Browsing by Subject "Parkinson's 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 Establishing Equivalent Aerobic Exercise Parameters Between Early-Stage Parkinson's Disease and Pink1 Knockout Rats(IOS Press, 2022-06-28) Salvatore, Michael F.; Soto, Isabel; Kasanga, Ella A.; James, Rachael; Shifflet, Marla K.; Doshier, Kirby; Little, Joel T.; John, Joshia; Alphonso, Helene M.; Cunningham, J. Thomas; Nejtek, Vicki A.BACKGROUND: Rodent Parkinson's disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. OBJECTIVE: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. METHOD: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr /=3 months, >/=3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased HR to an extent similar in human subjects. RESULTS: After completing aerobic exercise for approximately 30 min, PD subjects had increased HR approximately 35% above baseline ( approximately 63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naive PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8-10 m/min increased HR up to 25% above baseline ( approximately 67% maximum HR), with no further increases up to 16 m/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naive cohort at 5 months old. CONCLUSION: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models.Item Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway(Aging and Disease, 2023-05-18) Xie, Zhencao; Zhang, Mahui; Luo, Yuqi; Jin, Dana; Guo, Xingfang; Yang, Wanlin; Zheng, Jialing; Zhang, Hongfei; Zhang, Lu; Deng, Chao; Zheng, Wenhua; Tan, Eng-King; Jin, Kunlin; Zhu, Shuzhen; Wang, QingIncreasing evidence has shown that gut dysbacteriosis may play a crucial role in neuroinflammation in Parkinson's disease (PD). However, the specific mechanisms that link gut microbiota to PD remain unexplored. Given the critical roles of blood-brain barrier (BBB) dysfunction and mitochondrial dysfunction in the development of PD, we aimed to evaluate the interactions among the gut microbiota, BBB, and mitochondrial resistance to oxidation and inflammation in PD. We investigated the effects of fecal microbiota transplantation (FMT) on the physiopathology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The aim was to explore the role of fecal microbiota from PD patients and healthy human controls in neuroinflammation, BBB components, and mitochondrial antioxidative capacity via the AMPK/SOD2 pathway. Compared to control mice, MPTP-treated mice exhibited elevated levels of Desulfovibrio, whereas mice given FMT from PD patients exhibited enriched levels of Akkermansia and mice given FMT from healthy humans showed no significant alterations in gut microbiota. Strikingly, FMT from PD patients to MPTP-treated mice significantly aggravated motor impairments, dopaminergic neurodegeneration, nigrostriatal glial activation and colonic inflammation, and inhibited the AMPK/SOD2 signaling pathway. However, FMT from healthy human controls greatly improved the aforementioned MPTP-caused effects. Surprisingly, the MPTP-treated mice displayed a significant loss in nigrostriatal pericytes, which was restored by FMT from healthy human controls. Our findings demonstrate that FMT from healthy human controls can correct gut dysbacteriosis and ameliorate neurodegeneration in the MPTP-induced PD mouse model by suppressing microgliosis and astrogliosis, ameliorating mitochondrial impairments via the AMPK/SOD2 pathway, and restoring the loss of nigrostriatal pericytes and BBB integrity. These findings raise the possibility that the alteration in the human gut microbiota may be a risk factor for PD and provide evidence for potential application of FMT in PD preclinical treatment.Item Is there a Neurobiological Rationale for the Utility of the Iowa Gambling Task in Parkinson's Disease?(IOS Press, 2021-04-13) Salvatore, Michael F.; Soto, Isabel; Alphonso, Helene M.; Cunningham, Rebecca L.; James, Rachael; Nejtek, Vicki A.Up to 23% of newly diagnosed, non-demented, Parkinson's disease (PD) patients experience deficits in executive functioning (EF). In fact, EF deficits may occur up to 39-months prior to the onset of motor decline. Optimal EF requires working memory, attention, cognitive flexibility, and response inhibition underlying appropriate decision-making. The capacity for making strategic decisions requires inhibiting imprudent decisions and are associated with noradrenergic and dopaminergic signaling in prefrontal and orbitofrontal cortex. Catecholaminergic dysfunction and the loss of noradrenergic and dopaminergic cell bodies early in PD progression in the aforementioned cortical areas likely contribute to EF deficits resulting in non-strategic decision-making. Thus, detecting these deficits early in the disease process could help identify a significant portion of individuals with PD pathology (14-60%) before frank motor impairment. A task to evaluate EF in the domain of non-strategic decision-making might be useful to indicate the moderate loss of catecholamines that