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Jellinger K.A.,Institute of Clinical Neurobiology
Journal of Cellular and Molecular Medicine | Year: 2012

The misfolding and progressive aggregation of specific proteins in selective regions of the nervous system is a seminal occurrence in many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic and experimental differences, increasing evidence indicates considerable overlap between synucleinopathies, tauopathies and other protein-misfolding diseases. Inclusions, often characteristic hallmarks of these disorders, suggest interactions of pathological proteins enganging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Alzheimer, Parkinson, Huntington and prion diseases, have confirmed correlations/overlaps between these and other neurodegenerative disorders. Emerging evidence, in addition to synergistic effects of tau protein, amyloid-β, α-synuclein and other pathologic proteins, suggests that prion-like induction and spreading, involving secreted proteins, are major pathogenic mechanisms in various neurodegenerative diseases, depending on genetic backgrounds and environmental factors. The elucidation of the basic molecular mechanisms underlying the interaction and spreading of pathogenic proteins, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, is a major challenge for modern neuroscience, to provide a deeper insight into their pathogenesis as a basis of effective diagnosis and treatment. © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source

Jellinger K.A.,Institute of Clinical Neurobiology
Movement Disorders | Year: 2012

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is no longer considered a complex motor disorder characterized by extrapyramidal symptoms, but a progressive multisystem or-more correctly-multiorgan disease with variegated neurological and nonmotor deficiencies. It is morphologically featured not only by the degeneration of the dopaminergic nigrostriatal system, responsible for the core motor deficits, but by multifocal involvement of the central, peripheral and autonomic nervous system and other organs associated with widespread occurrence of Lewy bodies and dystrophic Lewy neurites. This results from deposition of abnormal α-synuclein (αSyn), the major protein marker of PD, and other synucleinopathies. Recent research has improved both the clinical and neuropathological diagnostic criteria of PD; it has further provided insights into the development and staging of αSyn and Lewy pathologies and has been useful in understanding the pathogenesis of PD. However, many challenges remain, for example, the role of Lewy bodies and the neurobiology of axons in the course of neurodegeneration, the relation between αSyn, Lewy pathology, and clinical deficits, as well as the interaction between αSyn and other pathologic proteins. Although genetic and experimental models have contributed to exploring the causes, pathomechanisms, and treatment options of PD, there is still a lack of an optimal animal model, and the etiology of this devastating disease is far from being elucidated. © 2011 Movement Disorder Society © 2011 Movement Disorder Society. Source

Jellinger K.A.,Institute of Clinical Neurobiology
Journal of Cellular and Molecular Medicine | Year: 2010

Neurodegenerative diseases are characterized by progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra and intracellular accumulation of misfolded proteins, the hallmarks of many neurodegenerative proteinopathies. Major basic processes include abnormal protein dynamics due to deficiency of the ubiquitin-proteosome-autophagy system, oxidative stress and free radical formation, mitochondrial dysfunction, impaired bioenergetics, dysfunction of neurotrophins, 'neuroinflammatory' processes and (secondary) disruptions of neuronal Golgi apparatus and axonal transport. These interrelated mechanisms lead to programmed cell death is a long run over many years. Neurodegenerative disorders are classified according to known genetic mechanisms or to major components of protein deposits, but recent studies showed both overlap and intraindividual diversities between different phenotypes. Synergistic mechanisms between pathological proteins suggest common pathogenic mechanisms. Animal models and other studies have provided insight into the basic neurodegeneration and cell death programs, offering new ways for future prevention/treatment strategies. © 2010 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source

Jellinger K.A.,Institute of Clinical Neurobiology
Expert Review of Neurotherapeutics | Year: 2012

Cognitive impairment is a frequent complication of Parkinson's disease (PD). Mild cognitive impairment (MCI) may progress to dementia more frequently and rapidly. PD dementia (PDD) and PD-MCI have a mean prevalence up to 75% each; a four-to six-times increased incidence rate compared with controls. Recent diagnostic clinical criteria for both PDD and PD-MCI require validation. Cognitive decline in PD can be probed clinically, comprehensive neuropsychological assessment being the best way to define it. Neuroimaging in both disorders revealed cortical atrophy, hypometabolism, white matter changes, dopaminergic/cholinergic dysfunction and increased amyloid burden. Combined analysis of imaging and cerebrospinal fluid markers (tau and Aβ-42) is the most promising method for indentifying PD-MCI and PDD. Morphological substrates are a combination of Lewy and Alzheimer pathologies causing destruction of essential neuronal networks. PDD and dementia with Lewy bodies are considered similar parts of a disease spectrum. Treatment with cholinesterase inhibitors revealed mild-to-moderate results. © 2012 Expert Reviews Ltd. Source

Jellinger K.A.,Institute of Clinical Neurobiology
Journal of Neural Transmission | Year: 2013

Cognitive impairment is common in Parkinson disease (PD), with long-term longitudinal studies reporting that most PD patients develop dementia. A high proportion of patients with PD and mild cognitive impairment (MCI) progress to dementia within a short time. Impairments occur in a range of cognitive domains, but single-domain impairment is more common than multiple one, non-amnestic more common than amnestic impairment. Although the term MCI applied to PD (PD-MCI) is not without controversy due to the lack of uniform diagnostic consensus criteria, the biological validity of PD-MCI is supported by many recent studies that show heterogenous mechanisms in the clinical presentation, neuropsychology, neuroimaging, biomarkers, and neuropathology, suggesting abnormal metabolic network activities involving several cortical and subcortical nervous systems. Prospective studies using specific biomarkers, including amyloid imaging, and cerebro-spinal fluid biomarkers are warranted for an exact diagnosis and prognostic assessment of early cognitive deficits in PD patients. © 2012 Springer-Verlag. Source

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