The Body, the Brain, the Environment, and Parkinson's Disease.

The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric nervous system. In both scenarios the pathology seems to arise in structures that are closely connected to the outside world. Environmental toxicants, including certain pesticides, industrial chemicals, and air pollution are therefore plausible trigger mechanisms for Parkinson's disease and dementia with Lewy bodies. Here, we propose that toxicants inhaled through the nose can lead to pathological changes in alpha-synuclein in the olfactory system that subsequently spread and give rise to a brain-first subtype of Lewy body disease. Similarly, ingested toxicants can pass through the gut and cause alpha-synuclein pathology that then extends via parasympathetic and sympathetic pathways to ultimately produce a body-first subtype. The resulting spread can be tracked by the development of symptoms, clinical assessments, in vivo imaging, and ultimately pathological examination. The integration of environmental exposures into the brain-first and body-first models generates testable hypotheses, including on the prevalence of the clinical conditions, their future incidence, imaging patterns, and pathological signatures. The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome, and the effects of ongoing exposures. Despite these limitations, the interaction of exogenous factors with the nose and the gut may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal -prevention.

The Prevalence of Parkinson's Disease in Poland: Regional and Sex-Related Differences.

Background: Given the growing evidence for an environmental contribution to the etiology of Parkinson's disease (PD), searching for local and regional differences in PD prevalence in multiple areas across the world may further clarify the role of environmental toxins. Objective: To provide local and regional prevalence estimates of PD in Poland. Methods: We analyzed the prevalence of PD and its trend over the last decade (2010 to 2019) based on data from the National Health Fund in Poland. We specifically examined sex differences in PD prevalence, as well as differences across Polish regions. Results: During the above period, the prevalence of PD in Poland increased from 226 per 100,000 to 269 per 100,000 inhabitants. Unexpectedly, we found that PD was 1.2-times more common in women than men. The increase in prevalence over the past decade was different between both sexes: an increase from 250 to 283 per 100,000 for women (13.3% increase), and from 200 to 254 per 100,000 for men (27.1% increase). In addition, we observed differences in prevalence across different Polish regions, with some regions having up to 51% lower prevalence rates than others. Conclusions: The prevalence of PD in Poland is in line with previously reported prevalence rates across Europe. However, unlike the situation in most of the world, PD was more prevalent in women than men. We discuss several possible explanations as well as potential measures that might help to reduce the growth of PD.

Parkinson's Disease in Sub-Saharan Africa: Pesticides as a Double-Edged Sword.

Long-term exposure to pesticides used in agriculture is increasingly being identified as a risk factor for developing Parkinson's disease. How chronic pesticide exposure might contribute to the growth of Parkinson's disease in the mainly agricultural communities of Sub-Saharan Africa has thus far received limited attention. There are specific concerns in this area of the world: aging of the population, in combination with chronic exposure to widely used pesticides, including those that have been restricted elsewhere in the world because of neurotoxicity and other health risks. Of interest, the prevalence of Parkinson's disease among specific (semi)nomadic populations in Tanzania seems very low, possibly due to their lack of exposure to agricultural chemicals. But at the same time, pesticides have also brought important benefits to this part of the world. Specifically, in Sub-Saharan Africa, pesticides have been directly helpful in preventing and controlling famine and in containing major human infectious diseases. This creates a complex risk-benefit ratio to the use of pesticides within a global perspective, and urgently calls for the development and implementation of affordable alternatives for areas such as Sub-Saharan Africa, including non-neurotoxic compounds and non-chemical alternatives for the use of pesticides.

Improved measurement of disease progression in people living with early Parkinson's disease using digital health technologies.

BACKGROUND: Digital health technologies show promise for improving the measurement of Parkinson's disease in clinical research and trials. However, it is not clear whether digital measures demonstrate enhanced sensitivity to disease progression compared to traditional measurement approaches. METHODS: To this end, we develop a wearable sensor-based digital algorithm for deriving features of upper and lower-body bradykinesia and evaluate the sensitivity of digital measures to 1-year longitudinal progression using data from the WATCH-PD study, a multicenter, observational digital assessment study in participants with early, untreated Parkinson's disease. In total, 82 early, untreated Parkinson's disease participants and 50 age-matched controls were recruited and took part in a variety of motor tasks over the course of a 12-month period while wearing body-worn inertial sensors. We establish clinical validity of sensor-based digital measures by investigating convergent validity with appropriate clinical constructs, known groups validity by distinguishing patients from healthy volunteers, and test-retest reliability by comparing measurements between visits. RESULTS: We demonstrate clinical validity of the digital measures, and importantly, superior sensitivity of digital measures for distinguishing 1-year longitudinal change in early-stage PD relative to corresponding clinical constructs. CONCLUSIONS: Our results demonstrate the potential of digital health technologies to enhance sensitivity to disease progression relative to existing measurement standards and may constitute the basis for use as drug development tools in clinical research.

