Longitudinal assessment of social cognition in de novo Parkinson's disease patients and its relationship with dopaminergic innervation.

BACKGROUND: Social Cognition (SC) has been scarcely studied in Parkinson's disease (PD), and findings in early disease are controversial. SC encompasses different capacities such as facial emotion recognition (FER); Theory of Mind (ToM), the ability to understand other people's intentions (cognitive-ToM) and emotions (affective-ToM); and self-monitoring, the ability to regulate one's own behavior in social contexts. A relationship between dopaminergic deficit and SC in PD has been suggested. OBJECTIVES: To prospectively assess, over a two-year period, SC in newly diagnosed drug-naïve, cognitively normal and non-depressed PD patients. Furthermore, we aimed to evaluate the relationship between SC and Fluorodopa (Positron Emission Tomography) Ki uptake, which is a marker of dopaminergic depletion. METHODS: We compared SC performance between 25 de novo PD patients and 20 healthy controls (HC), and within-patients at baseline and two-year follow-up. The SC assessment included FER, ToM, as well as self-monitoring measures. The relationship between SC and dopaminergic innervation was also assessed in patients. RESULTS: SC scores did not differ between PD and HC groups at baseline, nor between baseline and follow-up evaluation in PD. A significant positive correlation between self-monitoring and Fluorodopa Ki uptake in the left pallidum in PD patients was found at baseline. At follow-up, ToM (stories) positively correlated with Fluorodopa Ki uptake in the right thalamus and the left putamen. CONCLUSION: SC appears to be preserved in de novo PD and remains stable in the short-term. Although more evidence is needed, our results support a relationship between dopamine innervation in subcortical regions and SC.

Co-Designing Digital Technologies for Improving Clinical Care in People with Parkinson's Disease: What Did We Learn?

The healthcare model is shifting towards integrated care approaches. This new model requires patients to be more closely involved. The iCARE-PD project aims to address this need by developing a technology-enabled, home-based, and community-centered integrated care paradigm. A central part of this project is the codesign process of the model of care, exemplified by the active participation of patients in the design and iterative evaluation of three sensor-based technological solutions. We proposed a codesign methodology used for testing the usability and acceptability of these digital technologies and present initial results for one of them, MooVeo. Our results show the usefulness of this approach in testing the usability and acceptability as well as the opportunity to incorporate patients' feedback into the development. This initiative will hopefully help other groups incorporate a similar codesign approach and develop tools that are well adapted to patients' and care teams' needs.

Usability Evaluation of a Noninvasive Neutropenia Screening Device (PointCheck) for Patients Undergoing Cancer Chemotherapy: Mixed Methods Observational Study.

BACKGROUND: Patients with cancer undergoing cytotoxic chemotherapy face an elevated risk of developing serious infection as a consequence of their treatment, which lowers their white blood cell count and, more specifically, their absolute neutrophil count. This condition is known as neutropenia. Neutropenia accompanied by a fever is referred to as febrile neutropenia, a common side effect of chemotherapy with a high mortality rate. The timely detection of severe neutropenia (<500 absolute neutrophil count/µL) is critical in detecting and managing febrile neutropenia. Current methods rely on blood draws, which limit them to clinical settings and do not allow frequent or portable monitoring. In this study, we demonstrated the usability of PointCheck, a noninvasive device for neutropenia screening, in a simulated home environment without clinical supervision. PointCheck automatically performs microscopy through the skin of the finger to image the blood flowing through superficial microcapillaries and enables the remote monitoring of neutropenia status, without requiring venipuncture. OBJECTIVE: This study aimed to evaluate the usability of PointCheck, a noninvasive optical technology for screening severe neutropenia, with the goal of identifying potential user interface, functionality, and design issues from the perspective of untrained users. METHODS: We conducted a multicenter study using quantitative and qualitative approaches to evaluate the usability of PointCheck across 154 untrained participants. We used a mixed method approach to gather usability data through user testing observations, a short-answer qualitative questionnaire, and a standardized quantitative System Usability Scale (SUS) survey to assess perceived usability and satisfaction. RESULTS: Of the 154 participants, we found that 108 (70.1%) scored above 80.8 on the SUS across all sites, with a mean SUS score of 86.1 across all sites. Furthermore, the SUS results indicated that, out of the 151 users who completed the SUS survey, 145 (96%) found that they learned how to use PointCheck very quickly, and 141 (93.4%) felt very confident when using the device. CONCLUSIONS: We have shown that PointCheck, a novel technology for noninvasive, home-based neutropenia detection, can be safely and effectively operated by first-time users. In a simulated home environment, these users found it easy to use, with a mean SUS score of 86.1, indicating an excellent perception of usability and placing this device within the top tenth percentile of systems evaluated for usability by the SUS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04448314; https://clinicaltrials.gov/ct2/show/NCT04448314 (Hospital Universitario 12 de Octubre registration) and NCT04448301; https://clinicaltrials.gov/ct2/show/NCT04448301 (Boston Medical Center registration).

