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1
Pilipovich, A. A., V. L. Golubev, Al B. Danilov, and R. R. Tyutina. "Role of biometals in pathogenesis treatment of Parkinson's disease (overview)." Medical alphabet, no. 1 (June 11, 2020): 21–27. http://dx.doi.org/10.33667/2078-5631-2020-1-21-27.
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The role of exogenous factors in the occurrence of neurodegenerative diseases has been shown in many works: on the effects of radiation, neurotoxicants, pesticides and other organic and inorganic substances. One of the interesting and promising areas for studying the pathogenesis of neurodegeneration is the analysis of the composition and ratio of trace elements in various tissues and organs of a person. The influence of trace elements on the development of neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis, is given special attention, since such patients show multiple disorders in the homeostasis of the main endogenous brain biometals (calcium, magnesium, zinc, iron, manganese, copper, etc.). On the one hand, in a cell or its components, where metals play a key role in biological processes, a metal deficiency can occur, on the other hand, metals can accumulate in pathological proteins, causing cell dysfunction and death. Protein aggregation is a common feature of all neurodegenerative diseases. Specific changes in the concentration of biometals in various environments of the body can be considered as early biomarkers of neurodegenerations. And the identification of reliable biomarkers is considered a paramount task for the development of the direction of early therapy and prevention of the disease, in particular PD. A change in the distribution of metal, cell deficiency and sequestration in pathological proteins are abnormalities that must be addressed during neurodegeneration. Currently, approximately 800 compounds are used or tested for the treatment of PD, of which approximately 250 have the expected or established chelation properties of metals (CuII, CuI, FeII, FeIII, MnII, ZnII) that are involved in dyshomeostasis in PD. Today's knowledge of the pathogenesis of the most common neurodegenerations, such as AD and PD, is still not enough to develop clear recommendations for therapy with biometals and other trace elements, but work in this direction is actively ongoing.
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Svenningsson, Per, Eric Westman, Clive Ballard, and Dag Aarsland. "Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment." Lancet Neurology 11, no. 8 (August 2012): 697–707. http://dx.doi.org/10.1016/s1474-4422(12)70152-7.
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Raghunathan, Rekha, Kathleen Turajane, and Li Chin Wong. "Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 16 (August 18, 2022): 9299. http://dx.doi.org/10.3390/ijms23169299.
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Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) are both characterized by pathogenic protein aggregates that correlate with the progressive degeneration of neurons and the loss of behavioral functions. Both diseases lack biomarkers for diagnosis and treatment efficacy. Proteomics is an unbiased quantitative tool capable of the high throughput quantitation of thousands of proteins from minimal sample volumes. We review recent proteomic studies in human tissues, plasma, cerebrospinal fluid (CSF), and exosomes in ALS and PD that identify proteins with potential utility as biomarkers. Further, we review disease-related post-translational modifications in key proteins TDP43 in ALS and α-synuclein in PD studies, which may serve as biomarkers. We compare relative and absolute quantitative proteomic approaches in key biomarker studies in ALS and PD and discuss recent technological advancements which may identify suitable biomarkers for the early-diagnosis treatment efficacy of these diseases.
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Frutos, Laura López de, Francisco Almeida, Jessica Murillo-Saich, Vasco A. Conceição, Monica Guma, Oswald Queheberger, Pilar Giraldo, and Gabriel Miltenberger-Miltenyi. "Serum Phospholipid Profile Changes in Gaucher Disease and Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 18 (September 8, 2022): 10387. http://dx.doi.org/10.3390/ijms231810387.
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Alterations in the levels of serum sphingolipids and phospholipids have been reported in Gaucher disease and in Parkinson’s disease, suggesting a potential role of these lipids as biomarkers. This project’s objective is to detect novel associations and novel candidate biomarkers in the largest Spanish Gaucher and Parkinson diseases of the Iberian Peninsula. For that, 278 participants were included: 100 sporadic Parkinson’s patients, 70 Gaucher patients, 15 GBA1-mutation-carrier Parkinson’s patients and 93 controls. A serum lipidomics array including 10 phospholipid groups, 368 species, was performed using high-performance liquid chromatography–mass spectrometry. Lipid levels were compared between groups via multiple-regression analyses controlling for clinical and demographic parameters. Additionally, lipid levels were compared within the Gaucher and Parkinson’s groups controlling for medication and/or disease severity. Results were controlled for robustness by filtering of non-detectable lipid values. There was an increase in the levels of phosphatidylcholine, with a simultaneous decrease in lyso-phosphatidylcholine, in the Gaucher, Parkinson’s and GBA1-mutation-carrier Parkinson’s patients vs. controls. Phosphatidylethanolamine, lyso- and plasmalogen-phosphatidylethanolamine were also increased in Gaucher and Parkinson’s. Gaucher patients also showed an increase in lyso-phosphatidylserine and phosphatidylglycerol. While in the Gaucher and Parkinson’s groups, velaglucerase alpha and dopamine agonists, respectively, showed positive associations with the lipid changes, miglustat treatment in Gaucher patients normalized the altered phosphatidylcholine/lyso-phosphatidylcholine ratio. In conclusion, Gaucher and Parkinson’s patients showed changes in various serum phospholipid levels when compared with healthy controls, further supporting the role of such lipids in disease development and, possibly, as putative biomarkers. This hypothesis was reinforced by the normalizing effect of miglustat, and by controlling for data robustness, even though the limited number of participants, especially in the sub-distribution by treatment groups in GD requires validation in a larger number of patients.
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Polissidis, Alexia, Lilian Petropoulou-Vathi, Modestos Nakos-Bimpos, and Hardy J. Rideout. "The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson’s Disease." Biomolecules 10, no. 6 (June 16, 2020): 912. http://dx.doi.org/10.3390/biom10060912.
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Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson’s disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2) and glucocerebrosidase (GBA1). Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements.
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Russillo, Maria Claudia, Valentina Andreozzi, Roberto Erro, Marina Picillo, Marianna Amboni, Sofia Cuoco, Paolo Barone, and Maria Teresa Pellecchia. "Sex Differences in Parkinson’s Disease: From Bench to Bedside." Brain Sciences 12, no. 7 (July 13, 2022): 917. http://dx.doi.org/10.3390/brainsci12070917.
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Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and gender differences have been described on several aspects of PD. In the present commentary, we aimed to collect and discuss the currently available evidence on gender differences in PD regarding biomarkers, genetic factors, motor and non-motor symptoms, therapeutic management (including pharmacological and surgical treatment) as well as preclinical studies. Methods: A systematic literature review was performed by searching the Pubmed and Scopus databases with the search strings “biomarkers”, “deep brain stimulation”, “female”, “gender”, “genetic”, “levodopa”, “men”, “male”, “motor symptoms”, “non-motor symptoms”, “Parkinson disease”, “sex”, “surgery”, and “women”. Results: The present review confirms the existence of differences between men and women in Parkinson Disease, pointing out new information regarding evidence from animal models, genetic factors, biomarkers, clinical features and pharmacological and surgical treatment. Conclusions: The overall goal is to acquire new informations about sex and gender differences in Parkinson Disease, in order to develop tailored intervetions.