Parkinson's disease can impact a person's ability to move, which can result in slow or rigid movements. Wearable sensors can be used to measure these symptoms and could be particularly useful to detect changes early in the course of the disease when symptoms may be subtle. We developed a wearable sensor-based method to measure movement in people with early Parkinson's disease that uses wrist and foot-worn sensors. Our results demonstrate that our sensor-based measurements can accurately quantify progressive changes in movement function. Such measurements may allow researchers to more accurately evaluate how well treatments designed to slow the course of Parkinson's disease are working in the future.

Digital assessment of speech in Huntington disease.

Background: Speech changes are an early symptom of Huntington disease (HD) and may occur prior to other motor and cognitive symptoms. Assessment of HD commonly uses clinician-rated outcome measures, which can be limited by observer variability and episodic administration. Speech symptoms are well suited for evaluation by digital measures which can enable sensitive, frequent, passive, and remote administration. Methods: We collected audio recordings using an external microphone of 36 (18 HD, 7 prodromal HD, and 11 control) participants completing passage reading, counting forward, and counting backwards speech tasks. Motor and cognitive assessments were also administered. Features including pausing, pitch, and accuracy were automatically extracted from recordings using the BioDigit Speech software and compared between the three groups. Speech features were also analyzed by the Unified Huntington Disease Rating Scale (UHDRS) dysarthria score. Random forest machine learning models were implemented to predict clinical status and clinical scores from speech features. Results: Significant differences in pausing, intelligibility, and accuracy features were observed between HD, prodromal HD, and control groups for the passage reading task (e.g., p < 0.001 with Cohen'd = -2 between HD and control groups for pause ratio). A few parameters were significantly different between the HD and control groups for the counting forward and backwards speech tasks. A random forest classifier predicted clinical status from speech tasks with a balanced accuracy of 73% and an AUC of 0.92. Random forest regressors predicted clinical outcomes from speech features with mean absolute error ranging from 2.43-9.64 for UHDRS total functional capacity, motor and dysarthria scores, and explained variance ranging from 14 to 65%. Montreal Cognitive Assessment scores were predicted with mean absolute error of 2.3 and explained variance of 30%. Conclusion: Speech data have the potential to be a valuable digital measure of HD progression, and can also enable remote, frequent disease assessment in prodromal HD and HD. Clinical status and disease severity were predicted from extracted speech features using random forest machine learning models. Speech measurements could be leveraged as sensitive marker of clinical onset and disease progression in future clinical trials.

Dry-Cleaning Chemicals and a Cluster of Parkinson's Disease and Cancer: A Retrospective Investigation.

BACKGROUND: Environmental exposure to trichloroethylene (TCE), a carcinogenic dry-cleaning chemical, may be linked to Parkinson's disease (PD). OBJECTIVE: The objective of this study was to determine whether PD and cancer were elevated among attorneys who worked near a contaminated site. METHODS: We surveyed and evaluated attorneys with possible exposure and assessed a comparison group. RESULTS: Seventy-nine of 82 attorneys (96.3%; mean [SD] age: 69.5 [11.4] years; 89.9% men) completed at least one phase of the study. For comparison, 75 lawyers (64.9 [10.2] years; 65.3% men) underwent clinical evaluations. Four (5.1%) of them who worked near the polluted site reported PD, more than expected based on age and sex (1.7%; P = 0.01) but not significantly higher than the comparison group (n = 1 [1.3%]; P = 0.37). Fifteen (19.0%), compared to four in the comparison group (5.3%; P = 0.049), had a TCE-related cancer. CONCLUSIONS: In a retrospective study, diagnoses of PD and TCE-related cancers appeared to be elevated among attorneys who worked next to a contaminated dry-cleaning site. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson's Disease Is Predominantly an Environmental Disease.

Parkinson's disease is the world's fastest growing brain disorder, and exposure to environmental toxicants is the principal reason. In this paper, we consider alternative, but unsatisfactory, explanations for its rise, including improved diagnostic skills, aging populations, and genetic causes. We then detail three environmental toxicants that are likely among the main causes of Parkinson's disease- certain pesticides, the solvent trichloroethylene, and air pollution. All three environmental toxicants are ubiquitous, many affect mitochondrial functioning, and all can access humans via various routes, including inhalation and ingestion. We reach the hopeful conclusion that most of Parkinson's disease is thus preventable and that we can help to create a world where Parkinson's disease is increasingly rare.

