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Item A Pilot Randomized Controlled Trial Investigating MBSR for Parkinson’s Disease Patients and Their Caregiving Partners: Effects on Distress, Social support, Cortisol, and Inflammation(Springer, 2022) Siwik, Chelsea J.; Phillips, Kala; Litvan, Irene; Salmon, Paul; Rodgers, Allison; Jablonski, Megan; Sephton, Sandra E.; Psychology, School of ScienceObjectives: To examine the preliminary effects of the mindfulness-based stress reduction (MBSR) program in the management of biopsychosocial stress–related changes associated with Parkinson’s disease (PD) among patient/caregiving-partner dyads. Methods: PD patient/caregiving-partner dyads (N = 18) early in the disease trajectory were recruited from a university-affiliated movement disorders clinic and were randomized (1:1) to either the MBSR intervention or the control condition (treatment as usual [TAU]). Mixed methods ANOVAs were conducted to examine primary outcomes (disease-specific distress, perceived social support, circadian rhythmicity [cortisol], and markers of inflammation [IL-6, TNF-alpha, IL-1beta]) between groups (MBSR vs. TAU) among patients and caregiving partners separately. Results: No participants were lost to follow-up. Given the pilot nature of the current investigation, findings should be interpreted as exploratory opposed to confirmatory. Following MBSR, PD patients reported an increase in disease-specific distress and intrusive thoughts and demonstrated a decrease in mean bedtime cortisol and IL-1beta from baseline to follow-up compared to TAU. Caregiving partners who received MBSR reported an increase in perceived social support and demonstrated improved rhythmicity of diurnal cortisol slopes from baseline to follow-up compared to TAU. Conclusions: Both patients and caregiving partners who received MBSR demonstrated improvements in biomarkers of circadian function, and patients evidenced a decrease in a biomarker of systemic inflammation, pointing to an important area of further investigation. Given that patients reported an increase in disease-specific distress and intrusive thoughts, the salutary effects of MBSR may be experienced physiologically prior to, or in lieu of, psychological effects, although this should be explored further, especially given the improvement in perceived social support reported by caregiving partners.Item Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury(Elsevier, 2016-09-06) Shee, Kevin; Lucas, Alexandra; Flashman, Laura A.; Nho, Kwangsik; Tsongalis, Gregory J.; McDonald, Brenna C.; Saykin, Andrew J.; McAllister, Thomas W.; Rhodes, C. Harker; Psychiatry, School of MedicineProblems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between α-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p = 0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p = 0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation.Item The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen(Springer Nature, 2011-03) Rogers, Jack T.; Mikkilineni, Sohan; Castelvetri, Ippolita Cantuti; Smith, Deborah H.; Huang, Xudong; Bandyopadhyay, Sanghamitra; Cahill, Catherine M.; Maccecchini, Maria L.; Lahiri, Debomoy K.; Greig, Nigel H.; Psychiatry, School of MedicineIncreased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo.Item Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls(Wiley, 2019-09) Agalliu, llir; Ortega, Roberto A.; San Luciano, Marta; Mirelman, Anat; Pont-Sunyer, Claustre; Brockmann, Kathrin; Vilas, Dolores; Tolosa, Eduardo; Berg, Daniela; Warø, Bjørg; Glickman, Amanda; Raymond, Deborah; Inzelberg, Rivka; Ruiz-Martinez, Javier; Mondragon, Elisabet; Friedman, Eitan; Hassin-Baer, Sharon; Alcalay, Roy N.; Mejia-Santana, Helen; Aasly, Jan; Foroud, Tatiana; Marder, Karen; Giladi, Nir; Bressman, Susan; Saunders-Pullman, Rachel; Medical and Molecular Genetics, School of MedicineBACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.Item Comorbid Depression and Psychosis in Parkinson's Disease: A Report of 62,783 Hospitalizations in the United States(Cureus, 2019-07-24) Imran, Sundus; Patel, Rikinkumar S.; Onyeaka, Henry K.; Tahir, Muhammad; Madireddy, Sowmya; Mainali, Pranita; Hossain, Sadaf; Rashid, Wahida; Queeneth, Uwandu; Ahmad, Naveed; Neurology, School of MedicineBackground Depression and psychosis are common comorbidities that significantly affects the quality of life and disease outcomes in Parkinson's disease (PD) patients. Objective The aim of this study was to analyze and discern the differences in the hospitalization outcomes, comorbidities, and utilization of deep brain stimulation (DBS) in PD patients with comorbid depression and comorbid psychosis. Methods We used the Nationwide Inpatient Sample (2010-2014) and identified PD as a primary diagnosis (N = 62,783), and depression (N = 11,358) and psychosis (N = 2,475) as co-diagnosis using the International Classification of Diseases, Ninth Revision (ICD-9) codes. Pearson's chi-square test and independent-sample t-test were used for categorical data and continuous data, respectively. Results White male, older age, and comorbid psychosis were significantly associated with higher odds of having major severity of illness in PD inpatients. The mean length of stay (LOS) was higher in PD patients with psychosis compared to PD with depression (7.32 days vs. 4.23 days; P < 0.001), though the mean total charges of hospitalization were lower in psychosis ($31,240 vs. $38,581; P < 0.001). Utilization of DBS was lower in PD patients with psychosis versus with depression (3.9% vs. 24.3%; P < 0.001). Conclusion Psychiatric comorbidities are prevalent in PD patients and are associated with more disease severity, impaired quality of life, and increased use of healthcare resources (higher LOS and cost). They should be considered an integral part of the disease, and a multidisciplinary approach to managing this disease is crucial to improve the health-related quality of life of PD patients.Item Depression Comorbid With Stroke, Traumatic Brain Injury, Parkinson’s Disease, and Multiple Sclerosis: Diagnosis and Treatment(American Psychiatric Association, 2020-04) Conroy, Susan K.; Brownlowe, Katherine B.; McAllister, Thomas W.; Psychiatry, School of MedicineDepression is common among patients with neurologic disorders, and it has long been considered more difficult to treat than depression in the general population. In this review, the authors consider challenges in the diagnosis and treatment of depression among patients with stroke, traumatic brain injury, Parkinson’s disease, and multiple sclerosis. For each disorder, the authors discuss the epidemiology and time course of depression as well as review the physiologic and psychological etiologies of depression. In addition, for each disorder, they review screening tools and diagnostic considerations, including differential diagnosis; discuss etiological factors, both neurobiological and psychological; and assess evidence for various depression treatments, including pharmacologic, psychosocial, and neuromodulatory therapies. The evidence suggests that depression is common among patients with neurologic disorders and that it is crucial for general psychiatrists to provide treatment for this population.Item Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for α-Synuclein in Parkinson's Disease: The Systemic Synuclein Sampling Study (S4)(IOS Press, 2018) Chahine, Lana M.; Beach, Thomas G.; Seedorff, Nicholas; Caspell-Garcia, Chelsea; Coffey, Christopher S.; Brumm, Michael; Adler, Charles H.; Serrano, Geidy E.; Linder, Carly; Mosovsky, Sherri; Foroud, Tatiana; Riss, Holly; Ecklund, Dixie; Seibyl, John; Jennings, Danna; Arnedo, Vanessa; Riley, Lindsey; Dave, K.D.; Mollenhauer, Brit; SystemicSynuclein Sampling study; Medical and Molecular Genetics, School of MedicineBACKGROUND: α-synuclein is a lead Parkinson's disease (PD) biomarker. There are conflicting reports regarding accuracy of α-synuclein in different tissues and biofluids as a PD biomarker, and the within-subject anatomical distribution of α-synuclein is not well described. The Systemic Synuclein Sampling Study (S4) aims to address these gaps in knowledge. The S4 is a multicenter, cross-sectional, observational study evaluating α-synuclein in multiple tissues and biofluids in PD and healthy controls (HC). OBJECTIVE: To describe the baseline characteristics of the S4 cohort and safety and feasibility of this study. METHODS: Participants underwent motor and non-motor clinical assessments, dopamine transporter SPECT, biofluid collection (cerebrospinal fluid, saliva, and blood), and tissue biopsies (skin, sigmoid colon, and submandibular gland). Biopsy adequacy was determined based on presence of adequate target tissue. Tissue sections were stained with the 5C12 monoclonal antibody against unmodified α-synuclein. All specimens were acquired and processed in a standardized manner. Adverse events were systematically recorded. RESULTS: The final cohort consists of 82 participants (61 PD, 21 HC). In 68 subjects (83%), all types of specimens were obtained but only 50 (61%) of subjects had all specimens both collected and evaluable for α-synuclein. Mild adverse events were common, especially for submandibular gland biopsy, but only 1 severe adverse event occurred. CONCLUSION: Multicenter tissue and biofluid sampling for α-synuclein is feasible and generally safe. S4 will inform understanding of the concurrent distribution of α-synuclein pathology and biomarkers in biofluids and peripheral nervous system in PD.Item Healthcare Data Analytics for Parkinson’s Disease Patients: A Study of Hospital Cost and Utilization in the United