striatal acetylcholine-dopamine imbalance in PD patients. Using cholinergic and dopaminergic PET (F-fluoroethoxybenzovesamicol [F-FEOBV] and C-dihydrotetrabenazine [C-DTBZ], respectively) and correlational tractography, our aim was to investigate the acetylcholine-dopamine interaction at 2 levels of dopaminergic loss in PD subjects: integrity loss of the nigrostriatal dopaminergic white matter tract and loss at the presynaptic-terminal level.

α4β2 Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

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 [ F]fluoroethoxybenzovesamicol positron emission tomography (PET).

Classics in Neuroimaging: Imaging the Cholinergic System with Positron Emission Tomography.

Since the earliest days of nuclear medicine, there has been interest in using PET and SPECT imaging to interrogate and quantify the cholinergic system. In this Viewpoint we highlight key milestones in the development of cholinergic imaging agents, including identification of radiopharmaceuticals targeting the receptors, transporters, and enzymes of the cholinergic synapse, as well as fundamental developments in the radiopharmaceutical sciences (e.g.

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders.

Purpose Of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders.

Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors.

Cholinergic Denervation Patterns Across Cognitive Domains in Parkinson's Disease.

Background: The cholinergic system plays a key role in cognitive impairment in Parkinson's disease (PD). Previous acetylcholinesterase positron emission tomography imaging studies found memory, attention, and executive function correlates of global cortical cholinergic losses. Vesicular acetylcholine transporter positron emission tomography allows for more accurate topographic assessment of not only cortical but also subcortical cholinergic changes.

Dopaminergic Nigrostriatal Connectivity in Early Parkinson Disease: In Vivo Neuroimaging Study of C-DTBZ PET Combined with Correlational Tractography.

Previous histopathologic and animal studies have shown axonal impairment and loss of connectivity of the nigrostriatal pathway in Parkinson disease (PD). However, there are conflicting reports from in vivo human studies. C-dihydrotetrabenazine (C-DTBZ) is a vesicular monoamine type 2 transporter PET ligand that allows assessment of nigrostriatal presynaptic dopaminergic terminal integrity.

Feasibility and behavioral effects of prolonged static and dynamic standing as compared to sitting in older adults with type 2 diabetes mellitus.

Background: Physical inactivity is prevalent in older adults with type 2 diabetes mellitus (T2DM) and may exacerbate their clinical symptoms. The aim of this study was to examine the feasibility of 4-h regular versus more dynamic standing sessions while performing routine desktop activities as a non-exercise physical activity intervention in older adults with T2DM to increase non-exercise activity.

Methods: Twelve older adult patients with T2DM (3 female; age 71 ± 4 years; Body mass index 34 ± 5 kg/m) completed three sessions (baseline sitting followed by "static" or "dynamic" desktop standing sessions).