Towards interpretable speech biomarkers: exploring MFCCs.

While speech biomarkers of disease have attracted increased interest in recent years, a challenge is that features derived from signal processing or machine learning approaches may lack clinical interpretability. As an example, Mel frequency cepstral coefficients (MFCCs) have been identified in several studies as a useful marker of disease, but are regarded as uninterpretable. Here we explore correlations between MFCC coefficients and more interpretable speech biomarkers. In particular we quantify the MFCC2 endpoint, which can be interpreted as a weighted ratio of low- to high-frequency energy, a concept which has been previously linked to disease-induced voice changes. By exploring MFCC2 in several datasets, we show how its sensitivity to disease can be increased by adjusting computation parameters.

Unsupervised anomaly detection by densely contrastive learning for time series data.

Time series data continuously collected by different sensors play an essential role in monitoring and predicting events in many real-world applications, and anomaly detection for time series has received increasing attention during the past decades. In this paper, we propose an anomaly detection method by densely contrasting the whole time series with its sub-sequences at different timestamps in a latent space. Our approach leverages the locality property of convolutional neural networks (CNN) and integrates position embedding to effectively capture local features for sub-sequences. Simultaneously, we employ an attention mechanism to extract global features from the entire time series. By combining these local and global features, our model is trained using both instance-level contrastive learning loss and distribution-level alignment loss. Furthermore, we introduce a reconstruction loss applied to the extracted global features to prevent the potential loss of information. To validate the efficacy of our proposed technique, we conduct experiments on publicly available time-series datasets for anomaly detection. Additionally, we evaluate our method on an in-house mobile phone dataset aimed at monitoring the status of Parkinson's disease, all within an unsupervised learning framework. Our results demonstrate the effectiveness and potential of the proposed approach in tackling anomaly detection in time series data, offering promising applications in real-world scenarios.

Predicting Ambulatory Capacity in Parkinson's Disease to Analyze Progression, Biomarkers, and Trial Design.

BACKGROUND: In Parkinson's disease (PD), gait and balance is impaired, relatively resistant to available treatment and associated with falls and disability. Predictive models of ambulatory progression could enhance understanding of gait/balance disturbances and aid in trial design. OBJECTIVES: To predict trajectories of ambulatory abilities from baseline clinical data in early PD, relate trajectories to clinical milestones, compare biomarkers, and evaluate trajectories for enrichment of clinical trials. METHODS: Data from two multicenter, longitudinal, observational studies were used for model training (Tracking Parkinson's, n = 1598) and external testing (Parkinson's Progression Markers Initiative, n = 407). Models were trained and validated to predict individuals as having a "Progressive" or "Stable" trajectory based on changes of ambulatory capacity scores from the Movement Disorders Society Unified Parkinson's Disease Rating Scale parts II and III. Survival analyses compared time-to-clinical milestones and trial outcomes between predicted trajectories. RESULTS: On external evaluation, a support vector machine model predicted Progressive trajectories using baseline clinical data with an accuracy, weighted-F1 (proportionally weighted harmonic mean of precision and sensitivity), and sensitivity/specificity of 0.735, 0.799, and 0.688/0.739, respectively. Over 4 years, the predicted Progressive trajectory was more likely to experience impaired balance, loss of independence, impaired function and cognition. Baseline dopamine transporter imaging and select biomarkers of neurodegeneration were significantly different between predicted trajectory groups. For an 18-month, randomized (1:1) clinical trial, sample size savings up to 30% were possible when enrollment was enriched for the Progressive trajectory versus no enrichment. CONCLUSIONS: It is possible to predict ambulatory abilities from clinical data that are associated with meaningful outcomes in people with early PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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. Individual symptom maps were coded for types, frequencies, and bothersomeness of symptoms and their impacts, with thematic analysis of narratives to explore perceptions. RESULTS: The three most bothersome and important symptoms were tremor, fine motor difficulties, and slow movements. Symptoms had the greatest impact on sleep, job functioning, exercise, communication, relationships, and self-concept- commonly expressed as a sense of being limited by PD. Thematically, most bothersome symptoms were those that were personally limiting with broadest negative impact on well-being and activities. However, symptoms could be important to patients even when not present or limiting (e.g., speech, cognition). CONCLUSION: Meaningful symptoms of early PD can include symptoms that are present or anticipated future symptoms that are important to the individual. Systematic assessment of meaningful symptoms should aim to assess the extent to which symptoms are personally important, present, bothersome, and limiting.