Onset pattern of nigrostriatal denervation in early Parkinson's disease.

The striatal dopaminergic deficit in Parkinson's disease exhibits a typical pattern, extending from the caudal and dorsal putamen at onset to its more rostral region as the disease progresses. Clinically, upper-limb onset of cardinal motor features is the rule. Thus, according to current understanding of striatal somatotopy (i.e. the lower limb is dorsal to the upper limb) the assumed pattern of early dorsal striatal dopaminergic denervation in Parkinson's disease does not fit with an upper-limb onset. We have examined the topography of putaminal denervation in a cohort of 23 recently diagnosed de novo Parkinson's disease patients and 19 age-/gender-matched healthy subjects assessed clinically and by 18F-DOPA PET; 15 patients were re-assessed after 2 years. There was a net upper-limb predominance of motor features at onset. Caudal denervation of the putamen was confirmed in both the more- and less-affected hemispheres and corresponding hemibodies. Spatial covariance analysis of the most affected hemisphere revealed a pattern of 18F-DOPA uptake rate deficit that suggested focal dopamine loss starting in the posterolateral and intermediate putamen. Functional MRI group-activation maps during a self-paced motor task were used to represent the somatotopy of the putamen and were then used to characterize the decline in 18F-DOPA uptake rate in the upper- and lower-limb territories. This showed a predominant decrement in both hemispheres, which correlated significantly with severity of bradykinesia. A more detailed spatial analysis revealed a dorsoventral linear gradient of 18F-DOPA uptake rate in Parkinson's disease patients, with the highest putamen denervation in the caudal intermediate subregion (dorsoventral plane) compared to healthy subjects. The latter area coincides with the functional representation of the upper limb. Clinical motor assessment at 2-year follow-up showed modest worsening of parkinsonism in the primarily affected side and more noticeable increases in the upper limb in the less-affected side. Concomitantly, 18F-DOPA uptake rate in the less-affected putamen mimicked that recognized on the most-affected side. Our findings suggest that early dopaminergic denervation in Parkinson's disease follows a somatotopically related pattern, starting with the upper-limb representation in the putamen and progressing over a 2-year period in the less-affected hemisphere. These changes correlate well with the clinical presentation and evolution of motor features. Recognition of a precise somatotopic onset of nigrostriatal denervation may help to better understand the onset and progression of dopaminergic neurodegeneration in Parkinson's disease and eventually monitor the impact of putative therapies.

COVID-19 Vaccination for Persons with Parkinson's Disease: Light at the End of the Tunnel?

Several COVID-19 vaccines have recently been approved for emergency use according to governmental immunization programs. The arrival of these vaccines has created hope for people with Parkinson's disease (PD), as this can help to mitigate their risk of becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can lead to serious, life-threatening disease, at least among those with more advanced PD. However, both persons with PD and physicians looking after these individuals have expressed concerns about the vaccine's efficacy and safety in the specific context of PD and its symptomatic treatment. Here, we discuss our perspective on these concerns, based on our interpretation of the literature plus the unfolding experience with widespread vaccination in the population at large. Because the benefits and risks of COVID-19 vaccines do not appear to be different than in the general population, we recommend COVID-19 vaccination with approved vaccines to persons with PD, unless there is a specific contraindication. Some caution seems warranted in very frail and terminally ill elderly persons with PD living in long-term care facilities.

Motor Onset Topography and Progression in Parkinson's Disease: the Upper Limb Is First.

OBJECTIVE: To define the motor onset and progression of Parkinson's disease (PD) in a prospective cohort of early unmedicated patients. METHODS: We enrolled a consecutive cohort of recently diagnosed (<18 months) PD patients with unilateral manifestations using age and gender-matched controls. The most affected body region was determined using various clinical standard metrics and objective quantitative kinematic measurements. Parkinson's Progression Markers Initiative data were used for external validation of the results. RESULTS: Twenty-five drug-naive patients and 21 controls were studied. Upper limbs were (92%) the most affected body region at onset as ascertained by patients' self-assessment, neurologists' impression, and Movement Disorders Society Unified Parkinson's Disease Rating Scale score. The upper limb (ie, hand) was the site of onset in 80% of patients. Motor features progressed to involve the lower limb but remained limited to the initially affected body side over a 2-year follow-up. Agreement among the different metrics (96%) confirmed focal upper limb predominant motor impairment at onset. The findings were confirmed by quantitative kinematic analyses and from a cohort of 34 similar patients from the Parkinson's Progression Markers Initiative database. CONCLUSIONS: Motor manifestations in PD start distally in one upper limb. The complexity of the motor repertoire and, consequently, the presumed larger dopaminergic striatal demand for maintaining skillful motor function in the upper limb, may contribute to greater vulnerability of dopaminergic striatal terminals. Recognition of this motor pattern could be used to monitor the evolution of nigrostriatal degeneration and the putative impact of therapies. © 2021 International Parkinson and Movement Disorder Society.