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Redenšek, Sara, and Vita Dolžan. "The role of pharmacogenomics in the personalization of Parkinson's disease treatment." Pharmacogenomics 21, no. 14 (September 2020): 1033–43. http://dx.doi.org/10.2217/pgs-2020-0031.
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Parkinson's disease (PD)-related phenotypes can vary among patients substantially, including response to dopaminergic treatment in terms of efficacy and occurrence of adverse events. Many pharmacogenetic studies have already been conducted to find genetic markers of response to dopaminergic treatment. Integration of genetic and clinical data has already resulted in construction of clinical pharmacogenetic models for prediction of adverse events. However, the results of pharmacogenetic studies are inconsistent. More comprehensive genome-wide approaches are needed to find genetic biomarkers of PD-related phenotypes to better explain the variability in response to treatment. These genetic markers should be integrated with clinical, environmental, imaging, and other omics data to build clinically useful algorithms for personalization of PD management.
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Kwon, Eun Hae, Sabrina Tennagels, Ralf Gold, Klaus Gerwert, Léon Beyer, and Lars Tönges. "Update on CSF Biomarkers in Parkinson’s Disease." Biomolecules 12, no. 2 (February 18, 2022): 329. http://dx.doi.org/10.3390/biom12020329.
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Progress in developing disease-modifying therapies in Parkinson’s disease (PD) can only be achieved through reliable objective markers that help to identify subjects at risk. This includes an early and accurate diagnosis as well as continuous monitoring of disease progression and therapy response. Although PD diagnosis still relies mainly on clinical features, encouragingly, advances in biomarker discovery have been made. The cerebrospinal fluid (CSF) is a biofluid of particular interest to study biomarkers since it is closest to the brain structures and therefore could serve as an ideal source to reflect ongoing pathologic processes. According to the key pathophysiological mechanisms, the CSF status of α-synuclein species, markers of amyloid and tau pathology, neurofilament light chain, lysosomal enzymes and markers of neuroinflammation provide promising preliminary results as candidate biomarkers. Untargeted approaches in the field of metabolomics provide insights into novel and interconnected biological pathways. Markers based on genetic forms of PD can contribute to identifying subgroups suitable for gene-targeted treatment strategies that might also be transferable to sporadic PD. Further validation analyses in large PD cohort studies will identify the CSF biomarker or biomarker combinations with the best value for clinical and research purposes.
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Camicioli, Richard, and Serge Gauthier. "Clinical Trials in Parkinson's Disease Dementia and Dementia with Lewy Bodies." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 34, S1 (March 2007): S109—S117. http://dx.doi.org/10.1017/s0317167100005679.
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Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are pathological overlapping and important causes of dementia for which clinical trials are in their infancy. Cholinesterase inhibitors may be of benefit in DLB and PDD, as suggested by placebo-controlled clinical trials of rivastigmine and donepezil. The anti-psychotic agent clozapine has been of benefit in PD and PDD, but other agents, such as quetiapine, require adequate assessment. Barriers to trials include pathological overlap that can lead to inaccuracies in clinical diagnosis, unavailability of a consensus definition for PDD, unanswered questions regarding natural history and the paucity of validated outcome measures. Motor impairment must be considered in patients with PDD and DLB; conversely, cognitive impairment should be assessed in trials targeting motor impairment in advanced PD. Potential targets for treatment include onset of dementia, cognitive impairment, behavioral impairment, functional decline, falls, nursing home placement, mortality, quality of life and economic impact. Biomarkers including neuroimaging and cerebrospinal fluid markers are not currently established. At present PDD and DLB are distinct entities by definition. Future studies, including clinical trials and biomarker studies, will help to further define the clinical and therapeutic implications of this distinction.
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Lee, Ju-Young, Hyeo-il Ma, and Young Eun Kim. "Biomarker in Parkinson’s Disease: Clinical and Biochemical Biomarker." Journal of the Korean Neurological Association 39, no. 4 (November 1, 2021): 287–97. http://dx.doi.org/10.17340/jkna.2021.4.4.
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Parkinson’s disease is a neurodegenerative disease compromising progressive motor and non-motor features for a long disease course. Although many drugs controlling parkinsonian symptoms were discovered, treatment with disease-modifying or halting effect was not developed to date. The exploration of reliable biomarkers would be helpful for better predicting disease progression and thereby successful development of disease-modifying therapy. In this review, we will review the clinical biomarkers in the prodromal stage and biomarkers using biological tissue in Parkinson’s disease.
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Török, Nóra, Masaru Tanaka, and László Vécsei. "Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway." International Journal of Molecular Sciences 21, no. 24 (December 8, 2020): 9338. http://dx.doi.org/10.3390/ijms21249338.
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Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to the abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes, which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of KP alterations observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota in the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases.
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Reddy, Doodipala Samba, and Hasara Nethma Abeygunaratne. "Experimental and Clinical Biomarkers for Progressive Evaluation of Neuropathology and Therapeutic Interventions for Acute and Chronic Neurological Disorders." International Journal of Molecular Sciences 23, no. 19 (October 3, 2022): 11734. http://dx.doi.org/10.3390/ijms231911734.
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This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.
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Marino, Bianca L. B., Lucilene R. de Souza, Kessia P. A. Sousa, Jaderson V. Ferreira, Elias C. Padilha, Carlos H. T. P. da Silva, Carlton A. Taft, and Lorane I. S. Hage-Melim. "Parkinson’s Disease: A Review from Pathophysiology to Treatment." Mini-Reviews in Medicinal Chemistry 20, no. 9 (May 27, 2020): 754–67. http://dx.doi.org/10.2174/1389557519666191104110908.
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: Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.
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Pawlik, Patrycja, and Katarzyna Błochowiak. "The Role of Salivary Biomarkers in the Early Diagnosis of Alzheimer’s Disease and Parkinson’s Disease." Diagnostics 11, no. 2 (February 22, 2021): 371. http://dx.doi.org/10.3390/diagnostics11020371.
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Many neurodegenerative diseases present with progressive neuronal degeneration, which can lead to cognitive and motor impairment. Early screening and diagnosis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are necessary to begin treatment before the onset of clinical symptoms and slow down the progression of the disease. Biomarkers have shown great potential as a diagnostic tool in the early diagnosis of many diseases, including AD and PD. However, screening for these biomarkers usually includes invasive, complex and expensive methods such as cerebrospinal fluid (CSF) sampling through a lumbar puncture. Researchers are continuously seeking to find a simpler and more reliable diagnostic tool that would be less invasive than CSF sampling. Saliva has been studied as a potential biological fluid that could be used in the diagnosis and early screening of neurodegenerative diseases. This review aims to provide an insight into the current literature concerning salivary biomarkers used in the diagnosis of AD and PD. The most commonly studied salivary biomarkers in AD are β-amyloid1-42/1-40 and TAU protein, as well as α-synuclein and protein deglycase (DJ-1) in PD. Studies continue to be conducted on this subject and researchers are attempting to find correlations between specific biomarkers and early clinical symptoms, which could be key in creating new treatments for patients before the onset of symptoms.
