Psychostimulant drug co-ingestion in non-fatal opioid overdose.

Introduction: In 2019, there were over 16,000 deaths from psychostimulant overdose with 53.5% also involving an opioid. Given the substantial mortality stemming from opioid and psychostimulant co-exposure, evaluation of clinical management in this population is critical but remains understudied. This study aims to characterize and compare clinical management and outcomes in emergency department (ED) overdose patients with analytically confirmed exposure to both opioids and psychostimulants with those exposed to opioids alone. Methods: This was a secondary analysis of a prospective consecutive cohort of ED patients age 18+ with opioid overdose at 9 hospital sites from September 21, 2020 to August 17, 2021. Toxicologic analysis was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Patients were divided into opioid-only (OO) and opioid plus psychostimulants (OS) groups. The primary outcome was total naloxone bolus dose administered. Secondary outcomes included endotracheal intubation, cardiac arrest, troponin elevation, and abnormal presenting vital signs. We employed t-tests, chi-squared analyses and multivariable regression models to compare outcomes between OO and OS groups. Results: Of 378 enrollees with confirmed opioid overdose, 207 (54.8%) had psychostimulants present. OO patients were significantly older (mean 45.2 versus 40.6 years, p < 0.01). OS patients had significantly higher total naloxone requirements (mean total dose 2.79 mg versus 2.12 mg, p = 0.009). There were no significant differences in secondary outcomes. Conclusion: Approximately half of ED patients with confirmed opioid exposures were also positive for psychostimulants. Patients in the OS group required significantly higher naloxone doses, suggesting potential greater overdose severity.

Research Participants' Perspectives on Precision Diagnostics for Alzheimer's Disease.

BACKGROUND: Understanding research participants' responses to learning Alzheimer's disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies. OBJECTIVE: We assessed participants' perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk. METHODS: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of results. We analyzed responses to close-ended survey items by PET result using Fisher's exact test and qualitatively coded open-ended responses. RESULTS: A total of 88 participants completed surveys, most of whom had mild cognitive impairment due to AD (38.6%), AD (28.4%), or were cognitively unimpaired (21.6%). Participants subjectively understood their results (25.3% strongly agreed, 41.8% agreed), which could help them plan (16.5% strongly agreed, 49.4% agreed). Participants with a negative PET result (n = 25) reported feelings of relief (Fisher's exact p < 0.001) and happiness (p < 0.001) more frequently than those with a positive result. Most participants felt that they were treated respectfully and were comfortable voicing concerns during the disclosure process. Genetic testing was anticipated to be useful for medical care decisions (48.2%) and to inform family members about AD risk (42.9%). CONCLUSIONS: Participants had high subjective understanding and self-efficacy around their PET results and did not experience negative psychological effects. Interest in genetic testing was high.

Ocular injury from saltwater coral palytoxin.

We describe a case of a young male who presented to the emergency department with unilateral eye pain, blurred vision, conjunctival injection, and ocular pH of 9, one day after direct ocular exposure to palytoxin (PTX) from coral in a home saltwater fish tank. Although uncommon, ocular PTX toxicity is a potentially vision-threatening condition that requires prompt recognition. This case report documents the successful management of presumed ocular PTX exposure and suggests additional workup and treatment considerations for future patients.

Risk Factors and Clinical Correlates of Pediatric Serotonin Syndrome in Hospitalized Suicide Attempters.

Objective: To evaluate the risk factors and clinical correlates of pediatric serotonin syndrome (SS) given that research on SS in adults exists, there is a dearth of literature on pediatric SS. Study design: We conducted a retrospective chart review of 183 pediatric patients who were medically hospitalized after a suicide attempt. We investigated associations between SS and several of its risk factors and clinical correlates. We also assessed the sensitivity/specificity of Hunter's criteria and criterion symptoms in predicting SS. Results: SS occurred in 21.7% of patients with a serotonergic overdose. Recent marijuana use and overdose on a selective serotonin reuptake inhibitor were significantly associated with SS. Individuals with SS required a greater number of days to be medically stabilized and had a greater likelihood of being placed on a ventilator during treatment. Hunter's criteria had 66.7% sensitivity and 92.3% specificity in diagnosing SS. Conclusions: Our study reveals both novel risk factors associated with SS (eg, recent marijuana use) and clinical correlates for patients with pediatric SS. In children, Hunter's criteria appeared to have good specificity but poor sensitivity in identifying SS. Our results set the stage for future work aimed at enhancing clinicians' ability to more rapidly identify and treat pediatric SS.

Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity.

Tau polarizes an aging transcriptional signature to excitatory neurons and glia.

Aging is a major risk factor for Alzheimer's disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.

Opioid overdoses involving xylazine in emergency department patients: a multicenter study.

INTRODUCTION: Illicit opioids, consisting largely of fentanyl, novel synthetic opioids, and adulterants, are the primary cause of drug overdose fatality in the United States. Xylazine, an alpha-2 adrenergic agonist and veterinary tranquilizer, is being increasingly detected among decedents following illicit opioid overdose. Clinical outcomes in non-fatal overdose involving xylazine are unexplored. Therefore, among emergency department patients with illicit opioid overdose, we evaluated clinical outcome differences for patients with and without xylazine exposures. METHODS: This multicenter, prospective cohort study enrolled adult patients with opioid overdose who presented to one of nine United States emergency departments between 21 September 2020, and 17 August 2021. Patients with opioid overdose were screened and included if they tested positive for an illicit opioid (heroin, fentanyl, fentanyl analog, or novel synthetic opioid) or xylazine. Patient serum was analyzed via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect current illicit opioids, novel synthetic opioids, xylazine and adulterants. Overdose severity surrogate outcomes were: (a) cardiac arrest requiring cardiopulmonary resuscitation (primary); and (b) coma within 4 h of arrival (secondary). RESULTS: Three hundred and twenty-one patients met inclusion criteria: 90 tested positive for xylazine and 231 were negative. The primary outcome occurred in 37 patients, and the secondary outcome occurred in 111 patients. Using multivariable regression analysis, patients positive for xylazine had significantly lower adjusted odds of cardiac arrest (adjusted OR 0.30, 95% CI 0.10-0.92) and coma (adjusted OR 0.52, 95% CI 0.29-0.94). CONCLUSIONS: In this large multicenter cohort, cardiac arrest and coma in emergency department patients with illicit opioid overdose were significantly less severe in those testing positive for xylazine.

Genetics and Pathogenesis of Parkinson's Syndrome.

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.

Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes.

Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson's disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS does not provide functional information on the identified candidate loci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses in Drosophila to discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonal in silico methods and found to be functionally related to PD-associated pathways (i.e. endolysosome). We then mimicked these TWAS-predicted transcriptomic alterations in a Drosophila PD model and discovered that 50 candidates can modulate α-Synuclein(α-Syn)-induced neurodegeneration, allowing us to nominate new genes in previously known PD loci. We also uncovered additional novel PD candidate genes within GWAS suggestive loci (e.g. TTC19, ADORA2B, LZTS3, NRBP1, HN1L), which are also supported by clinical and functional evidence. These findings deepen our understanding of PD, and support applying our integrative approach to other complex trait disorders.

Identification of risk genes for Alzheimer's disease by gene embedding.

Most disease-gene association methods do not account for gene-gene interactions, even though these play a crucial role in complex, polygenic diseases like Alzheimer's disease (AD). To discover new genes whose interactions may contribute to pathology, we introduce GeneEMBED. This approach compares the functional perturbations induced in gene interaction network neighborhoods by coding variants from disease versus healthy subjects. In two independent AD cohorts of 5,169 exomes and 969 genomes, GeneEMBED identified novel candidates. These genes were differentially expressed in post mortem AD brains and modulated neurological phenotypes in mice. Four that were differentially overexpressed and modified neurodegeneration in vivo are PLEC, UTRN, TP53, and POLD1. Notably, TP53 and POLD1 are involved in DNA break repair and inhibited by approved drugs. While these data show proof of concept in AD, GeneEMBED is a general approach that should be broadly applicable to identify genes relevant to risk mechanisms and therapy of other complex diseases.

In Alzheimer-prone brain regions, metabolism and risk-gene expression are strongly correlated.

