Occupational Pesticide Exposure in Parkinson's Disease Related to GBA and LRRK2 Variants.

Background: The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood. Objective: To determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants. Methods: Participants of the Parkinson's Progression Markers Initiative (PPMI) with a LRRK2-G2019 S or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure. Results: 378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019 S (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7-18.5, p < 0.01). People with a LRRK2 variant and a history of occupational pesticide exposure had non-significantly elevated odds of PD (aOR 1.3, 95% CI 0.4-4.6, p = 0.7). Among those with PD, pesticide exposure was associated with a higher risk of balance problems and cognitive impairment in LRRK2-PD and functional impairment in GBA-PD, although associations were not statistically significant. Conclusions: Occupational pesticide exposure may increase penetrance of GBA-PD and may be associated with faster symptom progression. Further studies in larger cohorts are necessary.

Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study.

Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD. Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment. Results: Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003-0.005) and higher LEDD over time (P range <0.001-0.01) were significantly associated with increased risk for CI. Conclusions: Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course. TRIAL REGISTRATION: Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).

Early detection of Parkinson's disease through enriching the electronic health record using a biomedical knowledge graph.

Introduction: Early diagnosis of Parkinson's disease (PD) is important to identify treatments to slow neurodegeneration. People who develop PD often have symptoms before the disease manifests and may be coded as diagnoses in the electronic health record (EHR). Methods: To predict PD diagnosis, we embedded EHR data of patients onto a biomedical knowledge graph called Scalable Precision medicine Open Knowledge Engine (SPOKE) and created patient embedding vectors. We trained and validated a classifier using these vectors from 3,004 PD patients, restricting records to 1, 3, and 5 years before diagnosis, and 457,197 non-PD group. Results: The classifier predicted PD diagnosis with moderate accuracy (AUC = 0.77 ± 0.06, 0.74 ± 0.05, 0.72 ± 0.05 at 1, 3, and 5 years) and performed better than other benchmark methods. Nodes in the SPOKE graph, among cases, revealed novel associations, while SPOKE patient vectors revealed the basis for individual risk classification. Discussion: The proposed method was able to explain the clinical predictions using the knowledge graph, thereby making the predictions clinically interpretable. Through enriching EHR data with biomedical associations, SPOKE may be a cost-efficient and personalized way to predict PD diagnosis years before its occurrence.

Risk of Parkinson Disease Among Service Members at Marine Corps Base Camp Lejeune.

Importance: An increased risk of Parkinson disease (PD) has been associated with exposure to the solvent trichloroethylene (TCE), but data are limited. Millions of people in the US and worldwide are exposed to TCE in air, food, and water. Objective: To test whether the risk of PD is higher in veterans who served at Marine Corps Base Camp Lejeune, whose water supply was contaminated with TCE and other volatile organic compounds (VOCs), compared with veterans who did not serve on that base. Design, Setting, and Participants: This population-based cohort study examined the risk for PD among all Marines and Navy personnel who resided at Camp Lejeune, North Carolina (contaminated water) (n = 172 128), or Camp Pendleton, California (uncontaminated water) (n = 168 361), for at least 3 months between 1975 and 1985, with follow-up from January 1, 1997, until February 17, 2021. Veterans Health Administration and Medicare databases were searched for International Classification of Diseases diagnostic codes for PD or other forms of parkinsonism and related medications and for diagnostic codes indicative of prodromal disease. Parkinson disease diagnoses were confirmed by medical record review. Exposures: Water supplies at Camp Lejeune were contaminated with several VOCs. Levels were highest for TCE, with monthly median values greater than 70-fold the permissible amount. Main Outcome and Measures: Risk of PD in former residents of Camp Lejeune relative to residents of Camp Pendleton. In those without PD or another form of parkinsonism, the risk of being diagnosed with features of prodromal PD were assessed individually and cumulatively using likelihood ratio tests. Results: Health data were available for 158 122 veterans (46.4%). Demographic characteristics were similar between Camp Lejeune (5.3% women, 94.7% men; mean [SD] attained age of 59.64 [4.43] years; 29.7% Black, 6.0% Hispanic, 67.6% White; and 2.7% other race and ethnicity) and Camp Pendleton (3.8% women, 96.2% men; mean [SD] age, 59.80 [4.62] years; 23.4% Black, 9.4% Hispanic, 71.1% White, and 5.5% other race and ethnicity). A total of 430 veterans had PD, with 279 from Camp Lejeune (prevalence, 0.33%) and 151 from Camp Pendleton (prevalence, 0.21%). In multivariable models, Camp Lejeune veterans had a 70% higher risk of PD (odds ratio, 1.70; 95% CI, 1.39-2.07; P < .001). No excess risk was found for other forms of neurodegenerative parkinsonism. Camp Lejeune veterans also had a significantly increased risk of prodromal PD diagnoses, including tremor, anxiety, and erectile dysfunction, and higher cumulative prodromal risk scores. Conclusions and Relevance: The study's findings suggest that the risk of PD is higher in persons exposed to TCE and other VOCs in water 4 decades ago. Millions worldwide have been and continue to be exposed to this ubiquitous environmental contaminant.

