Browsing by Subject "Parkinson disease"
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Item A blood-based marker of mitochondrial DNA damage in Parkinson's disease(American Association for the Advancement of Science, 2023) Qi, Rui; Sammler, Esther; Gonzalez-Hunt, Claudia P.; Barraza, Ivana; Pena, Nicholas; Rouanet, Jeremy P.; Naaldijk, Yahaira; Goodson, Steven; Fuzzati, Marie; Blandini, Fabio; Erickson, Kirk I.; Weinstein, Andrea M.; Lutz, Michael W.; Kwok, John B.; Halliday, Glenda M.; Dzamko, Nicolas; Padmanabhan, Shalini; Alcalay, Roy N.; Waters, Cheryl; Hogarth, Penelope; Simuni, Tanya; Smith, Danielle; Marras, Connie; Tonelli, Francesca; Alessi, Dario R.; West, Andrew B.; Shiva, Sruti; Hilfiker, Sabine; Sanders, Laurie H.; Oral and Maxillofacial Surgery and Hospital Dentistry, School of DentistryParkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.Item Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study(Elsevier, 2023) Siderowf, Andrew; Concha-Marambio, Luis; Lafontant, David-Erick; Farris, Carly M.; Ma, Yihua; Urenia, Paula A.; Nguyen, Hieu; Alcalay, Roy N.; Chahine, Lana M.; Foroud, Tatiana; Galasko, Douglas; Kieburtz, Karl; Merchant, Kalpana; Mollenhauer, Brit; Poston, Kathleen L.; Seibyl, John; Simuni, Tanya; Tanner, Caroline M.; Weintraub, Daniel; Videnovic, Aleksandar; Choi, Seung Ho; Kurth, Ryan; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Frasier, Mark; Oliveira, Luis M. A.; Hutten, Samantha J.; Sherer, Todd; Marek, Kenneth; Soto, Claudio; Parkinson's Progression Markers Initiative; Medical and Molecular Genetics, School of MedicineBackground: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. Methods: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. Findings: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. Interpretation: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts.Item Deploying Digital Health Technologies for Remote Physical Activity Monitoring of Rural Populations With Chronic Neurologic Disease(Elsevier, 2022-12-05) Waddell, Kimberly J.; Patel, Mitesh S.; Wilkinson, Jayne R.; Burke, Robert E.; Bravata, Dawn M.; Koganti, Sreelatha; Wood, Stephanie; Morley, James F.; Medicine, School of MedicineObjective: The objective of this pilot study was to examine the feasibility of a remote physical activity monitoring program, quantify baseline activity levels, and examine predictors of activity among rurally residing adults with Parkinson disease (PD) or stroke. Design: Thirty-day observational study. Participants completed standardized assessments, connected a wearable device, and synced daily step counts via a remote monitoring platform. Setting: Community-based remote monitoring. Participants: Rurally residing adults with PD or stroke enrolled in the Veterans Health Administration. Intervention: N/A. Main outcome measures: Feasibility was evaluated using recruitment data (response rates), study completion (completed assessments and connected the wearable device), and device adherence (days recording ≥100 steps). Daily step counts were examined descriptively. Predictors of daily steps were explored across the full sample, then by diagnosis, using linear mixed-effects regression analyses. Results: Forty participants (n=20 PD; n=20 stroke) were included in the analysis with a mean (SD) age of 72.9 (7.6) years. Participants resided 252.6 (105.6) miles from the coordinating site. Recruitment response rates were 11% (PD) and 6% (stroke). Study completion rates were 71% (PD) and 80% (stroke). Device adherence rates were 97.0% (PD) and 95.2% (stroke). Participants with PD achieved a median [interquartile range] of 2618 [3896] steps per day and participants with stroke achieved 4832 [7383] steps. Age was the only significant predictor of daily steps for the full sample (-265 steps, 95% confidence interval [-407, -123]) and by diagnosis (PD, -175 steps, [-335, -15]; stroke, -357 steps [-603, -112]). Conclusions: A remote physical activity monitoring program for rurally residing individuals with PD or stroke was feasible. This study establishes a model for a scalable physical activity program for rural, older populations with neurologic conditions from a central coordinating site.Item Discovery of potent inhibitors of α-synuclein aggregation using structure-based iterative learning(Springer Nature, 2024) Horne, Robert I.; Andrzejewska, Ewa A.; Alam, Parvez; Brotzakis, Z. Faidon; Srivastava, Ankit; Aubert, Alice; Nowinska, Magdalena; Gregory, Rebecca C.; Staats, Roxine; Possenti, Andrea; Chia, Sean; Sormanni, Pietro; Ghetti, Bernardino; Caughey, Byron; Knowles, Tuomas P. J.; Vendruscolo, Michele; Pathology and Laboratory Medicine, School of MedicineMachine learning methods hold the promise to reduce the costs and the failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where the development of disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine learning approach