Neuroimaging in the preclinical phase of Alzheimer's disease provides information crucial to early intervention, particularly in people with a high genetic risk. Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer's disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer's disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3 ± 4.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer's disease. From their fluorodeoxyglucose PET we constructed metabolic networks, evaluated their modular structures using the Louvain algorithm, and compared them between risk groups. As the risk for Alzheimer's disease increased, the metabolic connections among brain regions weakened and became more modular, indicating network fragmentation and functional impairment of the brain. We then set out to determine the correlation between regional brain metabolism, particularly in the modules derived from the previous analysis, and the regional expression of Alzheimer-risk genes in the brain, obtained from the Allen Human Brain Atlas. In all risk groups of this elderly population, the regional brain expression of most Alzheimer-risk genes showed a strong correlation with brain metabolism, particularly in the module that corresponded to regions of the brain that are affected earliest and most severely in Alzheimer's disease. Among the genes, APOE and CD33 showed the strongest negative correlation and SORL1 showed the strongest positive correlation with brain metabolism. The Pearson correlation coefficients remained significant when contrasted against a null-hypothesis distribution of correlation coefficients across the whole transcriptome of 20 736 genes (SORL1: P = 0.0130; CD33, P = 0.0136; APOE: P = 0.0093). The strong regional correlation between Alzheimer-related gene expression in the brain and brain metabolism in older adults highlights the role of brain metabolism in the genesis of dementia.

Genome Sequencing in the Parkinson Disease Clinic.

Background and Objectives: Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics. Methods: In 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age = 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD (LRRK2); (2) risk of PD dementia (GBA); (3) PD genetic risk score; and (4) secondary, medically actionable variants (BRCA1). Results: Genome sequencing revealed a LRRK2 variant in 3% and a GBA risk variant in 10% of our clinical sample. The genetic risk score was normally distributed, identifying 41 subjects with a high risk of PD. Medically actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded that they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with a potential risk for dementia or medically actionable findings, and most (75%) expressed interest in learning their PD genetic risk score. Discussion: Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.

Contribution of a positive psychology-based conceptual framework in reducing physician burnout and improving well-being: a systematic review.

BACKGROUND: The PERMA Model, as a positive psychology conceptual framework, has increased our understanding of the role of Positive emotion, Engagement, Relationships, Meaning, and Achievements in enhancing human potentials, performance and wellbeing. We aimed to assess the utility of PERMA as a multidimensional model of positive psychology in reducing physician burnout and improving their well-being. METHODS: Eligible studies include peer-reviewed English language studies of randomized control trials and non-randomized design. Attending physicians, residents, and fellows of any specialty in the primary, secondary, or intensive care setting comprised the study population. Eligible studies also involved positive psychology interventions designed to enhance physician well-being or reduce physician burnout. Using free text and the medical subject headings we searched CINAHL, Ovid PsychINFO, MEDLINE, and Google Scholar (GS) electronic bibliographic databases from 2000 until March 2020. We use keywords for a combination of three general or block of terms (Health Personnel OR Health Professionals OR Physician OR Internship and Residency OR Medical Staff Or Fellow) AND (Burnout) AND (Positive Psychology OR PERMA OR Wellbeing Intervention OR Well-being Model OR Wellbeing Theory). RESULTS: Our search retrieved 1886 results (1804 through CINAHL, Ovid PsychINFO, MEDLINE, and 82 through GS) before duplicates were removed and 1723 after duplicates were removed. The final review included 21 studies. Studies represented eight countries, with the majority conducted in Spain (n = 3), followed by the US (n = 8), and Australia (n = 3). Except for one study that used a bio-psychosocial approach to guide the intervention, none of the other interventions in this review were based on a conceptual model, including PERMA. However, retrospectively, ten studies used strategies that resonate with the PERMA components. CONCLUSION: Consideration of the utility of PERMA as a multidimensional model of positive psychology to guide interventions to reduce burnout and enhance well-being among physicians is missing in the literature. Nevertheless, the majority of the studies reported some level of positive outcome regarding reducing burnout or improving well-being by using a physician or a system-directed intervention. Albeit, we found more favorable outcomes in the system-directed intervention. Future studies are needed to evaluate if PERMA as a framework can be used to guide system-directed interventions in reducing physician burnout and improving their well-being.

TBK1 interacts with tau and enhances neurodegeneration in tauopathy.

One of the defining pathological features of Alzheimer's disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau kinases attractive therapeutic targets. The full complement of tau-interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in human AD, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activation may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes.

