Browsing by Subject "Parkinson Disease"
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Item A proteomic signature for dementia with Lewy bodies(Elsevier Inc., 2019-03-15) O'Bryant, Sid E.; Ferman, Tanis J.; Zhang, Fan; Hall, James R.; Pedraza, Otto; Wszolek, Zbigniew K.; Como, Tori; Julovich, David A.; Mattevada, Sravan; Johnson, Leigh A.; Edwards, Melissa; Graff-Radford, Neill R.Introduction: We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease would distinguish patients with Lewy body disease from normal controls, and if it would distinguish dementia with Lewy bodies (DLB) from Parkinson's disease (PD). Methods: Stored plasma samples were obtained from 145 patients (DLB n = 57, PD without dementia n = 32, normal controls n = 56) enrolled from patients seen in the Behavioral Neurology or Movement Disorders clinics at the Mayo Clinic, Florida. Proteomic assays were conducted and analyzed as per our previously published protocols. Results: In the first step, the proteomic profile distinguished the DLB-PD group from controls with a diagnostic accuracy of 0.97, sensitivity of 0.91, and specificity of 0.86. In the second step, the proteomic profile distinguished the DLB from PD groups with a diagnostic accuracy of 0.92, sensitivity of 0.94, and specificity of 0.88. Discussion: These data provide evidence of the potential utility of a multitiered blood-based proteomic screening method for detecting DLB and distinguishing DLB from PD.Item Dopamine Signaling in Substantia Nigra and Its Impact on Locomotor Function-Not a New Concept, but Neglected Reality(MDPI, 2024-01-23) Salvatore, Michael F.The mechanistic influences of dopamine (DA) signaling and impact on motor function are nearly always interpreted from changes in nigrostriatal neuron terminals in striatum. This is a standard practice in studies of human Parkinson's disease (PD) and aging and related animal models of PD and aging-related parkinsonism. However, despite dozens of studies indicating an ambiguous relationship between changes in striatal DA signaling and motor phenotype, this perseverating focus on striatum continues. Although DA release in substantia nigra (SN) was first reported almost 50 years ago, assessment of nigral DA signaling changes in relation to motor function is rarely considered. Whereas DA signaling has been well-characterized in striatum at all five steps of neurotransmission (biosynthesis and turnover, storage, release, reuptake, and post-synaptic binding) in the nigrostriatal pathway, the depth of such interrogations in the SN, outside of cell counts, is sparse. However, there is sufficient evidence that these steps in DA neurotransmission in the SN are operational and regulated autonomously from striatum and are present in human PD and aging and related animal models. To complete our understanding of how nigrostriatal DA signaling affects motor function, it is past time to include interrogation of nigral DA signaling. This brief review highlights evidence that changes in nigral DA signaling at each step in DA neurotransmission are autonomous from those in striatum and changes in the SN alone can influence locomotor function. Accordingly, for full characterization of how nigrostriatal DA signaling affects locomotor activity, interrogation of DA signaling in SN is essential.Item Effects of Osteopathic Manipulative Treatment on Parkinsonian Gait: A Statistical Parametric Mapping Analysis(2021-05) Terrell, Zachary T.; Patterson, Rita M.; Moudy, Sarah; Hensel, KendiIntroduction/Background: Tens of thousands of people are diagnosed with Parkinson's disease (PD) each year, making it the second most common neurodegenerative disorder. PD results in a variety of gait disturbances that increase the fall risk of those afflicted. The overarching goal for this project is to examine the efficacy of Osteopathic Manipulative Treatment (OMT) and Osteopathic Cranial Manipulative Medicine (OCMM) in improving Parkinsonian gait. Objective: The purpose of this study was to compare joint range of motion (ROM) and joint angle waveforms before and after OMT to determine the effects of OMT and OCMM on Parkinsonian gait, as well as to compare the relative effects of each treatment protocol. We hypothesized that the application of a single OMT protocol on adults with PD will acutely increase joint ROM, and the addition of OCMM to the OMT treatment protocol will further improve gait kinematics. Methods: An 18-camera motion analysis system was used in conjunction with 54 reflective markers on the body to capture three-dimensional position data in a short treadmill walking trial before and after the application of a whole-body (OMT-WB), neck-down (OMTND), or sham OMT protocol. Ankle, knee, and hip joint ROM and waveforms in the sagittal plane during the gait cycle were compared before and after treatment, and across experimental groups. Results: No significant differences were found in baseline ROM and joint angle waveforms of the hip, knee, and ankle joints across experimental groups, or in post-treatment joint