Remote Evaluation of Parkinson's Disease Using a Conventional Webcam and Artificial Intelligence.

Objective: This study aimed to prove the concept of a new optical video-based system to measure Parkinson's disease (PD) remotely using an accessible standard webcam. Methods: We consecutively enrolled a cohort of 42 patients with PD and healthy subjects (HSs). The participants were recorded performing MDS-UPDRS III bradykinesia upper limb tasks with a computer webcam. The video frames were processed using the artificial intelligence algorithms tracking the movements of the hands. The video extracted features were correlated with clinical rating using the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale and inertial measurement units (IMUs). The developed classifiers were validated on an independent dataset. Results: We found significant differences in the motor performance of the patients with PD and HSs in all the bradykinesia upper limb motor tasks. The best performing classifiers were unilateral finger tapping and hand movement speed. The model correlated both with the IMUs for quantitative assessment of motor function and the clinical scales, hence demonstrating concurrent validity with the existing methods. Conclusions: We present here the proof-of-concept of a novel webcam-based technology to remotely detect the parkinsonian features using artificial intelligence. This method has preliminarily achieved a very high diagnostic accuracy and could be easily expanded to other disease manifestations to support PD management.

Modernizing Daily Function Assessment in Parkinson's Disease Using Capacity, Perception, and Performance Measures.

Many disease symptoms restrict the quality of life of the affected. This usually occurs indirectly, at least in most neurological diseases. Here, impaired daily function is interposed between the symptoms and the reduced quality of life. This is reflected in the International Classification of Function, Disability and Health model published by the World Health Organization in 2001. This correlation between symptom, daily function, and quality of life makes it clear that to evaluate the success of a therapy and develop new therapies, daily function must also be evaluated as accurately as possible. However, daily function is a complex construct and therefore difficult to quantify. To date, daily function has been measured primarily by capacity (clinical assessments) and perception (surveys and patient-reported outcomes) assessment approaches. Now, daily function can be captured in a new dimension, that is, performance, through new digital technologies that can be used in the home environment of patients. This viewpoint discusses the differences and interdependencies of capacity, perception, and performance assessment types using the example of Parkinson's disease. Options regarding how future study protocols should be designed to get the most comprehensive and validated picture of daily function in patients are presented. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Technology-Enabled Care: Integrating Multidisciplinary Care in Parkinson's Disease Through Digital Technology.

Parkinson's disease (PD) management requires the involvement of movement disorders experts, other medical specialists, and allied health professionals. Traditionally, multispecialty care has been implemented in the form of a multidisciplinary center, with an inconsistent clinical benefit and health economic impact. With the current capabilities of digital technologies, multispecialty care can be reshaped to reach a broader community of people with PD in their home and community. Digital technologies have the potential to connect patients with the care team beyond the traditional sparse clinical visit, fostering care continuity and accessibility. For example, video conferencing systems can enable the remote delivery of multispecialty care. With big data analyses, wearable and non-wearable technologies using artificial intelligence can enable the remote assessment of patients' conditions in their natural home environment, promoting a more comprehensive clinical evaluation and empowering patients to monitor their disease. These advances have been defined as technology-enabled care (TEC). We present examples of TEC under development and describe the potential challenges to achieve a full integration of technology to address complex care needs in PD.

Cortical disinhibition in Parkinson's disease.

In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease.

Moving towards home-based community-centred integrated care in Parkinson's disease.

People living with Parkinson's disease (PwP) experience a wide range of motor and non-motor symptoms associated with increasing complexity of care delivery. A multispecialty approach has been presented as an intuitive solution for tailored and comprehensive care delivery. Nevertheless, past trials of both multidisciplinary or interdisciplinary care models in PD suggested no measurable change to a small benefit in quality of life (QoL) and failed to show economic sustainability. We propose a home-based community-centred integrated care (iCARE-PD) for PwP as a pragmatic solution to harness the potential of existing care resources using an integrated care strategy, enable self-management support and implement technology-enabled care. The iCARE-PD model is based on Freeman's concept of continuity of care and the expanded Chronic Care Model for organization of care strategies. A home-based community-centred integrated care has immediate implications for clinical practice, with potential benefits in rural areas or lower-income countries, by enhancing access to care with optimized costs. There is a need to establish which and how interventions may be used as an instrument of care in each local deployment of the iCARE-PD model. We put forward a multidisciplinary framework to generate the evidence supportive of its implementation as the standard of care in the future and delineate the core strategies to secure the implementation of this care approach across different health care systems to ensure feasibility and economic sustainability. We envision this model becoming a paradigm of personalized care transferable to people with atypical forms of neurodegenerative parkinsonism.