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. Interviews combined: 1) symptom mapping to delineate meaningful symptoms/impacts of disease, 2) cognitive interviewing to assess content validity of digital measures, and 3) mapping of digital measures back to personal symptoms to assess relevance from the patient perspective. Content analysis and descriptive techniques were used to analyze data. RESULTS: Participants perceived mapping as deeply engaging, with 39/40 reporting improved ability to communicate important symptoms and relevance of measures. Most measures (9/10) were rated relevant by both cognitive interviewing (70-92.5%) and mapping (80-100%). Two measures related to actively bothersome symptoms for more than 80% of participants (Tremor, Shape rotation). Tasks were generally deemed relevant if they met three participant context criteria: 1) understanding what the task measured, 2) believing it targeted an important symptom of PD (past, present, or future), and 3) believing the task was a good test of that important symptom. Participants did not require that a task relate to active symptoms or "real" life to be relevant. CONCLUSION: Digital measures of tremor and hand dexterity were rated most relevant in early PD. Use of mapping enabled precise quantification of qualitative data for more rigorous evaluation of new measures.

Trichloroethylene: An Invisible Cause of Parkinson's Disease?

The etiologies of Parkinson's disease (PD) remain unclear. Some, such as certain genetic mutations and head trauma, are widely known or easily identified. However, these causes or risk factors do not account for the majority of cases. Other, less visible factors must be at play. Among these is a widely used industrial solvent and common environmental contaminant little recognized for its likely role in PD: trichloroethylene (TCE). TCE is a simple, six-atom molecule that can decaffeinate coffee, degrease metal parts, and dry clean clothes. The colorless chemical was first linked to parkinsonism in 1969. Since then, four case studies involving eight individuals have linked occupational exposure to TCE to PD. In addition, a small epidemiological study found that occupational or hobby exposure to the solvent was associated with a 500% increased risk of developing PD. In multiple animal studies, the chemical reproduces the pathological features of PD.Exposure is not confined to those who work with the chemical. TCE pollutes outdoor air, taints groundwater, and contaminates indoor air. The molecule, like radon, evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected. Despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited. Here, through a literature review and seven illustrative cases, we postulate that this ubiquitous chemical is contributing to the global rise of PD and that TCE is one of its invisible and highly preventable causes. Further research is now necessary to examine this hypothesis.

Monitoring gait at home with radio waves in Parkinson's disease: A marker of severity, progression, and medication response.

Parkinson's disease (PD) is the fastest-growing neurological disease in the world. A key challenge in PD is tracking disease severity, progression, and medication response. Existing methods are semisubjective and require visiting the clinic. In this work, we demonstrate an effective approach for assessing PD severity, progression, and medication response at home, in an objective manner. We used a radio device located in the background of the home. The device detected and analyzed the radio waves that bounce off people's bodies and inferred their movements and gait speed. We continuously monitored 50 participants, with and without PD, in their homes for up to 1 year. We collected over 200,000 gait speed measurements. Cross-sectional analysis of the data shows that at-home gait speed strongly correlates with gold-standard PD assessments, as evaluated by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III subscore and total score. At-home gait speed also provides a more sensitive marker for tracking disease progression over time than the widely used MDS-UPDRS. Further, the monitored gait speed was able to capture symptom fluctuations in response to medications and their impact on patients' daily functioning. Our study shows the feasibility of continuous, objective, sensitive, and passive assessment of PD at home and hence has the potential of improving clinical care and drug clinical trials.

A Remote Longitudinal Observational Study of Individuals at Genetic Risk for Parkinson Disease: Baseline Results.