to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson's disease and other synucleinopathies. Because the proliferation of α-synuclein aggregates takes place through autocatalytic secondary nucleation, we aim to identify compounds that bind the catalytic sites on the surface of the aggregates. To achieve this goal, we use structure-based machine learning in an iterative manner to first identify and then progressively optimize secondary nucleation inhibitors. Our results demonstrate that this approach leads to the facile identification of compounds two orders of magnitude more potent than previously reported ones.Item Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: A New Group of Tauopathies(Wiley, 1998-04) Spillantini, Maria Grazia; Bird, Thomas D.; Ghetti, Bernardino; Pathology and Laboratory Medicine, School of MedicineFrontotemporal dementia is a neurological disorder characterised by personality changes, deterioration of memory and executive functions as well as stereotypical behaviour. Sometimes a Parkinsonian syndrome is prominent. Several cases of frontotemporal dementia are hereditary and recently families have been identified where the disease is linked to chromosome 17q21-22. Although, there is clinical and neuropathological variability among and within families, they all consistently present a symptomathology that has led investigators to name the disease "Frontotemporal Dementia and Parkinsonism linked to chromosome 17." Neuropathologically, these patients present with atrophy of frontal and temporal cortex as well as of basal ganglia and substantia nigra. In the majority of cases these features are accompanied by neuronal loss, gliosis and microtubule-associated protein tau deposits which can be present in both neurones and glial cells. The distribution, structural and biochemical characteristics of the tau deposits differentiate them from those present in Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy and Pick's disease. No beta-amyloid deposits are present. The clinical and neuropathological features of the disease in these families suggest that Frontotemporal Dementia and Parkinsonism linked to chromosome 17 is a distinct disorder. The presence of abundant tau deposits in the majority of these families define this disorder as a new tauopathy.Item Genetic Testing for Parkinson Disease: Are We Ready?(American Academy of Neurology, 2021-02) Cook, Lola; Schulze, Jeanine; Kopil, Catherine; Hastings, Tara; Naito, Anna; Wojcieszek, Joanne; Payne, Katelyn; Alcalay, Roy N.; Klein, Christine; Saunders-Pullman, Rachel; Simuni, Tatyana; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicinePurpose of review: With the advent of precision medicine and demand for genomic testing information, we may question whether it is time to offer genetic testing to our patients with Parkinson disease (PD). This review updates the current genetic landscape of PD, describes what genetic testing may offer, provides strategies for evaluating whom to test, and provides resources for the busy clinician. Recent findings: Patients with PD and their relatives, in various settings, have expressed an interest in learning their PD genetic status; however, physicians may be hesitant to widely offer testing due to the perceived low clinical utility of PD genetic test results. The rise of clinical trials available for patients with gene-specific PD and emerging information on genotype-phenotype correlations are starting to shift this discussion about testing. Summary: By learning more about the various genetic testing options for PD and utility of results for patients and their care, clinicians may become more comfortable with widespread PD genetic testing in the research and clinical setting.Item Identifying and troubleshooting low-frequency artifacts mimicking atrial flutter caused by deep brain stimulator(Elsevier, 2021-07-22) Stelzer, Mitchell A.; Padanilam, Mathew S.; Miller, Jennifer J.; Foreman, Jason; Golden, Keith; Ahmed, Asim S.; Medicine, School of MedicineElectromagnetic interference from deep brain stimulators (DBS) is known to cause high-frequency artifact on some forms of cardiac telemetry.1 Here, we (1) present a unique case in which a DBS caused a low-frequency artifact mimicking typical atrial flutter leading to referral to electrophysiology; (2) demonstrate a method to confirm this; and (3) provide recommendations of how to minimize artifact and work around this interaction in future rhythm monitoring attempts.Item Mechanisms and consequences of regulating the spinophilin/NMDA receptor interaction(2016-07-12) Beiraghi Salek, Asma; Baucum, Anthony J., II; Belecky-Adams, Teri; Watson, John C.; Cummins, Theodore R.Parkinson disease (PD) is the second most common neurodegenerative disease. It is characterized by loss of dopaminergic cells in the substantia nigra, which causes loss of dopaminergic synapses onto striatal medium spiny neurons (MSNs). Dendritic spines that are localized to these striatal MSNs receive synaptic inputs from both the nigral dopamine neurons and cortical glutamate neurons. Signaling downstream of excitatory, glutamatergic drive is modulated by dopamine. This tripartite connection: glutamate, dopamine, and MSN dendritic spine, is important for normal motor function. Glutamate released from presynaptic terminals binds to and activates two classes of inotropic glutamate receptors that are localized to dendritic spines on striatal MSNs: the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and the N-methyl-D-aspartate receptor (NMDAR). Once these receptors are activated, they allow for Ca2+ influx, which in turn activates Ca2+-dependent processes that underlie neural plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Proper machinery in the pre- and post-synaptic neurons is required for normal signal transduction. Moreover, this signal transduction requires proper organization of synaptic proteins, which is achieved by specific protein-protein interactions. These protein-protein interactions are dynamic and can be modulated under various conditions, including pathological changes in the phosphorylation status of a specific protein. Catalytically active proteins called phosphatases and kinases specifically regulate the phosphorylation status of synaptic proteins. Pathologically, in PD there is increased autophosphorylation and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). This increased phosphorylation may be due to changes in the activity of the serine/threonine protein phosphatase 1 (PP1), a highly conserved protein serine/threonine phosphatase that has a diverse set of functions in eukaryotes. Serine/threonine phosphatase substrate specificity is obtained via interactions with targeting and regulatory proteins. One such protein, spinophilin, is a scaffolding protein that targets PP1 to various synaptic substrates to regulate their phosphorylation. Interestingly, the association of PP1 with spinophilin is enhanced in a rat model of PD. The NMDAR is another protein that has altered phosphorylation in animal models of PD. We have found that there is a decrease in the NMDAR-spinophilin interaction in an animal model of PD. Here, we have found that spinophilin and the NMDAR interact in brain tissue and when overexpressed in a mammalian cell system. Moreover, we have identified novel mechanisms that regulate this interaction and have identified putative consequences of altering this association. These studies give us novel insight into mechanisms and consequences underlying pathological changes observed in an animal model of PD. Understanding these changes will inform novel therapeutic targets that may be useful in modulating striatal function.Item Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics(American Society for Biochemistry and Molecular Biology, 2019-04-12) Wu, Chun-Xiang; Liao, Jingling; Park, Yangshin; Reed, Xylena; Engel, Victoria A.; Hoang, Neo C.; Takagi, Yuichiro; Johnson, Steven M.; Wang, Mu; Federici, Mark; Nichols, R. Jeremy; Sanishvili, Ruslan; Cookson, Mark R.; Hoang, Quyen Q.; Biochemistry and Molecular Biology, School of MedicineMutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). Recently, we showed that a disease-associated mutation R1441H rendered the GTPase domain of LRRK2 catalytically less active and thereby trapping it in a more persistently “on” conformation. However, the mechanism involved and characteristics of this on conformation remained unknown. Here, we report that the Ras of complex protein (ROC) domain of LRRK2 exists in a dynamic dimer–monomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the PD-associated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTP-bound–like monomeric conformation. Moreover, we show that residue Arg-1441 is critical for regulating the conformational dynamics of ROC. In summary, our results reveal that the PD-associated substitutions at Arg-1441 of LRRK2 alter monomer–dimer dynamics and thereby trap its GTPase domain in an activated state.Item Pros and Cons of Marijuana in Treatment of Parkinson's Disease(Cureus, 2019-06-03) Patel, Rikinkumar S.; Kamil, Saher; Shah, Mansi R.; Bhimanadham, Narmada Neerja; Imran, Sundus; Neurology, School of MedicineParkinson's disease (PD) is the second most common neurodegenerative disorder of adult onset in the United States. It is a debilitating condition and presents with both motor and non-motor symptoms. Current treatment options are scarce and include replacement of dopamine deficiency with levodopa which targets only motor symptoms of the disorder, does not halt its progression, and is associated with side effects of its own, including dyskinesia. With medical marijuana gaining popularity and being legalized in the United States, we examined the pros and cons of marijuana in the treatment of Parkinson's disease.