Enhancing Clinical Information Display to Improve Patient Encounters: Human-Centered Design and Evaluation of the Parkinson Disease-BRIDGE Platform.

BACKGROUND: People with Parkinson disease (PD) have a variety of complex medical problems that require detailed review at each clinical encounter for appropriate management. Care of other complex conditions has benefited from digital health solutions that efficiently integrate disparate clinical information. Although various digital approaches have been developed for research and care in PD, no digital solution to personalize and improve communication in a clinical encounter is readily available. OBJECTIVE: We intend to improve the efficacy and efficiency of clinical encounters with people with PD through the development of a platform (PD-BRIDGE) with personalized clinical information from the electronic health record (EHR) and patient-reported outcome (PRO) data. METHODS: Using human-centered design (HCD) processes, we engaged clinician and patient stakeholders in developing PD-BRIDGE through three phases: an inspiration phase involving focus groups and discussions with people having PD, an ideation phase generating preliminary mock-ups for feedback, and an implementation phase testing the platform. To qualitatively evaluate the platform, movement disorders neurologists and people with PD were sent questionnaires asking about the technical validity, usability, and clinical relevance of PD-BRIDGE after their encounter. RESULTS: The HCD process led to a platform with 4 modules. Among these, 3 modules that pulled data from the EHR include a longitudinal module showing motor ratings over time, a display module showing the most recently collected clinical rating scales, and another display module showing relevant laboratory values and diagnoses; the fourth module displays motor symptom fluctuation based on an at-home diary. In the implementation phase, PD-BRIDGE was used in 17 clinical encounters for patients cared for by 1 of 11 movement disorders neurologists. Most patients felt that PD-BRIDGE facilitated communication with their clinician (n=14, 83%) and helped them understand their disease trajectory (n=11, 65%) and their clinician's recommendations (n=11, 65%). Neurologists felt that PD-BRIDGE improved their ability to understand the patients' disease course (n=13, 75% of encounters), supported clinical care recommendations (n=15, 87%), and helped them communicate with their patients (n=14, 81%). In terms of improvements, neurologists noted that data in PD-BRIDGE were not exhaustive in 62% (n=11) of the encounters. CONCLUSIONS: Integrating clinically relevant information from EHR and PRO data into a visually efficient platform (PD-BRIDGE) can facilitate clinical encounters with people with PD. Developing new modules with more disparate information could improve these complex encounters even further.

Association of Motor and Nonmotor Symptoms With Health-Related Quality of Life in a Large Online Cohort of People With Parkinson Disease.