Background and Objectives: To recruit and characterize a national cohort of individuals who have a genetic variant (LRRK2 G2019S) that increases risk of Parkinson disease (PD), assess participant satisfaction with a decentralized, remote research model, and evaluate interest in future clinical trials. Methods: In partnership with 23andMe, Inc., a personal genetics company, LRRK2 G2019S carriers with and without PD were recruited to participate in an ongoing 36-month decentralized, remote natural history study. We examined concordance between self-reported and clinician-determined PD diagnosis. We applied the Movement Disorder Society Prodromal Parkinson's Disease Criteria and asked investigators to identify concern for parkinsonism to distinguish participants with probable prodromal PD. We compared baseline characteristics of LRRK2 G2019S carriers with PD, with prodromal PD, and without PD. Results: Over 15 months, we enrolled 277 LRRK2 G2019S carriers from 34 states. At baseline, 60 had self-reported PD (mean [SD] age 67.8 years [8.4], 98% White, 52% female, 80% Ashkenazi Jewish, and 67% with a family history of PD), and 217 did not (mean [SD] age 53.7 years [15.1], 95% White, 59% female, 73% Ashkenazi Jewish, and 57% with a family history of PD). Agreement between self-reported and clinician-determined PD status was excellent (κ = 0.94, 95% confidence interval 0.89-0.99). Twenty-four participants had prodromal PD; 9 met criteria for probable prodromal PD and investigators identified concern for parkinsonism in 20 cases. Compared with those without prodromal PD, participants with prodromal PD were older (63.9 years [9.0] vs 51.9 years [15.1], p < 0.001), had higher modified Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor scores (5.7 [4.3] vs 0.8 [2.1], p < 0.001), and had higher Scale for Outcomes in PD for Autonomic Symptoms scores (11.5 [6.2] vs 6.9 [5.7], p = 0.002). Two-thirds of participants enrolled were new to research, 97% were satisfied with the overall study, and 94% of those without PD would participate in future preventive clinical trials. Discussion: An entirely remote national cohort of LRRK2 G2019S carriers was recruited from a single site. This study will prospectively characterize a large LRRK2 G2019S cohort, refine a new model of clinical research, and engage new research participants willing to participate in future therapeutic trials.

Six Action Steps to Address Global Disparities in Parkinson Disease: A World Health Organization Priority.

Importance: The Global Burden of Disease study conducted between 1990 and 2016, based on a global study of 195 countries and territories, identified Parkinson disease (PD) as the fastest growing neurological disorder when measured using death and disability. Most people affected by PD live in low- and middle-income countries (LMICs) and experience large inequalities in access to neurological care and essential medicines. This Special Communication describes 6 actions steps that are urgently needed to address global disparities in PD. Observations: The adoption by the 73rd World Health Assembly (WHA) of resolution 73.10 to develop an intersectoral global action plan on epilepsy and other neurological disorders in consultation with member states was the stimulus to coordinate efforts and leverage momentum to advance the agenda of neurological conditions, such as PD. In April 2021, the Brain Health Unit at the World Health Organization convened a multidisciplinary, sex-balanced, international consultation workshop, which identified 6 workable avenues for action within the domains of disease burden; advocacy and awareness; prevention and risk reduction; diagnosis, treatment, and care; caregiver support; and research. Conclusions and Relevance: The dramatic increase of PD cases in many world regions and the potential costs of PD-associated treatment will need to be addressed to prevent possible health service strain. Across the board, governments, multilateral agencies, donors, public health organizations, and health care professionals constitute potential stakeholders who are urged to make this a priority.

The Huntington's Disease Health Index: Initial Evaluation of a Disease-Specific Patient Reported Outcome Measure.

BACKGROUND: When developed properly, disease-specific patient reported outcome measures have the potential to measure relevant changes in how a patient feels and functions in the context of a therapeutic trial. The Huntington's Disease Health Index (HD-HI) is a multifaceted disease-specific patient reported outcome measure (PROM) designed specifically to satisfy previously published FDA guidance for developing PROMs for product development and labeling claims. OBJECTIVE: In preparation for clinical trials, we examine the validity, reliability, clinical relevance, and patient understanding of the Huntington's Disease Health Index (HD-HI). METHODS: We partnered with 389 people with Huntington's disease (HD) and caregivers to identify the most relevant questions for the HD-HI. We subsequently utilized two rounds of factor analysis, cognitive interviews with fifteen individuals with HD, and test-retest reliability assessments with 25 individuals with HD to refine, evaluate, and optimize the HD-HI. Lastly, we determined the capability of the HD-HI to differentiate between groups of HD participants with high versus low total functional capacity score, prodromal versus manifest HD, and normal ambulation versus mobility impairment. RESULTS: HD participants identified 13 relevant and unique symptomatic domains to be included as subscales in the HD-HI. All HD-HI subscales had a high level of internal consistency and reliability and were found by participants to have acceptable content, relevance, and usability. The total HD-HI score and each subscale score statistically differentiated between groups of HD participants with high versus low disease burden. CONCLUSION: Initial evaluation of the HD-HI supports its validity and reliability as a PROM for assessing how individuals with HD feel and function.