waveforms across experimental groups. Knee ROM increased significantly following OMT-ND and OMT-WB protocols (p=0.018, p=0.032). Waveform analysis revealed no significant differences at the hip, knee, or ankle joints. Discussion/Conclusion: Comparison of baseline measurements validates participant randomization and an increase in sagittal knee ROM in individuals with PD following OMT and OCMM may have important implications for decreasing potential fall risk. However, waveform analysis shows no significant change in gait pattern as evidenced by sagittal joint angles following OMT-WB, OMT-ND, or SHAM treatments.Item Membrane androgen receptor-induced oxidative stress: mechanism involved in neurodegeneration(2019-05) Tenkorang, Mavis A. A.; Cunningham, Rebecca L.; O'Bryant, Sid; Schreihofer, Derek; Barber, Robert C.Oxidative stress-associated neurodegenerative diseases, such as Parkinson's disease (PD), affect millions of people worldwide. Although aging is the greatest risk factor for PD, other significant factors may be implicated, such as sex hormones that can mediate sex differences. Men have a higher incidence and prevalence of PD than women. Therefore, testosterone, a primary male sex hormone and a known oxidative stressor, is implicated in PD pathophysiology. Since androgens can have negative effects on dopaminergic cells, it is imperative to understand the underlying mechanisms in order to determine what mediates the observed sex differences in PD prevalence. NADPH Oxidase 1 and 2 are major oxidative stress generators in the brain, thus potential targets for testosterone-induced oxidative stress and cell death. This dissertation project therefore investigates the role of androgens and membrane androgen receptor activation on NOX1/2. We hypothesize that in dopaminergic cells, testosterone activates the membrane androgen receptor (AR45) that is complexed with NOX1/2 to increase oxidative stress. In an oxidative stress environment, androgen activation of this AR45-NOX complex leads to cell death. Results indicate that classical androgen receptor (AR) antagonists do not block testosterone's negative actions in an oxidative stress environment. The effects of AR45-NOX complex on cell viability can be blocked by either degrading AR45 protein or blocking NOX activation by apocynin. Further, these results show that testosterone's detrimental effect on cells is via a non-genomic mechanism, specifically via a novel membrane androgen receptor, AR45. The findings of this study help identify key players in testosterone-induced neurodegeneration, which could serve as potential therapeutic targets for PD. Ultimately, this project provides novel mechanisms to explain thought provoking questions on male sex bias in PD.Item Novel androgen receptor splice variant in the substantia nigra(2017-08-01) Contreras, Jo Garza; Cunningham, Rebecca L.; Basha, Riyaz; Salvatore, MichaelTestosterone can increase calcium influx and cell death in dopamine neurons via a putative membrane androgen receptor (mAR). The mAR induced calcium increase may be due to activation of G-proteins involved in calcium mobilization. Previous studies using an N-terminal targeted androgen receptor (AR) antibody yielded low AR expression in dopamine neurons. Studies in our lab show high AR expression using a C-terminal targeted AR antibody. This difference in expression may be due to an AR variant. We hypothesize an AR variant is present in the membrane of dopaminergic neurons and associated with G proteins. To identify the presence of AR in dopaminergic neurons. We performed immunoblot, sucrose gradient, and immunohistochemistry studies. To determine the protein-protein interaction between mAR and G-proteins we performed co-immunoprecipitation studies. Our results show AR45 localizes in the membrane lipid rafts of dopaminergic neurons. Furthermore, AR45 interacts with Gαq and Gαo G-proteins, which can impact calcium signaling.Item Potential two-step proteomic signature for Parkinson's disease: Pilot analysis in the Harvard Biomarkers Study(Elsevier Inc., 2019-05-02) O'Bryant, Sid E.; Edwards, Melissa; Zhang, Fan; Johnson, Leigh A.; Hall, James R.; Kuras, Yuliya; Scherzer, Clemens R.Introduction: We sought to determine if our previously validated proteomic profile for detecting Alzheimer's disease would detect Parkinson's disease (PD) and distinguish PD from other neurodegenerative diseases. Methods: Plasma samples were assayed from 150 patients of the Harvard Biomarkers Study (PD, n = 50; other neurodegenerative diseases, n = 50; healthy controls, n = 50) using electrochemiluminescence and Simoa platforms. Results: The first step proteomic profile distinguished neurodegenerative diseases from controls with a diagnostic accuracy of 0.94. The second step profile distinguished PD cases from other neurodegenerative diseases with a diagnostic accuracy of 0.98. The proteomic profile differed in step 1 versus step 2, suggesting that a multistep proteomic profile algorithm to detecting and distinguishing between neurodegenerative diseases