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Lesman-Segev, Orit H., Lauren Edwards, and Gil D. Rabinovici. "Chronic Traumatic Encephalopathy: A Comparison with Alzheimer's Disease and Frontotemporal Dementia." Seminars in Neurology 40, no. 04 (August 2020): 394–410. http://dx.doi.org/10.1055/s-0040-1715134.
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AbstractThe clinical diagnosis of chronic traumatic encephalopathy (CTE) is challenging due to heterogeneous clinical presentations and overlap with other neurodegenerative dementias. Depending on the clinical presentation, the differential diagnosis of CTE includes Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), Parkinson's disease, amyotrophic lateral sclerosis, primary mood disorders, posttraumatic stress disorder, and psychotic disorders. The aim of this article is to compare the clinical aspects, genetics, fluid biomarkers, imaging, treatment, and pathology of CTE to those of AD and bvFTD. A detailed clinical evaluation, neurocognitive assessment, and structural brain imaging can inform the differential diagnosis, while molecular biomarkers can help exclude underlying AD pathology. Prospective studies that include clinicopathological correlations are needed to establish tools that can more accurately determine the cause of neuropsychiatric decline in patients at risk for CTE.
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Lemieszewska, Marta, Agnieszka Zabłocka, and Joanna Rymaszewska. "Parkinson’s disease: Etiopathogenesis, molecular basis and potential treatment opportunities." Postępy Higieny i Medycyny Doświadczalnej 73 (May 15, 2019): 256–68. http://dx.doi.org/10.5604/01.3001.0013.2021.
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Neurodegenerative diseases affect the life quality and lifespan of aging populations. Among all forms of neurodegenerative diseases, Parkinson’s disease (PD) has a massive impact on the elderly. Oxidative stress and mitochondrial dysfunction are the main causes of neurodegeneration and progression of PD. Oxidative stress, which plays a vital role in the pathophysiology of PD, is related to the dysfunction of cellular antioxidant mechanisms as a result of enhanced production of reactive oxygen species. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of neurodegeneration and medications are available, but these only treat the symptoms. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases, using suitable animal models. The review focuses on the role of oxidative stress in the pathogenesis of Parkinson’s disease and the protective potential of natural products against neurodegeneration.
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Rees, Richard Nathaniel, Anita Prema Acharya, Anette Schrag, and Alastair John Noyce. "An early diagnosis is not the same as a timely diagnosis of Parkinson's disease." F1000Research 7 (July 18, 2018): 1106. http://dx.doi.org/10.12688/f1000research.14528.1.
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Parkinson’s disease is a common neurodegenerative condition that has significant costs to the individual patient and to society. The pathology starts up to a decade before symptoms are severe enough to allow a diagnosis using current criteria. Although the search for disease-modifying treatment continues, it is vital to understand what the right time is for diagnosis. Diagnosis of Parkinson’s disease is based on the classic clinical criteria, but the presence of other clinical features and disease biomarkers may allow earlier diagnosis, at least in a research setting. In this review, we identify the benefits of an early diagnosis, including before the classic clinical features occur. However, picking the right point for a “timely” diagnosis will vary depending on the preferences of the individual patient, efficacy (or existence) of disease-modifying treatment, and the ability for health systems to provide support and management for individuals at every stage of the disease. Good evidence for the quality-of-life benefits of existing symptomatic treatment supports the argument for earlier diagnosis at a time when symptoms are already present. This argument would be significantly bolstered by the development of disease-modifying treatments. Benefits of early diagnosis and treatment would affect not only the individual (and their families) but also the wider society and the research community. Ultimately, however, shared decision-making and the principles of autonomy, beneficence, and non-maleficence will need to be applied on an individual basis when considering a “timely” diagnosis.
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Taymans, Jean-Marc, Eugénie Mutez, Matthieu Drouyer, William Sibran, and Marie-Christine Chartier-Harlin. "LRRK2 detection in human biofluids: potential use as a Parkinson's disease biomarker?" Biochemical Society Transactions 45, no. 1 (February 8, 2017): 207–12. http://dx.doi.org/10.1042/bst20160334.
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Leucine-rich repeat kinase 2 (LRRK2) is a complex signalling protein that is a key therapeutic target, particularly in Parkinson's disease (PD). In addition, there is now evidence showing that LRRK2 expression and phosphorylation levels have potential as markers of disease or target engagement. Indeed, reports show increases in LRRK2 protein levels in the prefrontal cortex of PD patients relative to controls, suggesting that increase in total LRRK2 protein expression is correlated with disease progression. LRRK2 phosphorylation levels are reduced in experimental systems for most disease mutants, and LRRK2 is also rapidly dephosphorylated upon LRRK2 inhibitor treatment, considered potential therapeutics. Recently, the presence of LRRK2 was confirmed in exosomes from human biofluids, including urine and cerebrospinal fluid. Moreover, phosphorylation of LRRK2 at phosphosites S910, S935, S955 and S973, as well as at the autophosphoryation site S1292, was found in urinary exosomes. In this review, we summarize knowledge on detection of LRRK2 in human biofluids and the relevance of these findings for the development of PD-related biomarkers.
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Jankovic, Joseph, and Eng King Tan. "Parkinson’s disease: etiopathogenesis and treatment." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 8 (June 23, 2020): 795–808. http://dx.doi.org/10.1136/jnnp-2019-322338.
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The concept of ‘idiopathic’ Parkinson’s disease (PD) as a single entity has been challenged with the identification of several clinical subtypes, pathogenic genes and putative causative environmental agents. In addition to classic motor symptoms, non-motor manifestations (such as rapid eye movement sleep disorder, anosmia, constipation and depression) appear at prodromic/premotor stage and evolve, along with cognitive impairment and dysautonomia, as the disease progresses, often dominating the advanced stages of the disease. The key molecular pathogenic mechanisms include α-synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (associated with deficient ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. The involvement of dopaminergic as well as noradrenergic, glutamatergic, serotonergic and adenosine pathways provide insights into the rich and variable clinical phenomenology associated with PD and the possibility of alternative therapeutic approaches beyond traditional dopamine replacement therapies.One of the biggest challenges in the development of potential neuroprotective therapies has been the lack of reliable and sensitive biomarkers of progression. Immunotherapies such as the use of vaccination or monoclonal antibodies directed against aggregated, toxic α-synuclein.as well as anti-aggregation or protein clearance strategies are currently investigated in clinical trials. The application of glucagon-like peptide one receptor agonists, specific PD gene target agents (such as GBA or LRRK2 modifiers) and other potential disease modifying drugs provide cautious optimism that more effective therapies are on the horizon. Emerging therapies, such as new symptomatic drugs, innovative drug delivery systems and novel surgical interventions give hope to patients with PD about their future outcomes and prognosis.
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Milán-Tomás, Ángela, Marta Fernández-Matarrubia, and María Cruz Rodríguez-Oroz. "Lewy Body Dementias: A Coin with Two Sides?" Behavioral Sciences 11, no. 7 (June 22, 2021): 94. http://dx.doi.org/10.3390/bs11070094.
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Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on α-synuclein markers.
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Satue, Maria, Javier Obis, Maria J. Rodrigo, Sofia Otin, Maria I. Fuertes, Elisa Vilades, Hector Gracia, et al. "Optical Coherence Tomography as a Biomarker for Diagnosis, Progression, and Prognosis of Neurodegenerative Diseases." Journal of Ophthalmology 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/8503859.
