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https://www.readbyqxmd.com/read/27933309/impact-of-age-and-vector-construct-on-striatal-and-nigral-transgene-expression
#1
Nicole K Polinski, Fredric P Manfredsson, Matthew J Benskey, D Luke Fischer, Christopher J Kemp, Kathy Steece-Collier, Ivette M Sandoval, Katrina L Paumier, Caryl E Sortwell
Therapeutic protein delivery using viral vectors has shown promise in preclinical models of Parkinson's disease (PD) but clinical trial success remains elusive. This may partially be due to a failure to include advanced age as a covariate despite aging being the primary risk factor for PD. We investigated transgene expression following intracerebral injections of recombinant adeno-associated virus pseudotypes 2/2 (rAAV2/2), 2/5 (rAAV2/5), 2/9 (rAAV2/9), and lentivirus (LV) expressing green fluorescent protein (GFP) in aged versus young adult rats...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27928028/mitochondrial-pyruvate-carrier-regulates-autophagy-inflammation-and-neurodegeneration-in-experimental-models-of-parkinson-s-disease
#2
Anamitra Ghosh, Trevor Tyson, Sonia George, Erin N Hildebrandt, Jennifer A Steiner, Zachary Madaj, Emily Schulz, Emily Machiela, William G McDonald, Martha L Escobar Galvis, Jeffrey H Kordower, Jeremy M Van Raamsdonk, Jerry R Colca, Patrik Brundin
Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson's disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity. MSDC-0160 protected against 1-methyl-4-phenylpyridinium (MPP(+)) insult in murine and cultured human midbrain dopamine neurons and in an α-synuclein-based Caenorhabditis elegans model...
December 7, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27927762/urinary-incontinence-incident-parkinsonism-and-parkinson-s-disease-pathology-in-older-adults
#3
Noa M Buchman, Sue E Leurgans, Raj J Shah, Veronique VanderHorst, Robert S Wilson, Yaacov G Bachner, David Tanne, Julie A Schneider, David A Bennett, Aron S Buchman
OBJECTIVE: To test the hypothesis that urinary incontinence (UI) is associated with incident parkinsonism in older adults. METHODS: We used data from 2,617 older persons without dementia. Assessment included baseline self-report UI and annual structured exam which assessed parkinsonian signs, motor performances, cognitive function, and self-report disabilities. We used a series of Cox proportional hazards models to examine the association of UI with parkinsonism and adverse health outcomes and a mixed-effect model to examine the association of UI with the annual rate of cognitive decline...
December 7, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/27927222/tollip-an-early-regulator-of-the-acute-inflammatory-response-in-the-substantia-nigra
#4
Marie Humbert-Claude, D Duc, D Dwir, L Thieren, J Sandström von Tobel, C Begka, F Legueux, D Velin, M H Maillard, K Q Do, F Monnet-Tschudi, L Tenenbaum
BACKGROUND: Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease...
December 7, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27904494/anti-apoptotic-effect-of-shudipingchan-granule-in-the-substantia-nigra-of-rat-models-of-parkinson-s-disease
#5
Qing Ye, Xiao-Lei Yuan, Jing He, Jie Zhou, Can-Xing Yuan, Xu-Ming Yang
Levodopa is the gold-standard treatment for Parkinson's disease. However, although it alleviates the clinical symptoms, it cannot delay the progressive apoptosis of dopaminergic neurons or prevent motor complications in the long term. In the present study, we investigated the effect of Shudipingchan granule on neuronal apoptosis in a rat model of Parkinson's disease, established by injecting 6-hydroxydopamine into the substantia nigra pars compacta and ventral tegmental area. We then administered levodopa (20 mg/kg intraperitoneally, twice daily) with or without Shudipingchan granule (7...
October 2016: Neural Regeneration Research
https://www.readbyqxmd.com/read/27903866/nigral-dopaminergic-pak4-prevents-neurodegeneration-in-rat-models-of-parkinson-s-disease
#6
So-Yoon Won, Mee-Hee Park, Soon-Tae You, Seung-Won Choi, Hyong-Kyu Kim, Catriona McLean, Suk-Chul Bae, Sang Ryong Kim, Byung Kwan Jin, Kun Ho Lee, Eun-Young Shin, Eung-Gook Kim
Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. No neuroprotective treatments have successfully prevented the progression of this disease. We report that p21-activated kinase 4 (PAK4) is a key survival factor for DA neurons. We observed PAK4 immunoreactivity in rat and human DA neurons in brain tissue, but not in microglia or astrocytes. PAK4 activity was markedly decreased in postmortem brain tissue from PD patients and in rodent models of PD...
November 30, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27902767/towards-a-non-human-primate-model-of-alpha-synucleinopathy-for-development-of-therapeutics-for-parkinson-s-disease-optimization-of-aav1-2-delivery-parameters-to-drive-sustained-expression-of-alpha-synuclein-and-dopaminergic-degeneration-in-macaque
#7
James B Koprich, Tom H Johnston, Gabriela Reyes, Vanessa Omana, Jonathan M Brotchie
Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway...
