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Benskey M.J.,Michigan State University | Perez R.G.,Texas Tech University | Manfredsson F.P.,Michigan State University | Manfredsson F.P.,Hauenstein Neuroscience Center
Journal of Neurochemistry | Year: 2016

The aggregation of alpha synuclein (α-syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the α-syn gene result in familial PD. The high correlation between α-syn burden and PD has led to the hypothesis that α-syn aggregation produces toxicity through a gain-of-function mechanism. However, α-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α-syn results in toxicity because of a toxic loss of necessary α-syn function, following sequestration of functional forms α-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking α-syn to PD and the knowledge gained from current α-syn-based animal models of PD. We will then interpret these data from the viewpoint of the α-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of α-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. © 2016 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. Source


Farooq M.U.,Hauenstein Neuroscience Center
Current atherosclerosis reports | Year: 2013

Vascular cognitive impairment (VCI) is a term used to capture the entire spectrum of cognitive impairment from mild to more severe forms and includes all forms of stroke (e.g., ischemic and hemorrhagic forms) associated and underlying cognitive impairment related with subclinical vascular brain injury. Vascular contributions to cognitive impairment are common, especially as one ages. Therefore, both stroke and Alzheimer's disease may be important causes of cognitive impairment in later life, and the concomitant occurrence of these disorders may synergize to increase the risk of poor cognition in later life. In this review we discuss the definition and clinical presentation, mechanisms, cardiovascular risk factors and possible prevention and treatment of VCI. VCI is a potentially treatable and preventable cause of cognitive impairment in later life, and familiarity with this condition will help the practitioner provide better care to patients. Source


Farooq M.U.,Hauenstein Neuroscience Center | Gorelick P.B.,Michigan State University
Current Atherosclerosis Reports | Year: 2013

Vascular cognitive impairment (VCI) is a term used to capture the entire spectrum of cognitive impairment from mild to more severe forms and includes all forms of stroke (e.g., ischemic and hemorrhagic forms) associated and underlying cognitive impairment related with subclinical vascular brain injury. Vascular contributions to cognitive impairment are common, especially as one ages. Therefore, both stroke and Alzheimer's disease may be important causes of cognitive impairment in later life, and the concomitant occurrence of these disorders may synergize to increase the risk of poor cognition in later life. In this review we discuss the definition and clinical presentation, mechanisms, cardiovascular risk factors and possible prevention and treatment of VCI. VCI is a potentially treatable and preventable cause of cognitive impairment in later life, and familiarity with this condition will help the practitioner provide better care to patients. © 2013 Springer Science+Business Media New York. Source


Gibbons L.,University of Washington | Diouf M.,University Hospital of Amiens | Nyenhuis D.,Hauenstein Neuroscience Center | Black S.,Sunnybrook Health science Center | And 30 more authors.
Cortex | Year: 2014

Introduction: Although accurate diagnosis of deficit of mild intensity is critical, various methods are used to assess, dichotomize and integrate performance, with no validated gold standard. This study described and validated a framework for the analysis of cognitive performance. Methods: This study was performed by using the Groupe de Réflexion sur L'Evaluation des Fonctions EXécutives (GREFEX) database (724 controls and 461 patients) examined by 7 tests assessing executive functions. The first phase determined the criteria for the cutoff scores, the second phase, the effect of test number on diagnostic accuracy and the third phase, the best methods for combining test scores into an overall summary score. Four validation criteria were used: determination of impaired performance as compared to expected one, false-positive rate ≤5%, detection of both single and multiple impairments with optimal sensitivity. Results: The procedure based on 5th percentile cutoffs determined from standardized residuals was the most appropriate procedure. Although area under the curve (AUC) increased with the number of scores (p=.0001), the false-positive rate also increased (p=.0001), resulting in suboptimal sensitivity for detecting selective impairment. Two overall summary scores, the average of the seven process scores and the Item Response Theory (IRT) score, had significantly (p=.0001) higher AUCs, even for patients with a selective impairment, and provided higher resulting prevalence of dysexecutive disorders (p=.0001). Conclusions: The present study provides and validates a generative framework for the interpretation of cognitive data. Two overall summary score metall 4 validation criteria. A practical consequence is the need to profoundly modify the analysis and interpretation of cognitive assessments for both routine use and clinical research. © 2014 Elsevier Ltd. Source


Marechal E.,University of Antwerp | Denoiseux B.,University of Antwerp | Thys E.,University of Antwerp | Crosiers D.,University of Antwerp | And 6 more authors.
Journal of Neurology | Year: 2015

Parkinson’s disease (PD) is the second most common neurodegenerative brain disorder and is characterized by motor symptoms such as tremor, bradykinesia, rigidity and postural instability. A majority of the patients also develop non-motor symptoms. Impulse control disorders (ICD) are behavioural changes that often fail to be detected in clinical practice. The prevalence of ICD in PD varies widely from 6.1 to 31.2 % and treatment with dopaminergic medication is considered to be the greatest risk factor. Management consists mainly of reducing dopaminergic medication. In our experience, ICD has a tremendous impact on the quality of life of the patients and their families and should therefore not be disregarded. Studies addressing the role of ICD in PD caregiver strain are imperative. We attempt to give a comprehensive overview of the literature on the complicated neurobiology of ICD and discuss risk factors, genetic susceptibility, screening modalities and management. © Springer-Verlag Berlin Heidelberg 2014. Source

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