States(American Medical Informatics Association, 2017-02-10) Mukherjee, Sunanda; Wu, Huanmei; Jones, Josette; Department of Biohealth Informatics, School of Informatics and ComputingParkinson's Disease (PD), a prevalent problem, especially for the aged populations, is a progressive but non-fatal nervous system disorder. PD patients have special motor as well as non-motor symptoms over time. There are several limitations in the study of PD such as unavailability of data, proper diagnosis and treatment methods. These limitations significantly reduce the quality of PD patient life quality, either directly or indirectly. PD also imposes great financial burdens to PD patients and their family. This project aims to analyze the most common reasons for PD patient hospitalization, review complications that occur during inpatient stays, and measure the costs associated with PD patient characteristics. Using the HCUP NIS data, comprehensive data analysis has been performed. The results are customized visualized using Tableau and other software systems. The preliminary findings sheds light into how to improve the life quality of PD patients.Item Home Modification and Adaptation Educational Seminar for Individuals with Parkinson Disease to Reduce Risk of Falls(2022-05-02) Kidwell, Hannah R.; Bednarski, Julie A.; Bednarski, Julie A.; Department of Occupational Therapy, School of Health and Human Sciences; Williams, KimClients with Parkinson’s disease have high rates of falls within their homes due to the movement disorders typically associated with the disease. This study used quantitative methods to determine the program evaluation of educational seminars on home modifications and adaptations to reduce the risk of falls in Parkinson’s disease (PD) clients. Two educational seminars were given to PD clients and caregivers on how to make modifications and adaptations to their homes and included resources for where to find adaptive equipment and services for providing installations and modifications. Data was collected through pre and post-surveys and analyzed using an independent samples t-test analysis. There was a significant difference in the knowledge of how to make living spaces, bathrooms, and bedrooms safer to reduce the risk of falls in the home. There was also a significant difference in the overall satisfaction of participants’ knowledge on how to complete home modifications and adaptations and for their knowledge on resources/places to find adaptive equipment. Recommendations included continuing to provide home modification education to people with Parkinson’s to ensure further safety and help reduce the risk of falls within the home. The results propose that PD clients are not receiving education on home modifications at rates that would be of benefit to them.Item Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson’s Disease(MDPI, 2019-01-29) Pesch, Beate; Casjens, Swaantje; Woitalla, Dirk; Dharmadhikari, Shalmali; Edmondson, David A.; Zella, Maria Angela Samis; Lehnert, Martin; Lotz, Anne; Herrmann, Lennard; Muhlack, Siegfried; Kraus, Peter; Yeh, Chien-Lin; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Gold, Ralf; van Thriel, Christoph; Brüning, Thomas; Tönges, Lars; Dydak, Ulrike; Department of Radiology and Imaging Sciences, Indiana University School of MedicineWe took advantage of magnetic resonance imaging (MRI) and spectroscopy (MRS) as non-invasive methods to quantify brain iron and neurometabolites, which were analyzed along with other predictors of motor dysfunction in Parkinson's disease (PD). Tapping hits, tremor amplitude, and the scores derived from part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS3 scores) were determined in 35 male PD patients and 35 controls. The iron-sensitive MRI relaxation rate R2* was measured in the globus pallidus and substantia nigra. γ-aminobutyric acid (GABA)-edited and short echo-time MRS was used for the quantification of neurometabolites in the striatum and thalamus. Associations of R2*, neurometabolites, and other factors with motor function were estimated with Spearman correlations and mixed regression models to account for repeated measurements (hands, hemispheres). In PD patients, R2* and striatal GABA correlated with MDS-UPDRS3 scores if not adjusted for age. Patients with akinetic-rigid PD subtype (N = 19) presented with lower creatine and striatal glutamate and glutamine (Glx) but elevated thalamic GABA compared to controls or mixed PD subtype. In PD patients, Glx correlated with an impaired dexterity when adjusted for covariates. Elevated myo-inositol was associated with more tapping hits and lower MDS-UPDRS3 scores. Our neuroimaging study provides evidence that motor dysfunction in PD correlates with alterations in brain iron and neurometabolites.
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