OBJECTIVE: To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms. METHODS: In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis. RESULTS: Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, p subtype = 0.01, p ratio = 0.03), SH3GL2 (rs10756907, p subtype = 0.02, p ratio = 0.01), HIP1R (rs10847864, p subtype = 0.02), RIT2 (rs12456492, p subtype = 0.02), and FBRSL1 (rs11610045, p subtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, p ratio = 6.6 × 10-7), which harbors an independent risk allele for essential tremor. CONCLUSIONS: Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

Targeted Quantification of Detergent-Insoluble RNA-Binding Proteins in Human Brain Reveals Stage and Disease Specific Co-aggregation in Alzheimer's Disease.

Core spliceosome and related RNA-binding proteins aggregate in Alzheimer's disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including tau and amyloid beta (Aß) in detergent insoluble fractions from control, AsymAD, AD and Parkinson's disease (PD) brain. Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aß and tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles showed stage-specific enrichment of insoluble RBPs from AsymAD and AD brains, whereas the RNA splicing module was reduced specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across the specific neurodegenerative diseases we examined.

Proteomic Profiling of the Substantia Nigra to Identify Determinants of Lewy Body Pathology and Dopaminergic Neuronal Loss.

Proteinaceous aggregates containing α-synuclein protein called Lewy bodies in the substantia nigra is a hallmark of Parkinson's disease. The molecular mechanisms of Lewy body formation and associated neuronal loss remain largely unknown. To gain insights into proteins and pathways associated with Lewy body pathology, we performed quantitative profiling of the proteome. We analyzed substantia nigra tissue from 51 subjects arranged into three groups: cases with Lewy body pathology, Lewy body-negative controls with matching neuronal loss, and controls with no neuronal loss. Using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, we characterized the proteome both in terms of protein abundances and peptide modifications. Statistical testing for differential abundance of the most abundant 2963 proteins, followed by pathway enrichment and Bayesian learning of the causal network structure, was performed to identify likely drivers of Lewy body formation and dopaminergic neuronal loss. The identified pathways include (1) Arp2/3 complex-mediated actin nucleation; (2) synaptic function; (3) poly(A) RNA binding; (4) basement membrane and endothelium; and (5) hydrogen peroxide metabolic process. According to the data, the endothelial/basement membrane pathway is tightly connected with both pathologies and likely to be one of the drivers of neuronal loss. The poly(A) RNA-binding proteins, including the ones relevant to other neurodegenerative disorders (e.g., TDP-43 and FUS), have a strong inverse correlation with Lewy bodies and may reflect an alternative mechanism of nigral neurodegeneration.

Frequency of Parkinsonism and Parkinson Disease in African Americans in the Chicago Community.

BACKGROUND: There is paucity of data about African American (AA) patients with Parkinson's disease (PD) and parkinsonism which may precede PD in older adults. Prior studies suggest that there are lower rates of PD in the AA population, with more cognitive impairment in AA with PD. This study aimed to investigate differences in PD, parkinsonism, and cognition between White and AA populations in 3 longitudinal epidemiologic cohort studies of aging. METHODS: This study examined parkinsonism, PD frequency, and cognition of community-dwelling older individuals in 3 longitudinal epidemiologic cohort studies. Parkinsonism was based on an exam utilizing the modified Unified Parkinson's Disease Rating Scale performed by a nurse. PD was based on self-report, medications used for treatment of PD, and examination findings. Cognition was assessed using 19 performance-based tests that assess 5 cognitive domains. RESULTS: AA participants were less likely to have parkinsonism compared to Whites, even with age and gender differences. Frequency of PD was not significant between groups. AA were more likely to have lower cognitive scores as compared to Whites. AA were less likely to have parkinsonism even with controlling for cognitive differences between groups. CONCLUSIONS: Parkinsonian signs are present among AA in the community at lower rates than in White individuals. Cognitive profiles of AA and Whites with parkinsonism may be different, suggesting differing contributions of pathology to cognitive decline and parkinsonism between groups. Additional research is needed to understand the progression of parkinsonism to PD, as well as to understanding the cognitive differences in AA with parkinsonism.

Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity.

INTRODUCTION: Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS). METHODS: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS. RESULTS: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity. CONCLUSION: Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.