2016: PloS One
https://www.readbyqxmd.com/read/27900791/robust-graft-survival-and-normalized-dopaminergic-innervation-does-not-obligate-recovery-in-a-pd-patient
#8
Jeffrey H Kordower, Christopher G Goetz, Yaping Chu, Glenda M Halliday, Daniel A Nicholson, Timothy Musial, David J Marmion, A Jon Stoessl, Vesna Sossi, Thomas B Freeman, C Warren Olanow
OBJECTIVE: The main goal of dopamine cell replacement therapy in Parkinson's disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying sixteen years following fetal nigral grafting. METHODS: A 55-year-old levodopa-responsive woman with PD received bilateral putamenal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial...
November 30, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27862327/an-order-in-lewy-body-disorders-retrograde-degeneration-in-hyperbranching-axons-as-a-fundamental-structural-template-accounting-for-focal-multifocal-lewy-body-disease
#9
REVIEW
Toshiki Uchihara 内原 俊記
Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs)...
November 14, 2016: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/27813160/subcortical-18-f-av-1451-binding-patterns-in-progressive-supranuclear-palsy
#10
Hanna Cho, Jae Yong Choi, Mi Song Hwang, Seung Ha Lee, Young Hoon Ryu, Myung Sik Lee, Chul Hyoung Lyoo
BACKGROUND: Accumulation of cortical and subcortical tau pathology is the primary pathological substrate for progressive supranuclear palsy (PSP). (18) F-AV-1451, a radiotracer that binds to the pathological tau protein, may be helpful for in vivo visualization and quantitation of tau pathology in PSP. OBJECTIVES: The objectives of this study were to investigate cortical and subcortical (18) F-AV-1451 binding patterns in patients with PSP. METHODS: We recruited 14 PSP patients and compared their cortical and subcortical binding patterns in (18) F-AV-1451 positron emission tomography (PET) studies with those of 15 Parkinson's disease (PD) patients and 15 healthy controls...
November 3, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27803984/%C3%AE-synuclein-in-the-colon-and-premotor-markers-of-parkinson-disease-in-neurologically-normal-subjects
#11
Joong-Seok Kim, In-Seok Park, Hyung-Eun Park, Su-Young Kim, Jung A Yun, Chan Kwon Jung, Hye-Young Sung, Jin-Kwon Lee, Won-Kyung Kang
Extranigral non-motor signs precede the first motor manifestations of Parkinson's disease by many years in some patients. The presence of α-synuclein deposition within colon tissues in patients with Parkinson's disease can aid in identifying early neuropathological changes prior to disease onset. In the present study, we evaluated the roles of non-motor symptoms and signs and imaging biomarkers of nigral neuronal changes and α-synuclein accumulation in the colon. Twelve subjects undergoing colectomy for primary colon cancer were recruited for this study...
November 1, 2016: Neurological Sciences
https://www.readbyqxmd.com/read/27802243/the-proteasome-inhibition-model-of%C3%A2-parkinson-s-disease
#12
Eduard Bentea, Lise Verbruggen, Ann Massie
The pathological hallmarks of Parkinson's disease are the progressive loss of nigral dopaminergic neurons and the formation of intracellular inclusion bodies, termed Lewy bodies, in surviving neurons. Accumulation of proteins in large insoluble cytoplasmic aggregates has been proposed to result, partly, from a failure in the function of intracellular protein degradation pathways. Evidence in support for such a hypothesis emerged in the beginning of the years 2000 with studies demonstrating structural and functional deficits in the ubiquitin-proteasome pathway in post-mortem nigral tissue of patients with Parkinson's disease...
October 11, 2016: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/27792255/fluorodopa-is-a-promising-fluorine-19-mri-probe-for-evaluating-striatal-dopaminergic-function-in-a-rat-model-of-parkinson-s-disease
#13
Daijiro Yanagisawa, Keisuke Oda, Masatoshi Inden, Shigehiro Morikawa, Toshiro Inubushi, Takashi Taniguchi, Masanori Hijioka, Yoshihisa Kitamura, Ikuo Tooyama
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum. It has been estimated that approximately 80% of the striatal dopamine and 50% of nigral dopaminergic neurons are lost before the onset of typical motor symptoms, indicating that early diagnosis of PD using noninvasive imaging is feasible. Fluorine-19 ((19) F) magnetic resonance imaging (MRI) represents a highly sensitive, easily available, low-background, and cost-effective approach to evaluate dopaminergic function using non-radioactive fluorine-containing dopaminergic agents...
October 28, 2016: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/27789613/grafted-neural-precursors-integrate-into-mouse-striatum-differentiate-and-promote-recovery-of-function-through-release-of-erythropoietin-in-mptp-treated-mice
#14
Stephana Carelli, Toniella Giallongo, Cristina Viaggi, Zuzana Gombalova, Elisa Latorre, Massimiliano Mazza, Francesca Vaglini, Anna Maria Di Giulio, Alfredo Gorio
Erythropoietin-releasing neural precursor cells (Er-NPCs) are a subclass of subventricular zone-derived neural progenitors, capable of surviving for 6 hr after death of donor. They present higher neural differentiation. Here, Er-NPCs were studied in animal model of Parkinson's disease. Dopaminergic degeneration was caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intraperitoneal administration in C57BL/6 mice. The loss of function was evaluated by specific behavioral tests. Er-NPCs (2.5 × 10(5)) expressing the green fluorescent protein were administered by stereotaxic injection unilaterally in the left striatum...