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Neurodegenerative diseases present a current challenge for accurate diagnosis and for providing precise prognostic information. Developing imaging biomarkers for multiple sclerosis (MS), Parkinson disease (PD), and Alzheimer’s disease (AD) will improve the clinical management of these patients and may be useful for monitoring treatment effectiveness. Recent research using optical coherence tomography (OCT) has demonstrated that parameters provided by this technology may be used as potential biomarkers for MS, PD, and AD. Retinal thinning has been observed in these patients and new segmentation software for the analysis of the different retinal layers may provide accurate information on disease progression and prognosis. In this review we analyze the application of retinal evaluation using OCT technology to provide better understanding of the possible role of the retinal layers thickness as biomarker for the detection of these neurodegenerative pathologies. Current OCT analysis of the retinal nerve fiber layer and, specially, the ganglion cell layer thickness may be considered as a good biomarker for disease diagnosis, severity, and progression.
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von Euler Chelpin, Marianne, Linda Söderberg, Johanna Fälting, Christer Möller, Marco Giorgetti, Radu Constantinescu, Kaj Blennow, Henrik Zetterberg, and Kina Höglund. "Alpha-Synuclein Protofibrils in Cerebrospinal Fluid: A Potential Biomarker for Parkinson's Disease." Journal of Parkinson's Disease 10, no. 4 (October 27, 2020): 1429–42. http://dx.doi.org/10.3233/jpd-202141.
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Background: Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective: To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α-synuclein protofibrils (α-syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods: A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer’s disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ42)>530 pg/mL, and phosphorylated tau (p-tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α-synuclein (α-syn) levels were analyzed with a commercial ELISA-kit. Results: The assay is specific to α-syn PF, with no cross-reactivity to monomeric α-syn, or the β- and γ-synuclein variants. CSF α-syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p = 0.02). The accuracy of predicting PD using α-syn PF is significantly different from controls (area under the curve 0.68, p = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α-syn were significantly different between the PD and CBD groups (p = 0.04). Conclusion: The developed method specifically quantifies α-syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls.
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Ghanta, Mohan K., P. Elango, and Bhaskar L. V. K. S. "Current Therapeutic Strategies and Perspectives for Neuroprotection in Parkinson’s Disease." Current Pharmaceutical Design 26, no. 37 (October 26, 2020): 4738–46. http://dx.doi.org/10.2174/1381612826666200217114658.
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Parkinson’s disease is a progressive neurodegenerative disorder of dopaminergic striatal neurons in basal ganglia. Treatment of Parkinson’s disease (PD) through dopamine replacement strategies may provide improvement in early stages and this treatment response is related to dopaminergic neuronal mass which decreases in advanced stages. This treatment failure was revealed by many studies and levodopa treatment became ineffective or toxic in chronic stages of PD. Early diagnosis and neuroprotective agents may be a suitable approach for the treatment of PD. The essentials required for early diagnosis are biomarkers. Characterising the striatal neurons, understanding the status of dopaminergic pathways in different PD stages may reveal the effects of the drugs used in the treatment. This review updates on characterisation of striatal neurons, electrophysiology of dopaminergic pathways in PD, biomarkers of PD, approaches for success of neuroprotective agents in clinical trials. The literature was collected from the articles in database of PubMed, MedLine and other available literature resources.
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Doroszkiewicz, Julia, Magdalena Groblewska, and Barbara Mroczko. "Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases." International Journal of Molecular Sciences 23, no. 9 (April 21, 2022): 4610. http://dx.doi.org/10.3390/ijms23094610.
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The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs—i.e., Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)—as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy.
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Waleed, Madeeha. "Parkinsonism and D-512, dopamine D2/3 receptor agonist; A review of literature." International Journal of Clinical Case Reports and Reviews 4, no. 1 (October 24, 2020): 01–03. http://dx.doi.org/10.31579/2690-4861/077.
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In 1817, James Parkinson first coined the term Paralysis Agitans (An Essay on the Shaking Palsy), Jean-Marie Charcot was the first to coin term Parkinson’s disease (PD). Three most common and obvious symptoms in patients with PD are tremor, rigidity, and bradykinesia. A multidisciplinary team involving neurologists, primary care practitioners, nurses, physical therapists, social workers is used to diagnose PD. Nonpharmacological and pharmacological treatment is given to the patient. However, this disease demands more clinical translational and prognostic research, identifying biomarkers that can help in early diagnosis of the disease and on developing future disease-modifying interventions.
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Singh, Sarita, Sunil Kumar Gupta, and Prahlad Kishore Seth. "Biomarkers for detection, prognosis and therapeutic assessment of neurological disorders." Reviews in the Neurosciences 29, no. 7 (September 25, 2018): 771–89. http://dx.doi.org/10.1515/revneuro-2017-0097.
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Abstract Neurological disorders have aroused a significant concern among the health scientists globally, as diseases such as Parkinson’s, Alzheimer’s and dementia lead to disability and people have to live with them throughout the life. Recent evidence suggests that a number of environmental chemicals such as pesticides (paraquat) and metals (lead and aluminum) are also the cause of these diseases and other neurological disorders. Biomarkers can help in detecting the disorder at the preclinical stage, progression of the disease and key metabolomic alterations permitting identification of potential targets for intervention. A number of biomarkers have been proposed for some neurological disorders based on laboratory and clinical studies. In silico approaches have also been used by some investigators. Yet the ideal biomarker, which can help in early detection and follow-up on treatment and identifying the susceptible populations, is not available. An attempt has therefore been made to review the recent advancements of in silico approaches for discovery of biomarkers and their validation. In silico techniques implemented with multi-omics approaches have potential to provide a fast and accurate approach to identify novel biomarkers.
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Schäffer, Eva, and Daniela Berg. "Redefinition of Parkinson’s Disease." Neurology International Open 1, no. 02 (April 2017): E65—E70. http://dx.doi.org/10.1055/s-0043-102916.
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AbstractIn 2015, a working group of the International Parkinsonʼs and Movement Disorders Society (MDS) presented new clinical diagnostic criteria for Parkinsonʼs disease (PD). This review outlines the key insights with regard to pathophysiology, various clinical manifestations and clinical progression which form the basis for a redefinition and the new, summarized clinical diagnostic criteria of Parkinson’s disease. Essential findings, which led to the new diagnostic criteria, include (i) the recognition of the importance of non-motor symptoms, which may have a tremendous influence on the quality of life of patients and have an increasing relevance with regard to early and differential diagnosis of PD is stated. (ii) The categorization of dementia in the course of Parkinson’s disease. While there has been a clear separation between Parkinson’s disease and dementia with Lewy bodies so far, now a continuum is postulated which summarizes Parkinson’s disease without, with late and with early (within the first year after the occurrence of motor symptoms) dementia under the umbrella term of Lewy Body Diseases (LBD). (iii) The realization of a slowly spreading process of neurodegeneration occurring throughout different parts of the nervous system. This resulted in the definition of different phases of the disease, the preclinical, prodromal and clinical phase. In particular, the definition of the prodromal phase, characterized by different clinical parameters and further biomarkers still to be implemented, opens up new possibilities for early diagnosis and in the long run early treatment of Parkinson’s disease. (iv) The insight that the clinical phase is characterized by different forms of disease progression. For genetic variants (e. g., GBA or LRRK2) a separate clinical-genetic category is proposed, in idiopathic Parkinson’s disease subtypes should be characterized by clearly distinct prognosis, progression and/or treatment strategies. The MDS Task Force proposes to keep the current gold standard of typical clinical motor symptom presentation and post-mortem verification of α-synucleinopathy for the diagnosis of PD. The new clinical diagnostic criteria were designed using a typical clinical expert as benchmark, codifying the expert diagnostic process to make it reproducible and easily applicable. The new diagnostic criteria now contain absolute exclusion criteria, supportive criteria and “red flags” in addition to the assessment of the cardinal motor symptoms. Specific ancillary diagnostic tests (e. g., imaging techniques) can be implemented; furthermore the time course and severity of symptoms are taken into account.