BACKGROUND AND OBJECTIVES: There is growing interest in health-related quality of life (HRQOL) as a comprehensive view of the patient's well-being, guiding concept for the treating clinician, and therapeutic trial outcome measure for patients with Parkinson disease (PwPD). The key determinants of HRQOL have not been investigated in large populations of PwPD. Our objective was to evaluate correlates of HRQOL in a large, online cohort of PwPD. METHODS: As part of an ongoing online cohort study, we performed a cross-sectional analysis at enrollment of 23,058 PwPD. We conducted univariate and stepwise multivariate linear regression analyses of HRQOL as measured by the EQ-5D-5L tool. In addition, we performed an interaction analysis to evaluate heterogeneity of the effect of motor symptoms on HRQOL and Spearman correlation analysis to evaluate the association of nonmotor symptoms with HRQOL. RESULTS: In the multivariate linear regression model, participants with moderate or severe depression, more severe motor symptoms, and a higher burden of medical comorbidities had the most substantially decreased HRQOL as measured by the EQ index (ß -0.11, -0.18, -0.02, -0.01, respectively; p < 0.001 for all). An interaction analysis showed that more severe motor symptoms had a higher effect on individuals with female sex, lower educational level, lower income, more severe depression, or more severe cognitive impairment (p ≤ 0.01 for interaction terms). Neuropsychiatric symptoms and falls had the most negative associations with HRQOL (ρ -0.31 to 0.37; p < 0.0001). DISCUSSION: Potentially treatable motor and nonmotor symptoms, particularly neuropsychiatric symptoms, account for a large amount of the variation in HRQOL in PwPD. Motor symptoms may have differential effects on HRQOL in different demographic and clinical subpopulations, highlighting important areas for future health disparities research. Our findings provide targets for clinician intervention and future research on symptom management to optimize HRQOL in PD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that motor and neuropsychiatric symptoms are associated with HRQOL in PwPD.

Elevated Mood States in Patients With Parkinson's Disease Treated With Deep Brain Stimulation: Diagnosis and Management Strategies.

OBJECTIVE: Deep brain stimulation (DBS) is an effective surgical treatment for patients with Parkinson's disease (PD). DBS therapy, particularly with the subthalamic nucleus (STN) target, has been linked to rare psychiatric complications, including depression, impulsivity, irritability, and suicidality. Stimulation-induced elevated mood states can also occur. These episodes rarely meet DSM-5 criteria for mania or hypomania. METHODS: The investigators conducted a chart review of 82 patients with PD treated with DBS. RESULTS: Nine (11%) patients developed stimulation-induced elevated mood. Five illustrative cases are described (all males with STN DBS; mean age=62.2 years [SD=10.5], mean PD duration=8.6 years [SD=1.6]). Elevated mood states occurred during or shortly after programming changes, when more ventral contacts were used (typically in monopolar mode) and lasted minutes to months. Four patients experienced elevated mood at low amplitudes (1.0 V/1.0 mA); all had psychiatric risk factors (history of impulse-control disorder, dopamine dysregulation syndrome, substance use disorder, and/or bipolar diathesis) that likely contributed to mood destabilization. CONCLUSIONS: Preoperative DBS evaluations should include a thorough assessment of psychiatric risk factors. The term "stimulation-induced elevated mood states" is proposed to describe episodes of elevated, expansive, or irritable mood and psychomotor agitation that occur during or shortly after DBS programming changes and may be associated with increased goal-directed activity, impulsivity, grandiosity, pressured speech, flight of ideas, or decreased need for sleep and may persist beyond stimulation adjustments. This clinical phenomenon should be considered for inclusion in the bipolar disorder category in future DSM revisions, allowing for increased recognition and appropriate management.

The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism.

The Trial of Parkinson's And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants' homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.

DBS targeting for essential tremor using intersectional dentato-rubro-thalamic tractography and direct proton density visualization of the VIM: technical note on 2 cases.

OBJECTIVE: Direct visualization of the ventral intermediate nucleus (VIM) of the thalamus on standard MRI sequences remains elusive. Therefore, deep brain stimulation (DBS) surgery for essential tremor (ET) indirectly targets the VIM using atlas-derived consensus coordinates and requires awake intraoperative testing to confirm clinical benefits. The objective of this study was to evaluate the utility of proton density (PD)-weighted MRI and tractography of the intersecting dentato-rubro-thalamic tract (DRTT) for direct "intersectional" targeting of the VIM in ET. METHODS: DBS targets were selected by identifying the VIM on PD-weighted images relative to the DRTT in 2 patients with ET. Tremor reduction was confirmed with intraoperative clinical testing. Intended target coordinates based on the direct intersectional targeting technique were compared with consensus coordinates obtained with indirect targeting. Pre- and postoperative tremor scores were assessed using the Fahn-Tolosa-Marin tremor rating scale (TRS). RESULTS: Planned DBS coordinates based on direct versus indirect targeting of the VIM differed in both the anteroposterior (range 0 to 2.3) and lateral (range -0.7 to 1) directions. For 1 patient, indirect targeting-without PD-weighted visualization of the VIM and DRTT-would have likely resulted in suboptimal electrode placement within the VIM. At the 3-month follow-up, both patients demonstrated significant improvement in tremor symptoms subjectively and according to the TRS (case 1: 68%, case 2: 72%). CONCLUSIONS: Direct intersectional targeting of the VIM using PD-weighted imaging and DRTT tractography is a feasible method for DBS placement in patients with ET. These advanced targeting techniques can supplement awake intraoperative testing or be used independently in asleep cases to improve surgical efficiency and confidence.