Visualization of blood cell contrast in nailfold capillaries with high-speed reverse lens mobile phone microscopy.

Quantification of optical absorption gaps in nailfold capillaries has recently shown promise as a non-invasive technique for neutropenia screening. Here we demonstrate a low-cost, portable attachment to a mobile phone that can resolve optical absorption gaps in nailfold capillaries using a reverse lens technique and oblique 520nm illumination. Resolution <4µm within a 1mm2 on-axis region is demonstrated, and wide field of view (3.5mm × 4.8mm) imaging is achieved with resolution <6µm in the periphery. Optical absorption gaps (OAGs) are visible in superficial capillary loops of a healthy human participant by an ∼8-fold difference in contrast-to-noise ratio with respect to red blood cell absorption contrast. High speed video capillaroscopy up to 240 frames per second (fps) is possible, though 60fps is sufficient to resolve an average frequency of 37 OAGs/minute passing through nailfold capillaries. The simplicity and portability of this technique may enable the development of an effective non-invasive tool for white blood cell screening in point-of-care and global health settings.

A data mining approach for classification of orthostatic and essential tremor based on MRI-derived brain volume and cortical thickness.

OBJECTIVE: Orthostatic tremor (OT) is an extremely rare, misdiagnosed, and underdiagnosed disorder affecting adults in midlife. There is debate as to whether it is a different condition or a variant of essential tremor (ET), or even, if both conditions coexist. Our objective was to use data mining classification methods, using magnetic resonance imaging (MRI)-derived brain volume and cortical thickness data, to identify morphometric measures that help to discriminate OT patients from those with ET. METHODS: MRI-derived brain volume and cortical thickness were obtained from 14 OT patients and 15 age-, sex-, and education-matched ET patients. Feature selection and machine learning methods were subsequently applied. RESULTS: Four MRI features alone distinguished the two, OT from ET, with 100% diagnostic accuracy. More specifically, left thalamus proper volume (normalized by the total intracranial volume), right superior parietal volume, right superior parietal thickness, and right inferior parietal roughness (i.e., the standard deviation of cortical thickness) were shown to play a key role in OT and ET characterization. Finally, the left caudal anterior cingulate thickness and the left caudal middle frontal roughness allowed us to separate with 100% diagnostic accuracy subgroups of OT patients (primary and those with mild parkinsonian signs). CONCLUSIONS: A data mining approach applied to MRI-derived brain volume and cortical thickness data may differentiate between these two types of tremor with an accuracy of 100%. Our results suggest that OT and ET are distinct conditions.

Diffusion tensor imaging in orthostatic tremor: a tract-based spatial statistics study.

OBJECTIVE: The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT-related white matter changes and their correlations with scores from a neuropsychological testing battery. METHODS: Diffusion tensor imaging measures were compared between 14 OT patients and 14 age- and education-matched healthy controls, using whole-brain tract-based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed. RESULTS: In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients' cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients. INTERPRETATION: White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal-thalamic-cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences.

Remote Monitoring of Treatment Response in Parkinson's Disease: The Habit of Typing on a Computer.

OBJECTIVE: The recent advances in technology are opening a new opportunity to remotely evaluate motor features in people with Parkinson's disease (PD). We hypothesized that typing on an electronic device, a habitual behavior facilitated by the nigrostriatal dopaminergic pathway, could allow for objectively and nonobtrusively monitoring parkinsonian features and response to medication in an at-home setting. METHODS: We enrolled 31 participants recently diagnosed with PD who were due to start dopaminergic treatment and 30 age-matched controls. We remotely monitored their typing pattern during a 6-month (24 weeks) follow-up period before and while dopaminergic medications were being titrated. The typing data were used to develop a novel algorithm based on recursive neural networks and detect participants' responses to medication. The latter were defined by the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) minimal clinically important difference. Furthermore, we tested the accuracy of the algorithm to predict the final response to medication as early as 21 weeks prior to the final 6-month clinical outcome. RESULTS: The score on the novel algorithm based on recursive neural networks had an overall moderate kappa agreement and fair area under the receiver operating characteristic (ROC) curve with the time-coincident UPDRS-III minimal clinically important difference. The participants classified as responders at the final visit (based on the UPDRS-III minimal clinically important difference) had higher scores on the novel algorithm based on recursive neural networks when compared with the participants with stable UPDRS-III, from the third week of the study onward. CONCLUSIONS: This preliminary study suggests that remotely gathered unsupervised typing data allows for the accurate detection and prediction of drug response in PD. © 2019 International Parkinson and Movement Disorder Society.