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Calvo, Ana C., Raquel Manzano, Deise M. F. Mendonça, María J. Muñoz, Pilar Zaragoza, and Rosario Osta. "Amyotrophic Lateral Sclerosis: A Focus on Disease Progression." BioMed Research International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/925101.
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Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives.
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Liu, Tsai-Wei, Chiung-Mei Chen, and Kuo-Hsuan Chang. "Biomarker of Neuroinflammation in Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 8 (April 8, 2022): 4148. http://dx.doi.org/10.3390/ijms23084148.
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Parkinson’s disease (PD) is caused by abnormal accumulation of α-synuclein in dopaminergic neurons of the substantia nigra, which subsequently causes motor symptoms. Neuroinflammation plays a vital role in the pathogenesis of neurodegeneration in PD. This neuroinflammatory neurodegeneration involves the activation of microglia, upregulation of proinflammatory factors, and gut microbiota. In this review, we summarized the recent findings on detection of PD by using inflammatory biomarkers, such as interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor (TNF)-α; regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and high-sensitivity c-reactive protein (hsCRP); and radiotracers such as [11C]PK11195 and [18F]-FEPPA, as well as by monitoring disease progression and the treatment response. Many PD-causing mutations in SNCA, LRRK2, PRKN, PINK1, and DJ-1 are also associated with neuroinflammation. Several anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAID), inhibitors of TNF-α and NLR family pyrin domain containing 3 (NLRP3), agonists of nuclear factor erythroid 2-related factor 2 (NRF2), peroxisome proliferator-activated receptor gamma (PPAR-γ), and steroids, have demonstrated neuroprotective effects in in vivo or in vitro PD models. Clinical trials applying objective biomarkers are required to investigate the therapeutic potential of anti-inflammatory medications for PD.
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Price, J. Blair, Aaron E. Rusheen, Abhijeet S. Barath, Juan M. Rojas Cabrera, Hojin Shin, Su-Youne Chang, Christopher J. Kimble, et al. "Clinical applications of neurochemical and electrophysiological measurements for closed-loop neurostimulation." Neurosurgical Focus 49, no. 1 (July 2020): E6. http://dx.doi.org/10.3171/2020.4.focus20167.
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The development of closed-loop deep brain stimulation (DBS) systems represents a significant opportunity for innovation in the clinical application of neurostimulation therapies. Despite the highly dynamic nature of neurological diseases, open-loop DBS applications are incapable of modifying parameters in real time to react to fluctuations in disease states. Thus, current practice for the designation of stimulation parameters, such as duration, amplitude, and pulse frequency, is an algorithmic process. Ideal stimulation parameters are highly individualized and must reflect both the specific disease presentation and the unique pathophysiology presented by the individual. Stimulation parameters currently require a lengthy trial-and-error process to achieve the maximal therapeutic effect and can only be modified during clinical visits. The major impediment to the development of automated, adaptive closed-loop systems involves the selection of highly specific disease-related biomarkers to provide feedback for the stimulation platform. This review explores the disease relevance of neurochemical and electrophysiological biomarkers for the development of closed-loop neurostimulation technologies. Electrophysiological biomarkers, such as local field potentials, have been used to monitor disease states. Real-time measurement of neurochemical substances may be similarly useful for disease characterization. Thus, the introduction of measurable neurochemical analytes has significantly expanded biomarker options for feedback-sensitive neuromodulation systems. The potential use of biomarker monitoring to advance neurostimulation approaches for treatment of Parkinson’s disease, essential tremor, epilepsy, Tourette syndrome, obsessive-compulsive disorder, chronic pain, and depression is examined. Further, challenges and advances in the development of closed-loop neurostimulation technology are reviewed, as well as opportunities for next-generation closed-loop platforms.
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Bencze, János, Viktória Simon, Erika Bereczki, Réka Majer, Gréta Varkoly, Balázs Murnyák, János Kálmán, and Tibor Hortobágyi. "A Lewy-testes demencia klinikai és neuropatológiai jellemzői." Orvosi Hetilap 158, no. 17 (April 2017): 643–52. http://dx.doi.org/10.1556/650.2017.30735.
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Abstract: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. The accurate diagnosis is often possible only by neuropathological examination. The morphologic hallmarks are the presence of α-synuclein-rich Lewy bodies and Lewy neurites, identical to those seen in Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD). Neurotransmitter deficits, synaptic and ubiquitin-proteasome system (UPS) dysfunction play major role in the pathomechanism. Characteristic symptoms are cognitive fluctuation, parkinsonism and visual hallucinations. Due to the often atypical clinical presentation novel imaging techniques and biomarkers could help the early diagnosis. Although curative treatment is not available, therapies can improve quality of life. Clinicopathological studies are important in exploring pathomechanisms, ensuring accurate diagnosis and identifying therapeutic targets. Orv Hetil. 2017; 158(17): 643–652.
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Fricova, Dominika, Jana Harsanyiova, and Alzbeta Kralova Trancikova. "Alpha-Synuclein in the Gastrointestinal Tract as a Potential Biomarker for Early Detection of Parkinson’s Disease." International Journal of Molecular Sciences 21, no. 22 (November 17, 2020): 8666. http://dx.doi.org/10.3390/ijms21228666.
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The primary pathogenesis associated with Parkinson’s disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general.
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Fernández, Belén, Antonio Jesús Lara Ordóñez, Elena Fdez, Eugénie Mutez, Thomas Comptdaer, Coline Leghay, Alexandre Kreisler, et al. "Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients." Biochemical Journal 476, no. 19 (October 11, 2019): 2797–813. http://dx.doi.org/10.1042/bcj20190315.
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Abstract Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cell-derived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients.
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Sciancalepore, Francesco, Giulia Remoli, Leonardo Tariciotti, Giulia Sarti, Federica Trentin, Gabriele Riccardi, Eleonora Lacorte, et al. "A Systematic Review of the Biological Processes Involved in Deep-Brain Stimulation for Parkinson's disease: A Focus on the Potential Disease-Modifying Effects." OBM Neurobiology 05, no. 02 (February 5, 2021): 1. http://dx.doi.org/10.21926/obm.neurobiol.2102097.