occurs early in PD pathology prior to motor decline and cognitive impairment. In this review, we focus on the potential utility of the Iowa Gambling Task (IGT) for this purpose, given significant overlap between in loss of dopaminergic and noradrenergic cells bodies in early PD and the deficits in catecholamine function associated with decreased EF. As such, given the loss of catecholamines already well-underway after PD diagnosis, we evaluate the potential utility of the IGT to identify the risk of therapeutic non-compliance and a potential companion approach to detect PD in premotor stages.Item Mechanisms by which 17β-Estradiol (E2) suppress neuronal cox-2 expression(2015-12-01) Stacey, Winfred; Rosalie M. Uht; Rebecca L. Cunningham; Eric B. GonzalesData from animal models indicate that 17β-estradiol (E2) deprivation increases susceptibility to neurodegenerative diseases. E2 attenuates inflammatory response by suppressing expression of pro-inflammatory genes; however, the mechanisms by which E2 suppress neuronal pro-inflammatory genes are not well established. Histological analyses of postmortem human brains suggest that neuronal cyclooxygenase-2 (COX-2) is upregulated in early stages of Alzheimer’s disease (AD) and in Parkinson’s disease (PD). Given that COX-2 is selectively expressed in a subset of neurons in the hippocampus, cerebral cortex, and amygdala, we investigated mechanisms by which E2 could down-regulate cox-2 expression in a neuronal system. To characterize the effect of E2 on cox 2 in a neuronal system, we used the AR-5 and N27 rat neuronal cell line models. Our data indicate that E2 and ERβ agonist diarylpropionitrile (DPN) suppress COX-2 pre-mRNA and mRNA levels to the same extent in AR-5 but not in N27. Furthermore, PHTPP, a selective ERβ antagonist, reversed the effect of both E2 and DPN in AR-5. Because the cox-2 promoter lacks palindromic estrogen response elements (EREs), we targeted a proximal promoter region with a nuclear factor- ĸB (NF-ĸB) response element implicated in cox-2 regulation. E2 and DPN failed to increase ERβ occupancy at the cox-2 promoter. Rather, DPN decreased promoter occupancy of p65 NF-κB subunit and acetylation of histone 4 (Ac-H4). Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the effect of TSA, E2 and DPN increase HDAC1 promoter occupancy; however recruitment of HDAC3 was unchanged. HDAC1 is known to form a complex with Swi-independent A (Sin3A); E2 and DPN increased Sin3A occupancy. The recruitment of HDAC1 seems to correlate with decreased acetylation of histone 4 (H4) and not histone 3 (H3). Furthermore E2 alone increased methylation status in the cox-2 proximal promoter. Taken together, these data suggest that E2 suppresses neuronal cox-2 expression through ERβ-mediated recruitment of HDAC1, Sin3A and a concomitant reduction of p65 and H4 levels. Here we conclude that E2 suppresses neuronal cox-2 expression through a mechanism that involves a combination of decreasing activator and increasing repressor recruitment to the cox-2 promoter.Item OXIDATIVE STRESS NEGATIVELY INFLUENCES THE EFFECTS OF ANDROGENS ON DOPAMINE NEURONAL VIABILITY(2013-04-12) Holmes, Shaletha S.Purpose: Parkinson's disease (PD) is a neurodegenerative disease characterized by oxidative stress and loss of dopaminergic neurons in the nigrostriatal pathway, in which men have a higher risk than women. The mechanisms involved in this gender bias remains elusive, one possibility may be that oxidative stress converts the neuronal response to androgens, which is toxic. Specifically, we hypothesize that in an oxidative stress environment, androgens such as testosterone compromises the viability of dopamine neurons. Methods: To test our hypothesis, we exposed a dopaminergic cell line (N27 cells) to a sublethal concentration of the pro-oxidant, tert-butyl-hydrogen peroxide (H202) for 24 hours and assessed cell viability in the presence or absence of testosterone. Results: Physiologically relevant concentrations of the androgen, testosterone (0, 1, 10, 100 nM) failed to compromise cell viability in non-oxidatively stressed cells. In contrast, testosterone and testosterone conjugated to BSA (T-BSA) did promote cell death in the H202 pre-treated cells. Interestingly, androgen pre-treatment protected dopamine cells from H202-induced cell death. Supporting the role of oxidative stress as a switch in this effect, the antioxidant, N-acetyl cysteine, prevented the damage promoting effects of testosterone in H202 pretreated cells. Neither the androgen receptor nor the estrogen receptor antagonists, flutamide (10 uM) and ICI 182, 780(1 uM), respectively, altered the death promoting effect of testosterone. Conclusions: Coupled with the observation that the membrane-impermeable T-BSA mimicked the effects of testosterone, we suggest that the cell death promoting effects may be mediated by a putative membrane-associated androgen receptor. Overall, these results indicate that oxidative stress acts as a molecular switch in dopamine neurons that can reverse the neuroprotective effects of androgens to that, which is neurotoxic. Thus, the interplay between oxidative stress and androgens on dopamine neuronal viability may underlie the male gender bias found in PD.