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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.


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.


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.


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.


Jellinger K.A.,Institute of Clinical Neurobiology
Neurodegenerative Diseases | Year: 2010

Background: Data on the prevalence of cerebrovascular lesions (CVLs) and their impact on cognitive decline in Alzheimer disease (AD) and Lewy body disease are conflicting. Objective: Retrospective examination of the prevalence of CVL in a consecutive autopsy series. Material and Methods: 1,339 cases of autopsy-proven AD, Parkinson disease (PD), dementia with Lewy bodies (± AD), and 486 age-matched controls were examined according to standardized neuropathologic methods including immunohistochemistry. Diagnoses followed current consensus criteria, classification of CVLs and of cerebral amyloid angiopathy (CAA) in 5 grades [Acta Neurol Scand 2006;114:38-46; Acta Neuropathol 2005;110:345-359]. Results: Lewy body variant of AD and AD showed significantly more frequent CVLs (91.9 and 67.8%) than the other groups (29.4 to 45.7%), with the highest frequency of severe CVLs (old, recent infarcts and hemorrhages) in AD (23.6%), but 2.0-8.3% in the other groups. Severe CAA was most frequent in AD and the Lewy body variant of AD (97.9 and 85%), less in PD (36%) and controls (30%). CAA was more frequent/severe in demented than in nondemented cases. CVLs in cortico-subcortical and hippocampal areas were most frequent in AD; subcortical CVLs (lacunes) in both AD and PD were more frequent than in controls. The incidence and severity of CVLs significantly correlated with neuritic Braak stages. Cognitive impairment was largely independent of coexisting CVLs, but related to the severity/location of AD and/or Lewy pathology. Conclusions: The present data confirm the importance of CVLs in AD and in dementia with Lewy bodies with severe AD, and the little impact of CVLs alone, but show a close association of CAA with clinical dementia associated with AD pathology. Copyright © 2010 S. Karger AG, Basel.


Jellinger K.A.,Institute of Clinical Neurobiology
Journal of Neural Transmission | Year: 2015

Parkinson disease (PD) is a multisystem disorder associated with α-synuclein aggregates throughout the central, autonomic, and peripheral nervous system, clinically characterized by motor and non-motor (NM) symptoms. The NMS in PD, many of which antedating motor dysfunction and representing a preclinical phase spanning 20 or more years, are linked to widespread distribution of α-synuclein pathology not restricted to the dopaminergic nigrostriatal system that is responsible for core motor features of PD. The pathologic substrate of NM manifestations such as olfactory, autonomic (gastrointestinal, urogenital, cardia, respiratory), sensory, skin, sleep, visual, neuropsychiatric dysfunctions (cognitive, mood, dementia), and others are critically reviewed. In addition to non-nigral brainstem nuclei, α-synuclein pathology involves sympathetic and parasympathetic, enteric, cardiac and pelvic plexuses, and many other organs indicating a topographical and chronological spread, particularly in the prodromal stages of the disease. Few animal models recapitulate NMS in PD. The relationship between regional α-synuclein/Lewy pathology, neurodegeneration and the corresponding clinical deficits awaits further elucidation. Controlled clinicopathologic studies will refine the correlations between presymptomatic and late-developing NM features of PD and neuropathology, and new premotor biomarkers will facilitate early diagnosis of PD as a basis for more effective preventive and therapeutic options of this devastating disease. © 2015, Springer-Verlag Wien.


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.


Jellinger K.A.,Institute of Clinical Neurobiology
Expert Review of Neurotherapeutics | Year: 2014

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is a progressive multi-organ proteinopathy caused by misfolded α-synuclein (αSyn) with variegated motor and nonmotor deficits owing to a spreading process of synaptic and neuronal loss in the nervous system. The motor core deficits of PD including rigidity, akinesia, rest tremor, and postural instability are attributed to the loss of dopaminergic nigrostriatal system, while the nonmotor alterations, such as hyposmia, autonomic and other dysfunctions frequently antedating motor symptoms are linked to widespread distribution of αSyn in the central, autonomic and peripheral nervous system and multiple organs. Recent studies have shown that αSyn aggregation in presynaptic terminals that predates the formation of Lewy bodies (LB), the characteristic markers of PD, is a key event in the pathogenesis of PD and other synucleinopathies. Progress in our understanding of the underlying mechanisms include insights into the functional organization of the basal ganglia and related cortico-subcortical circuits and their relations with morphological and pathophysiological lesions in the nervous system. The pathomechanisms underlying the cardinal motor abnormalities and nonmotor manifestations are briefly reviewed. © 2014 Informa UK, Ltd.


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

Late-life depression (LLD) is frequently associated with cognitive impairment and increases the risk of subsequent dementia. Cerebrovascular disease, deep white matter lesions, Alzheimer disease (AD) and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, and a host of studies have looked at the interplay between cerebrovascular disease and LLD. This has resulted in new concepts of LLD, such as "vascular depression", but despite multiple magnetic resonance imaging (MRI) studies in this field, the relationship between structural changes in human brain and LLD is still controversial. While pathological findings of suicide in some elderly persons revealed multiple lacunes, small vessel cerebrovascular disease, AD-related lesions or multiple neurodegenerative pathologies, recent autopsy data challenged the role of subcortical lacunes and white matter lesions as major morphological substrates of depressive symptoms as well as poorer executive function and memory. Several neuropathological studies, including a personal clinico-pathological study in a small cohort of elderly persons with LLD and age-matched controls confirmed that lacunes, periventricular and deep white matter demyelination as well as AD-related lesions are usually unrelated to the occurrence of LLD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of age-related neurodegenerative changes. Very recent data on the critical role of glia-modulating neuronal dysfunction and degeneration in depression are discussed. © 2013 Springer-Verlag Wien.


Jellinger K.A.,Institute of Clinical Neurobiology
International Review of Neurobiology | Year: 2013

Neurodegenerative disorders are featured by a variety of pathological conditions that share similar critical processes, such as oxidative stress, free radical activity, proteinaceous aggregations, mitochondrial dysfunctions, and energy failure. They are mediated or triggered by an imbalance of metal ions leading to changes of critical biological systems and initiating a cascade of events finally leading to neurodegeneration and cell death. Their causes are multifactorial, and although the source of the shift in oxidative homeostasis is still unclear, current evidence points to changes in the balance of redox transition metals, especially iron, copper, and other trace metals. They are present at elevated levels in Alzheimer disease, Parkinson disease, multisystem atrophy, etc., while in other neurodegenerative disorders, copper, zinc, aluminum, and manganese are involved. This chapter will review the recent advances of the role of metals in the pathogenesis and pathophysiology of major neurodegenerative diseases and discuss the use of chelating agents as potential therapies for metal-related disorders. © 2013 Elsevier Inc.

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