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Deep-Brain Stimulation (DBS) is an important treatment option for the management of Parkinson’s disease (PD) and is a common symptomatic treatment. However, an increasing number of studies have examined the biological processes to assess if DBS can also modify the natural history of PD by acting on its pathophysiological mechanisms. Relevant literature published up to November 2020 was systematically searched on databases such as PubMed, ISI Web of Knowledge, Academic Search Index, and Science Citation Index. The following predefined inclusion criteria were applied to the full-text versions of the selected articles: i) recruiting and monitoring of PD subjects that were previously treated with DBS and ii) investigating the electrophysiological, biochemical, epigenetic, or neuroimaging effects of DBS. Studies focusing exclusively on motor and clinical changes were excluded. Reviews, case reports, studies on animal models, and computational studies were also not considered. Out of 2,960 records screened, 43 studies met the inclusion criteria. Only three studies described a potential disease-modifying effect of DBS. However, a wide heterogeneity was observed in the investigated biomarkers, and the design and methodological issues of several studies limited their ability to find potential disease-modifying features. Specifically, 60.4% of the trials followed-up subjects for no more than 1 year from the surgical intervention, and 67.4% observed patients with PD only once after DBS. Moreover, 64.2% of the studies enrolled late-stage PD patients. Most of the studies (88.4%) reported that DBS only had a symptomatic effect, with several of them showing some limitations in the study design and recruitment of patients. Further studies using shared biomarkers are encouraged to assess if and how DBS might affect the progression of PD. Based on the existing preclinical literature, prospective clinical trials examining the course of PD in early-stage patients are needed.
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Stephenson, Diane, Reham Badawy, Soania Mathur, Maria Tome, and Lynn Rochester. "Digital Progression Biomarkers as Novel Endpoints in Clinical Trials: A Multistakeholder Perspective." Journal of Parkinson's Disease 11, s1 (July 16, 2021): S103—S109. http://dx.doi.org/10.3233/jpd-202428.
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The burden of Parkinson’s disease (PD) continues to grow at an unsustainable pace particularly given that it now represents the fastest growing brain disease. Despite seminal discoveries in genetics and pathogenesis, people living with PD oftentimes wait years to obtain an accurate diagnosis and have no way to know their own prognostic fate once they do learn they have the disease. Currently, there is no objective biomarker to measure the onset, progression, and severity of PD along the disease continuum. Without such tools, the effectiveness of any given treatment, experimental or conventional cannot be measured. Such tools are urgently needed now more than ever given the rich number of new candidate therapies in the pipeline. Over the last decade, millions of dollars have been directed to identify biomarkers to inform progression of PD typically using molecular, fluid or imaging modalities. These efforts have produced novel insights in our understanding of PD including mechanistic targets, disease subtypes and imaging biomarkers. While we have learned a lot along the way, implementation of robust disease progression biomarkers as tools for quantifying changes in disease status or severity remains elusive. Biomarkers have improved health outcomes and led to accelerated drug approvals in key areas of unmet need such as oncology. Quantitative biomarker measures such as HbA1c a standard test for the monitoring of diabetes has impacted patient care and management, both for the healthcare professionals and the patient community. Such advances accelerate opportunities for early intervention including prevention of disease in high-risk individuals. In PD, progression markers are needed at all stages of the disease in order to catalyze drug development—this allows interventions aimed to halt or slow disease progression (very early) but also facilitates symptomatic treatments at moderate stages of the disease. Recently, attention has turned to the role of digital health technologies to complement the traditional modalities as they are relatively low cost, objective and scalable. Success in this endeavor would be transformative for clinical research and therapeutic development. Consequently, significant investment has led to a number of collaborative efforts to identify and validate suitable digital biomarkers of disease progression.
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Santos García, Diego, Marta Blázquez-Estrada, Matilde Calopa, Francisco Escamilla-Sevilla, Eric Freire, Pedro J. García Ruiz, Francisco Grandas, et al. "Present and Future of Parkinson’s Disease in Spain: PARKINSON-2030 Delphi Project." Brain Sciences 11, no. 8 (July 31, 2021): 1027. http://dx.doi.org/10.3390/brainsci11081027.
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Parkinson’s disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000–150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients’ and caregivers’ lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.
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Park, Sangmin, Aeyung Kim, Gunhyuk Park, Ojin Kwon, Sangsoo Park, Horyong Yoo, and Junghee Jang. "Investigation of Therapeutic Response Markers for Acupuncture in Parkinson’s Disease: An Exploratory Pilot Study." Diagnostics 11, no. 9 (September 17, 2021): 1697. http://dx.doi.org/10.3390/diagnostics11091697.
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In this preliminary pilot study, we investigated the specific genes implicated in the therapeutic response to acupuncture in patients with Parkinson’s disease (PD). Transcriptome alterations following acupuncture in blood samples collected during our previous clinical trial were analyzed along with the clinical data of six patients with PD, of which a representative patient was selected for transcriptomic analysis following acupuncture. We also examined the changes in the expression of PD biomarker genes known to be dysregulated in both the brain and blood of patients with PD. We validated these gene expression changes using quantitative real-time polymerase chain reaction (qPCR) in the blood of the remaining five patients with PD who received acupuncture treatment. Following acupuncture treatment, the transcriptomic alterations in the representative patient were similar to those induced by dopaminergic therapy. Among the PD biomarkers, ankyrin repeat domain 22 (ANKRD22), upregulated following dopaminergic therapy, and synapsin 1 (SYN1), a common gene marker for synaptic dysfunction in PD, were upregulated following acupuncture. These alterations correlated with changes in gait parameters in patients with PD. Our data suggest ANKRD22 and SYN1 as potential biomarkers to predict/monitor therapeutic responses to acupuncture in patients with PD, especially in those with gait disturbance. Further research is needed to confirm these findings in a large sample of patients with PD.
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Olson, Katherine E., Krista L. Namminga, Yaman Lu, Aaron D. Schwab, Mackenzie J. Thurston, Mai M. Abdelmoaty, Vikas Kumar, et al. "Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson's disease." EBioMedicine 67 (May 2021): 103380. http://dx.doi.org/10.1016/j.ebiom.2021.103380.
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Rojas Cabrera, Juan M., J. Blair Price, Aaron E. Rusheen, Abhinav Goyal, Danielle Jondal, Abhijeet S. Barath, Hojin Shin, et al. "Advances in neurochemical measurements: A review of biomarkers and devices for the development of closed-loop deep brain stimulation systems." Reviews in Analytical Chemistry 39, no. 1 (January 1, 2020): 188–99. http://dx.doi.org/10.1515/revac-2020-0117.