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 QEEG Signatures are Associated with Nonmotor Dysfunctions in Parkinson's Disease and Atypical Parkinsonism: An Integrative Analysis(Aging and Disease, 2023-02-24) Liu, Hailing; Huang, Zifeng; Deng, Bin; Chang, Zihan; Yang, Xiaohua; Guo, Xinfang; Yuan, Feilan; Yang, Qin; Wang, Liming; Zou, Haiqiang; Li, Mengyan; Zhu, Zhaohua; Jin, Kunlin; Wang, QingParkinson's disease (PD) and atypical parkinsonism (AP), including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), share similar nonmotor symptoms. Quantitative electroencephalography (QEEG) can be used to examine the nonmotor symptoms. This study aimed to characterize the patterns of QEEG and functional connectivity (FC) that differentiate PD from PSP or MSA, and explore the correlation between the differential QEEG indices and nonmotor dysfunctions in PD and AP. We enrolled 52 patients with PD, 31 with MSA, 22 with PSP, and 50 age-matched health controls to compare QEEG indices among specific brain regions. One-way analysis of variance was applied to assess QEEG indices between groups; Spearman's correlations were used to examine the relationship between QEEG indices and nonmotor symptoms scale (NMSS) and mini-mental state examination (MMSE). FCs using weighted phase lag index were compared between patients with PD and those with MSA/PSP. Patients with PSP revealed higher scores on the NMSS and lower MMSE scores than those with PD and MSA, with similar disease duration. The delta and theta powers revealed a significant increase in PSP, followed by PD and MSA. Patients with PD presented a significantly lower slow-to-fast ratio than those with PSP in the frontal region, while patients with PD presented significantly higher EEG-slowing indices than patients with MSA. The frontal slow-to-fast ratio showed a negative correlation with MMSE scores in patients with PD and PSP, and a positive correlation with NMSS in the perception and mood domain in patients with PSP but not in those with PD. Compared to PD, MSA presented enhanced FC in theta and delta bands in the posterior region, while PSP revealed decreased FC in the delta band within the frontal-temporal cortex. These findings suggest that QEEG might be a useful tool for evaluating the nonmotor dysfunctions in PD and AP. Our QEEG results suggested that with similar disease duration, the cortical neurodegenerative process was likely exacerbated in patients with PSP, followed by those with PD, and lastly in patients with MSA.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.Item The Effects of Oxidative Stress and Testosterone on Dopamine Neuron Viability: Implications for Parkinson’s Disease(2015-12-01) Holmes, Shaletha S.; Cunningham, Rebecca L.; Singh, Meharvan; Schreihofer, DerekParkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress, mitochondrial dysfunction, inflammation and apoptosis are mechanisms implicated in Parkinson’s pathology. Interestingly, males have a higher incidence of PD than females. Therefore, the major male sex hormone, testosterone may play a role in oxidative stress-induced dopamine neurodegeneration and thus underlie the sex bias observed in PD. Oxidative stress, the imbalance of antioxidant mechanisms and reactive oxygen species, mediates downstream signaling of mitochondria dysfunction, inflammation and apoptosis. Oxidative stress can induce mitochondria dysfunction via calcium neurotoxicity, and oxidative stress can stimulate the pro-inflammatory mediators of NFkB and COX2. This activation of mitochondrial dysfunction and inflammation can trigger apoptosis in dopaminergic neurons. Therefore, it is hypothesized that under oxidative stress conditions, testosterone will induce dopaminergic neurodegeneration by increasing mitochondrial dysfunction and inflammation, leading to apoptosis in dopamine neurons. To test this hypothesis, a N27 dopaminergic cell line was treated with tert-butyl hydrogen peroxide followed by exposure to physiologically relevant concentrations of testosterone to assess cell viability, mitochondria function, calcium influx, inflammation, oxidative stress and apoptosis. These results show that testosterone, alone, increase calcium influx and acts as an oxidative stressor without affecting cell viability. However, under conditions of oxidative stress, testosterone decreases cell viability and exacerbates inflammation, resulting in increased apoptosis. These results indicate that testosterone, only in an oxidative stress environment, can increase pathological features associated with dopamine neurodegeneration in PD. In conclusion, these results suggest that a testosterone mediated mechanism may underlie the increased risk of PD for men compared to women.