October 2016: ASN Neuro
https://www.readbyqxmd.com/read/27771354/paradoxical-lower-sensitivity-of-locus-coeruleus-than-substantia-nigra-pars-compacta-neurons-to-acute-actions-of-rotenone
#15
Andrew G Yee, Peter S Freestone, Ji-Zhong Bai, Janusz Lipski
Parkinson's disease (PD) is not only associated with degeneration of dopaminergic (DAergic) neurons in the Substantia Nigra, but also with profound loss of noradrenergic neurons in the Locus Coeruleus (LC). Remarkably, LC degeneration may exceed, or even precede the loss of nigral DAergic neurons, suggesting that LC neurons may be more susceptible to damage by various insults. Using a combination of electrophysiology, fluorescence imaging and electrochemistry, we directly compared the responses of LC, nigral DAergic and nigral non-dopaminergic (non-DAergic) neurons in rat brain slices to acute application of rotenone, a mitochondrial toxin used to create animal and in vitro models of PD...
October 19, 2016: Experimental Neurology
https://www.readbyqxmd.com/read/27763643/mitochondrial-angiotensin-receptors-in-dopaminergic-neurons-role-in-cell-protection-and-aging-related-vulnerability-to-neurodegeneration
#16
Rita Valenzuela, Maria A Costa-Besada, Javier Iglesias-Gonzalez, Emma Perez-Costas, Begoña Villar-Cheda, Pablo Garrido-Gil, Miguel Melendez-Ferro, Ramon Soto-Otero, Jose L Lanciego, Daniel Henrion, Rafael Franco, Jose L Labandeira-Garcia
The renin-angiotensin system (RAS) was initially considered as a circulating humoral system controlling blood pressure, being kidney the key control organ. In addition to the 'classical' humoral RAS, a second level in RAS, local or tissular RAS, has been identified in a variety of tissues, in which local RAS play a key role in degenerative and aging-related diseases. The local brain RAS plays a major role in brain function and neurodegeneration. It is normally assumed that the effects are mediated by the cell-surface-specific G-protein-coupled angiotensin type 1 and 2 receptors (AT1 and AT2)...
October 20, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27755935/utility-of-nigral-signal-intensity-changes-on-mr-images-to-differentiate-drug-induced-parkinsonism-from-parkinson-disease
#17
Roberto De Marzi, Werner Poewe, Elke R Gizewski, Philipp Mahlknecht, Klaus Seppi
No abstract text is available yet for this article.
November 2016: Radiology
https://www.readbyqxmd.com/read/27732886/oxidative-stress-and-mitochondrial-dysfunction-are-the-underlying-events-of-dopaminergic-neurodegeneration-in-homocysteine-rat-model-of-parkinson-s-disease
#18
Nivedita Bhattacharjee, Anupom Borah
Homocysteine (Hcy) when injected intranigrally in rat caused parkinsonian behavioural phenotypes and loss of nigral dopaminergic neurons but the underlying mechanisms of neurotoxicity remains elusive. In the present study, we focused on oxidative stress as one of the mechanisms of neurotoxicity in Hcy-induced hemiparkinsonian rat model. Unilateral intranigral infusion of Hcy (1.0 μmol in 2 μl) caused inhibition of mitochondrial complex-I activity, decrease in the level of striatal dopamine, loss of midbrain dopaminergic neurons, and motor abnormalities...
December 2016: Neurochemistry International
https://www.readbyqxmd.com/read/27731537/transcranial-sonography-in-dopa-responsive-dystonia
#19
M Svetel, A Tomić, M Mijajlović, V Dobričić, I Novaković, T Pekmezović, L Brajković, V S Kostić
BACKGROUND AND PURPOSE: Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder. METHODS: Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs)...
October 12, 2016: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/27704331/admixing-of-mptp-resistant-and-susceptible-mice-strains-augments-nigrostriatal-neuronal-correlates-to-resist-mptp-induced-neurodegeneration
#20
D J Vidyadhara, H Yarreiphang, T R Raju, Phalguni Anand Alladi
Disease genetics in admixed populations like Hispanic-Americans, African-Americans, etc. are gaining importance due to high disease burden in them. Furthermore, epidemiological studies conclusively prove ethnicity-based differential prevalence of Parkinson's disease (PD), since the American-Caucasians are more susceptible than Asian-Indians and Africans. Contradictorily, Anglo-Indians, an admixture of Europeans and Asian-Indians are five-times less susceptible than Indians. We evaluated the neural basis of this phenomenon using the cytomorphological features of susceptibility to nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...
October 4, 2016: Molecular Neurobiology
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