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Abstract Neurochemical recording techniques have expanded our understanding of the pathophysiology of neurological disorders, as well as the mechanisms of action of treatment modalities like deep brain stimulation (DBS). DBS is used to treat diseases such as Parkinson’s disease, Tourette syndrome, and obsessive-compulsive disorder, among others. Although DBS is effective at alleviating symptoms related to these diseases and improving the quality of life of these patients, the mechanism of action of DBS is currently not fully understood. A leading hypothesis is that DBS modulates the electrical field potential by modifying neuronal firing frequencies to non-pathological rates thus providing therapeutic relief. To address this gap in knowledge, recent advances in electrochemical sensing techniques have given insight into the importance of neurotransmitters, such as dopamine, serotonin, glutamate, and adenosine, in disease pathophysiology. These studies have also highlighted their potential use in tandem with electrophysiology to serve as biomarkers in disease diagnosis and progression monitoring, as well as characterize response to treatment. Here, we provide an overview of disease-relevant neurotransmitters and their roles and implications as biomarkers, as well as innovations to the biosensors used to record these biomarkers. Furthermore, we discuss currently available neurochemical and electrophysiological recording devices, and discuss their viability to be implemented into the development of a closed-loop DBS system.
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Sreeja C Nair, Sujaid Thayyilakandy, Arjun KK, Gayathri Krishnakumar, and Gayathri PS. "A futuristic perspective in subsiding the symptoms of Parkinson’s Disease." International Journal of Research in Pharmaceutical Sciences 10, no. 2 (April 14, 2019): 975–89. http://dx.doi.org/10.26452/ijrps.v10i2.369.
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Parkinson's disease (PD) is a neurodegenerative disorder that primarily impinges the dopaminergic neurons in a particular region of Brain termed as Substantia Nigra. The disease affects more than 1900 people per 100,000 aged 80 years and above. Furthermore, men are 1.5 times more prone than their counterpart. Potential biomarkers escalated the precise diagnosis and helped to initiate treatment to limit its adversity. The current therapeutic schemes are focused on administration of Dopamine precursor, Dopamine agonist, Monoamine oxidase (MAO) inhibitor, Catechol-o-methyl transferase (COMT) inhibitors and deep brain stimulation. The CNS delivery focuses mainly on increasing the dopamine level in the brain. CNS drug delivery faces a crucial challenge of crossing Blood Brain Barrier. Blood-Brain Barrier Penetration can be attained by several techniques. Conventional drug therapy yields harmful affects to the patients without much therapeutics. It is visible that crossing BBB is quite strenuous process. It is mandatory for developing a novel approach untangling these situations. Nanotechnology-based formulations like nanosuspensions, nanotubes etc. promotes the penetration of drug across the sophisticated barrier without creating any deterioration to cells or organs. Several novel routes for drug administration reduce dose intake with increased and precise pharmacological action. Nanoformulations and Novel routes of drug administration are a promising tool to enhance the action of drug which helps to abate the symptoms of the Disease and assist in the betterment in treatment.
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Hölscher, Christian. "Insulin, incretins and other growth factors as potential novel treatments for Alzheimer's and Parkinson's diseases." Biochemical Society Transactions 42, no. 2 (March 20, 2014): 593–99. http://dx.doi.org/10.1042/bst20140016.
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Recently, it has been shown that in patients with AD (Alzheimer's disease) and, to some degree, in patients with PD (Parkinson's disease) insulin signalling is impaired. This finding has initiated a range of research projects that showed remarkable improvements using treatments that initially had been developed to treat diabetes. Pre-clinical studies showed good neuroprotective effects when applying insulin or long-lasting analogues of incretin peptides. In transgenic animal models of AD and PD, analogues of the incretin GLP-1 (glucagon-like peptide 1) prevented neurodegenerative processes and improved neuronal and synaptic functionality in AD and PD. Amyloid plaque load and synaptic loss as well as cognitive impairment had been ameliorated in AD models, and dopaminergic loss of transmission and motor function was reversed in models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results being published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for Type 2 diabetes also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients. The present review summarizes the range of neuroprotective effects that these drugs have demonstrated and emphasizes the great promise that this approach has in providing novel treatments that have protective and even restorative properties that no current drug treatment can offer.
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Broich, Karl. "Outcome measures in clinical trials on medicinal products for the treatment of dementia: a European regulatory perspective." International Psychogeriatrics 19, no. 3 (April 16, 2007): 509–24. http://dx.doi.org/10.1017/s1041610207005273.
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Based on efficacy and safety data, several drugs have been approved for symptomatic improvement of dementia of the Alzheimer type and one for the symptomatic improvement of dementia associated with Parkinson's disease. However, established treatment effects must be considered as modest. Randomized clinical trials in other subtypes of dementia (e.g. vascular dementia) have not been able to demonstrate clinically relevant symptomatic improvement, nor has it yet been possible to establish disease-modifying effects in any dementia syndrome or its subtypes. Recent progress in basic science and molecular biology of the dementias has now fostered new interest for more efficacious symptomatic treatments as well as for disease-modifying approaches in the degenerative dementias.For regulatory purposes this requires better standardization and refinement of diagnostic criteria, which allow the study of homogeneous disease populations in specialized academic centers as well as in the general community setting. Depending on the disease stages (early versus late, mild to moderate to severe impairment) and disease entities, distinct assessment tools for cognitive, functional and global endpoints should be used or newly developed. The typical design to show symptomatic improvement is a randomized, double-blind, placebo-controlled, parallel group study comparing change in two primary endpoints, one of them reflecting the cognitive domain and the second preferably reflecting the functional domain of impairment. The changes must be robust and clinically meaningful in favor of active treatment versus placebo.If a treatment claim for prevention of the emergence, slowing or stabilizing deterioration is strived for, it has to be shown that the treatment has an impact on the underlying neurobiology and pathophysiology of the process of dementia. Establishing such an effect in a highly variable progressing syndrome is complex and difficult; however, a variety of trial designs has been provided, including baseline designs, survival designs, randomized start or randomized withdrawal designs, with or without incorporation of biomarkers as surrogate endpoints (e.g. magnetic resonance tomography, emission tomography, cerebrospinal fluid markers). To be accepted as a surrogate endpoint such a biomarker ideally should respond to treatment, predict clinical response and be compellingly related to the pathophysiological process of the dementia. However, careful and sufficient validation of proposed biomarkers as a potential surrogate endpoint is a prerequisite for acceptance by regulatory bodies.This review outlines the regulatory requirements for approval of a new medicinal product for symptomatic improvement or disease-modifying effects in patients with dementia, with special emphasis on the importance of validation of the assessment tools and potential surrogate endpoints based on recent experience and discussion regarding anti-dementia drugs in the European framework.
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Goldstein, David S. "Biomarkers, Mechanisms, and Treatment of Autonomic Failure in Parkinson Disease and Related Disorders." Autonomic Neuroscience 163, no. 1-2 (September 2011): 38. http://dx.doi.org/10.1016/j.autneu.2011.05.014.
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HAMZEHLOEI, Leila, Mohammad Ebrahim REZVANI, and Ziba RAJAEI. "Effects of carvacrol and physical exercise on motor and memory impairments associated with Parkinson’s disease." Arquivos de Neuro-Psiquiatria 77, no. 7 (July 2019): 493–500. http://dx.doi.org/10.1590/0004-282x20190079.