Modulation of the Microbiome in Parkinson's Disease: Diet, Drug, Stool Transplant, and Beyond.

The gastrointestinal microbiome is altered in Parkinson's disease and likely plays a key role in its pathophysiology, affecting symptoms and response to therapy and perhaps modifying progression or even disease initiation. Gut dysbiosis therefore has a significant potential as a therapeutic target in Parkinson's disease, a condition elusive to disease-modifying therapy thus far. The gastrointestinal environment hosts a complex ecology, and efforts to modulate the relative abundance or function of established microorganisms are still in their infancy. Still, these techniques are being rapidly developed and have important implications for our understanding of Parkinson's disease. Currently, modulation of the microbiome can be achieved through non-pharmacologic means such as diet, pharmacologically through probiotic, prebiotic, or antibiotic use and procedurally through fecal transplant. Novel techniques being explored include the use of small molecules or genetically engineered organisms, with vast potential. Here, we review how some of these approaches have been used to date, important areas of ongoing research, and how microbiome modulation may play a role in the clinical management of Parkinson's disease in the future.

The Effect of the COVID-19 Pandemic on People with Parkinson's Disease.

BACKGROUND: The effect of the COVID-19 pandemic on people with Parkinson's disease (PD) is poorly understood. OBJECTIVE: To rapidly identify areas of need and improve care in people with PD during the COVID-19 pandemic, we deployed a survey to assess COVID-19 symptoms and the pandemic's effect among those with and without COVID-19. METHODS: People with and without PD participating in the online study Fox Insight (FI) were invited to complete a survey between April 23 and May 23, 2020. Among people reporting COVID-19 diagnoses, we compared symptoms and outcomes in people with and without PD. Among people not reporting COVID-19, we assessed access to healthcare and services and PD symptoms. RESULTS: 7,209/9,762 active FI users responded (approximately 74% response rate), 5,429 people with PD and 1,452 without PD. COVID-19 diagnoses were reported by 51 people with and 26 without PD. Complications were more frequent in people with longer PD duration. People with PD and COVID-19 experienced new or worsening motor (63%) and nonmotor (75%) symptoms. People with PD not diagnosed with COVID-19 reported disrupted medical care (64%), exercise (21%), and social activities (57%), and worsened motor (43%) and non-motor (52%) symptoms. Disruptions were more common for those living alone, with lower income and non-White race. CONCLUSIONS: The COVID-19 pandemic is associated with wide-ranging effects on people with PD, and certain groups may be at particular risk. FI provides a rapid, patient-centered means to assess these effects and identify needs that can be used to improve the health of people with PD.

The Visual Word Form Area compensates for auditory working memory dysfunction in schizophrenia.

Auditory working memory impairments feature prominently in schizophrenia. However, the existence of altered and perhaps compensatory neural dynamics, sub-serving auditory working memory, remains largely unexplored. We compared the dynamics of induced high gamma power (iHGP) across cortex in humans during speech-sound working memory in individuals with schizophrenia (SZ) and healthy comparison subjects (HC) using magnetoencephalography (MEG). SZ showed similar task performance to HC while utilizing different brain regions. During encoding of speech sounds, SZ lacked the correlation of iHGP with task performance in posterior superior temporal gyrus (STGp) that was observed in healthy subjects. Instead, SZ recruited the visual word form area (VWFA) during both stimulus encoding and response preparation. Importantly, VWFA activity during encoding correlated with the magnitude of SZ hallucinations, task performance and an independent measure of verbal working memory. These findings suggest that VWFA plasticity is harnessed to compensate for STGp dysfunction in schizophrenia patients with hallucinations.