may be optimal. Discussion: These data provide evidence of the potential use of a multitiered blood-based proteomic screening method for detecting individuals with neurodegenerative disease and then distinguishing PD from other neurodegenerative diseases.Item Prenatal Hypoxic Insults Impact Brain Vulnerability(2021-05) Wilson, Elizabeth N.; Cunningham, Rebecca L.; Goulopoulou, Styliani; Jones, Harlan P.; Sumien, NathalieMaternal hypoxic insults during gestation may lead to an increased risk for neurodegenerative diseases, such as Parkinson's disease (PD), in progeny. Maternal hypoxic stress is a common consequence of many late-stage prenatal stressors (e.g., preeclampsia, eclampsia, inflammation, placental abruption). It is unknown whether maternal hypoxic insults during late gestation have long-term effects on brain regions associated with PD, such as the nigrostriatal pathway. We hypothesized that late gestational maternal hypoxia would result in sustained nigrostriatal impairment in male progeny. To determine whether late-stage gestational hypoxia exposure induced PD-associated behaviors and oxidative stress in progeny, timed pregnant Long-Evans rats were exposed to five days (gestational days: 15-19) of chronic intermittent hypoxia (CIH) or room air normoxia. Progeny were tested during two developmental stages (pubertal and young adult) as late-stage gestational insults can impair the neuronal organization of the brain, which can impact pubertal and young adult functions. To examine PD-associated behavioral phenotype of motor dysfunction, we quantified fine and gross motor behaviors in an open field arena. To examine the integrity of the nigrostriatal pathway, we quantified ultrasonic vocalizations. Our results showed that maternal CIH during late gestation did not impact gross or fine motor behaviors nor circulating oxidative stress. However, maternal CIH during late gestation did impair the nigrostriatal pathway integrity during puberty and young adulthood in both male and female progeny. Long-lasting consequences of maternal CIH during late gestation was most evident in young adult male progeny. Overall, we conclude that maternal hypoxia during late gestation induced sustained nigrostriatal pathway impairment in males more than females, which may underlie the increased risk for PD in men compared to women.Item Strategies & mechanisms to reduce locomotor impairment in aging & Parkinson's disease(2021-05) Kasanga, Ella A.; Salvatore, Michael; Sumien, Nathalie; Luedtke, Robert R.; Bugnariu, Nicoleta L.; Goulopoulou, StylianiThe maintenance of physical function throughout the lifespan is a hallmark of successful aging. However, vulnerability to motor impairment during aging is evident in a substantial fraction of those reaching their seventh to ninth decade of life. Aging-related Parkinsonism is a major source of aging-related motor impairment and manifests similarly to Parkinson's disease (PD). Such disability is associated with a loss of independent living, frailty and mortality. Aging is a major risk factor for these two conditions and with the expected exponential increase in the aging population, their prevalence will also increase. Thus, there is the need to identify interventions which can attenuate this motor impairment, and elucidate the mechanisms mediating their protective benefits. Both pharmacological and non-pharmacological interventions, including exercise, have been proposed to ameliorate motor impairment in this target population. However, most of these interventions are instituted in preclinical models before motor function decline is evident. Also, in the quest to elucidate the underlying neurobiological mechanisms, most studies investigate the role of striatal dopamine (DA) regulation which is presumed to be paramount for the initiation or maintenance of locomotor activities. However, many studies do not report a corresponding increase in striatal DA regulation despite improved motor function. This dissertation research, therefore, evaluates interventions designed to prevent further motor decline in both aging and PD rat models after the onset of motor decline. It is hypothesized that improvement in motor function from the implemented interventions: caloric restriction, treadmill exercise and a pharmacological therapy-ceftriaxone, may not be dependent on only increased striatal, but also nigral, dopaminergic transmission. From several angles of intervention to mitigate motor decline in the models used, it is clear that motor function preservation or recovery can occur if interventions are initiated at a time-point when motor decline is already evident. The body of results show that preservation of motor function is not associated with preservation or restoration of striatal tyrosine hydroxylase expression, the rate-limiting enzyme in the synthesis of DA. Taken together, this dissertation delineates the efficacy of select interventions to attenuate motor decline and identifies key mechanistic targets for possible translation in this vulnerable population.