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ABSTRACT The present study was undertaken to investigate the effects of carvacrol and treadmill exercise on memory deficit, rotational behavior and oxidative stress biomarkers in a 6-OHDA-lesioned rat model of Parkinson’s disease. Wistar rats were treated with carvacrol at a dose of 25 mg/kg and/or ran on a treadmill for a week. Then, 6-OHDA was microinjected into the medial forebrain bundle and treatments continued for six more weeks. Aversive memory, rotational behavior and oxidative stress biomarkers were assessed at the end of week six. The 6-OHDA-lesioned group showed a significant increase in rotational behavior and a decrease in step-through latency in the passive avoidance test compared with the sham group. These behaviors were accompanied by increased lipid peroxidation levels and decreased total thiol concentration in the striatum and/or hippocampus of the hemiparkinsonian rats. Moreover, treatment with carvacrol and exercise reduced rotational behavior and improved aversive memory deficit, which was accompanied by decreased lipid peroxidation levels and increased total thiol concentration in the striatum and/or hippocampus. In conclusion, treatment with carvacrol and treadmill exercise ameliorated motor and memory deficits by modulating oxidative stress in the striatum and hippocampus of hemiparkinsonian rats. Therefore, the combination of carvacrol and treadmill exercise could be an effective therapeutic tool for treatment of neurobehavioral deficits in Parkinson’s disease patients.
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Hosaka, Takashi, Takenari Yamashita, Akira Tamaoka, and Shin Kwak. "Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases." International Journal of Molecular Sciences 20, no. 13 (June 27, 2019): 3148. http://dx.doi.org/10.3390/ijms20133148.
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Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including β-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell–cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS.
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Cabreira, Verónica, and João Massano. "Doença de Parkinson: Revisão Clínica e Atualização." Acta Médica Portuguesa 32, no. 10 (October 1, 2019): 661. http://dx.doi.org/10.20344/amp.11978.
Full textAbstract:
Parkinson’s disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented. Environmental and genetic factors contribute to the pathophysiology of this disease, and 5% – 10% of cases have a monogenic cause. The diagnosis relies on clinical findings, supported by adequate testing. There is no absolute method to diagnose Parkinson’s disease in vivo, except for genetic testing in specific circumstances, whose usefulness is limited to a minority of cases. New diagnostic criteria have been recently proposed with the aim of improving diagnostic accuracy, emphasizing findings that might point to other causes of parkinsonism. The available therapeutic options are clinically useful, as they improve the symptoms as well as the quality of life of patients. After the introduction of levodopa, deep brain stimulation emerged as the second therapy with an important symptomatic impact in the treatment of Parkinson’s disease. Non-motor symptoms and motor complications are responsible for a large proportion of disability, so these should be identified and treated. Current scientific research is focused on the identification of disease biomarkers allowing correct and timely diagnosis, and on creating more effective therapies, thus fulfilling current clinical unmet needs. This paper presents an updated review on Parkinson’s disease, guiding the readership through current concepts, and allowing their application to daily clinical practice.
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Tomasiuk, Ryszard, Stanislaw Szlufik, Andrzej Friedman, and Dariusz Koziorowski. "Ropinirole treatment in Parkinson's disease associated with higher serum level of inflammatory biomarker NT-proCNP." Neuroscience Letters 566 (April 2014): 147–50. http://dx.doi.org/10.1016/j.neulet.2014.02.053.
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Shpilyukova, Yuliya A., Ekaterina Yu Fedotova, and Sergey N. Illarioshkin. "Corticobasal syndrome as a phenotype of various neurodegenerative disorders: a case series." Annals of Clinical and Experimental Neurology 16, no. 1 (January 15, 2022): 64–70. http://dx.doi.org/10.54101/acen.2022.1.9.
Full textAbstract:
Corticobasal syndrome (CBS) is a variant of atypical parkinsonism. The underlying cause may be corticobasal degeneration or other proteinopathies, which can be verified only after studying specific biomarkers. The disease aetiology in CBS needs to be established to determine the disease prognosis. It can also affect the choice of pathogenetic treatment due to the differences in the molecular pathogenesis of proteinopathies that cause neurodegenerative processes. Four clinical cases of CBS are presented: in patients with four-repeat tauopathy, Alzheimer's disease, frontotemporal dementia and CreutzfeldtJakob disease. Examples are provided of the clinical, genetic and biochemical biomarkers available for differential diagnosis of CBS.
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Virgilio, Eleonora, Fabiola De Marchi, Elena Contaldi, Umberto Dianzani, Roberto Cantello, Letizia Mazzini, and Cristoforo Comi. "The Role of Tau beyond Alzheimer’s Disease: A Narrative Review." Biomedicines 10, no. 4 (March 24, 2022): 760. http://dx.doi.org/10.3390/biomedicines10040760.
Full textAbstract:
Nowadays, there is a need for reliable fluid biomarkers to improve differential diagnosis, prognosis, and the prediction of treatment response, particularly in the management of neurogenerative diseases that display an extreme variability in clinical phenotypes. In recent years, Tau protein has been progressively recognized as a valuable neuronal biomarker in several neurological conditions, not only Alzheimer’s disease (AD). Cerebrospinal fluid and serum Tau have been extensively investigated in several neurodegenerative disorders, from classically defined proteinopathy, e.g., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), but also in inflammatory conditions such as multiple sclerosis (MS), as a marker of axonal damage. In MS, total Tau (t-Tau) may represent, along with other proteins, a marker with diagnostic and prognostic value. In ALS, t-Tau and, mainly, the phosphorylated-Tau/t-Tau ratio alone or integrated with transactive DNA binding protein of ~43 kDa (TDP-43), may represent a tool for both diagnosis and differential diagnosis of other motoneuron diseases or tauopathies. Evidence indicated the crucial role of the Tau protein in the pathogenesis of PD and other parkinsonian disorders. This narrative review summarizes current knowledge regarding non-AD neurodegenerative diseases and the Tau protein.
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Chang, Kuo-Hsuan, and Chiung-Mei Chen. "The Role of Oxidative Stress in Parkinson’s Disease." Antioxidants 9, no. 7 (July 8, 2020): 597. http://dx.doi.org/10.3390/antiox9070597.
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Parkinson’s disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra (SN). Studies have suggested the potential involvement of dopamine, iron, calcium, mitochondria and neuroinflammation in contributing to overwhelmed oxidative stress and neurodegeneration in PD. Function studies on PD-causative mutations of SNCA, PRKN, PINK1, DJ-1, LRRK2, FBXO7 and ATP13A2 further indicate the role of oxidative stress in the pathogenesis of PD. Therefore, it is reasonable that molecules involved in oxidative stress, such as DJ-1, coenzyme Q10, uric acid, 8-hydroxy-2’-deoxyguanosin, homocysteine, retinoic acid/carotenes, vitamin E, glutathione peroxidase, superoxide dismutase, xanthine oxidase and products of lipid peroxidation, could be candidate biomarkers for PD. Applications of antioxidants to modulate oxidative stress could be a strategy in treating PD. Although a number of antioxidants, such as creatine, vitamin E, coenzyme Q10, pioglitazone, melatonin and desferrioxamine, have been tested in clinical trials, none of them have demonstrated conclusive evidence to ameliorate the neurodegeneration in PD patients. Difficulties in clinical studies may be caused by the long-standing progression of neurodegeneration, lack of biomarkers for premotor stage of PD and inadequate drug delivery across blood–brain barrier. Solutions for these challenges will be warranted for future studies with novel antioxidative treatment in PD patients.