Cerebellar Deep Brain Stimulation for Acquired Hemidystonia.

BACKGROUND: The cerebellum's role in dystonia is increasingly recognized. Dystonia can be a disabling and refractory condition; deep brain stimulation can help many patients, but it is traditionally less effective in acquired dystonia. New surgical targets would be instrumental in providing treatment options and understanding dystonia further. OBJECTIVE: To evaluate the efficacy of deep brain stimulation of the cerebellum in acquired dystonia. METHODS: We report our management of a 37-year-old woman with severe left arm and leg dystonia, a complication of an ischemic stroke in childhood. She had already had 2 thalamotomies with only transient benefit. These procedures, in addition to her initial stroke that had damaged the basal ganglia, left traditional deep brain stimulation targets unavailable. RESULTS: After implantation of bilateral deep cerebellar nuclei, dystonia improved with a 40% reduction in severity on scales and subjective reports of improved posturing, gait, and pain. This improvement has been maintained for almost 2 years after implantation. CONCLUSION: Cerebellar stimulation has potential for therapeutic benefit in acquired dystonia and should be further explored.

Intervention-specific patterns of cortical function plasticity during auditory encoding in people with schizophrenia.

Schizophrenia is a neurocognitive illness characterized by behavioral and neural impairments in both early auditory processing and higher order verbal working memory. Previously we have shown intervention-specific cognitive performance improvements with computerized, targeted training of auditory processing (AT) when compared to a computer games (CG) control intervention that emphasized visual processing. To investigate spatiotemporal changes in patterns of neural activity specific to the AT intervention, the current study used magnetoencephalography (MEG) imaging to derive induced high gamma band oscillations (HGO) during auditory encoding, before and after 50 h (∼10 weeks) of exposure to either the AT or CG intervention. During stimulus encoding, AT intervention-specific changes in high gamma activity occurred in left middle frontal and left middle-superior temporal cortices. In contrast, CG intervention-specific changes were observed in right medial frontal and supramarginal gyri during stimulus encoding, and in bilateral temporal cortices during response preparation. These data reveal that, in schizophrenia, intensive exposure to either training of auditory processing or exposure to visuospatial activities produces significant but complementary patterns of cortical function plasticity within a distributed fronto-temporal network. These results underscore the importance of delineating the specific neuroplastic effects of targeted behavioral interventions to ensure desired neurophysiological changes and avoid unintended consequences on neural system functioning.

Evaluation of a multicomponent pathway to address inpatient delirium on a neurosciences ward.

BACKGROUND: Delirium is a frequent and detrimental complication of inpatient hospitalization. Multicomponent intervention in selected groups has been shown to prevent and treat delirium, though little data exists on the effect of intervention in neurological patients. We studied the efficacy of a multicomponent delirium care pathway implemented on a largely neurology and neurosurgery hospital ward among unselected patients. METHODS: We incorporated a multicomponent delirium care pathway into the workflow of a university hospital for patients older than 50 years. The pathway involved risk-stratification for development of delirium, delirium screening, and non-pharmacologic behavioral prevention and intervention. We then retrospectively reviewed admissions before and after implementation of the care pathway. Our primary endpoint was incidence of delirium; secondary endpoints included delirium days, length of stay, restraint use, readmission rates, and discharge disposition. RESULTS: Seven hundred ninety eight admissions from before the delirium care pathway went into effect and 797 admissions from afterwards were reviewed. Baseline characteristics between groups were similar. Delirium incidence between the two groups did not change (7.0% before vs 7.2% after, p = 0.89). Length of stay among delirious patients significantly decreased after implementation of the delirium care pathway (9.60 before vs 7.06 after, ß = - 0.16, adjusted p-value = 0.001). CONCLUSION: Implementation of a delirium care pathway on a neurosciences ward was not associated with changes in the rate of delirium development, though length of stay among delirious patients decreased. In a largely neurologic population, multicomponent intervention to prevent and treat delirium may not change delirium incidence, but may be effective in mitigating delirium complications.