Journal of Parkinson's Disease - Volume 3, issue 4

Authors: Wales, Pauline | Pinho, Raquel | Lázaro, Diana F. | Outeiro, Tiago F.

Article Type: Review Article

Abstract: The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause …familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies. Show more

Keywords: Alpha-synuclein, synucleinopathies, neurodegeneration, Lewy body, aggregation

DOI: 10.3233/JPD-130216

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 415-459, 2013

Authors: Dias, Vera | Junn, Eunsung | Mouradian, M. Maral

Article Type: Review Article

Abstract: Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. Evidence has been developed for oxidative and nitrative damage to key cellular components in the PD substantia nigra. A number of sources and mechanisms for the generation of reactive oxygen species (ROS) are recognized including the metabolism of dopamine itself, mitochondrial dysfunction, iron, neuroinflammatory cells, calcium, and aging. PD causing gene products including DJ-1, PINK1, parkin, alpha-synuclein and LRRK2 also impact in complex …ways mitochondrial function leading to exacerbation of ROS generation and susceptibility to oxidative stress. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress. It is apparent that the interplay between these various mechanisms contributes to neurodegeneration in PD as a feed forward scenario where primary insults lead to oxidative stress, which damages key cellular pathogenetic proteins that in turn cause more ROS production. Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD. However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection. Show more

Keywords: Neurodegeneration, neuroprotection, neuroinflammation, reactive oxygen species, dopamine, mitochondria

DOI: 10.3233/JPD-130230

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 461-491, 2013

Authors: Kannarkat, George T. | Boss, Jeremy M. | Tansey, Malú G.

Article Type: Review Article

Abstract: In recent years, inflammation has become implicated as a major pathogenic factor in the onset and progression of Parkinson's disease. Understanding the precise role for inflammation in PD will likely lead to understanding of how sporadic disease arises. In vivo evidence for inflammation in PD includes microglial activation, increased expression of inflammatory genes in the periphery and in the central nervous system (CNS), infiltration of peripheral immune cells into the CNS, and altered composition and phenotype of peripheral immune cells. These findings are recapitulated in various animal models of PD and are reviewed herein. Furthermore, we examine the potential relevance …of PD-linked genetic mutations to altered immune function and the extent to which environmental exposures that recapitulate these phenotypes, which may lead to sporadic PD through similar mechanisms. Given the implications of immune system involvement on disease progression, we conclude by reviewing the evidence supporting the potential efficacy of immunomodulatory therapies in PD prevention or treatment. There is a clear need for additional research to clarify the role of immunity and inflammation in this chronic, neurodegenerative disease. Show more

Keywords: Immune system, Parkinson's disease, lymphocytes, inflammation, immunomodulation, adaptive immunity

DOI: 10.3233/JPD-130250

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 493-514, 2013

Authors: Parashos, Sotirios A. | Wielinski, Catherine L. | Giladi, Nir | Gurevich, Tanya | on behalf of The National Parkinson Foundation Quality Improvement Initiative Investigators

Article Type: Research Article

Abstract: Background: Falls remain a significant cause of morbidity in PD. Risk factors are not well understood. Objective: In this study we explore risk factors for falls in PD utilizing the cross-sectional, baseline data in the National Parkinson Foundation Quality Improvement Initiative (NPF-QII) database. Subjects are being followed prospectively, and this study will provide the basis for subsequent longitudinal analyses. Methods: A cross-sectional analysis of data from 2,876 ambulatory patients with Parkinson disease enrolled in the NPF-QII at 18 sites. Main outcome measure was falling history in the 3 months preceding assessment. The following were considered as possible predictor variables: age, …sex, height, weight, body mass index, disease duration, age at disease onset, investigator's confidence in the diagnosis, Hoehn and Yahr stage, rest tremor, ability to stand unassisted, coexistent pathologies (cardiovascular, respiratory, diabetes, cancer, neurological, osteoarthritis, and “other” comorbidities), anticholinergics, antidepressants, antipsychotics, cognitive enhancers, deep brain stimulation surgery, timed-up-and-go, semantic fluency, and 5 word recall. Variables with associations to the outcome measure in univariate analyses were analyzed in multivariable models using logistic regression. Results: 37.2% of subjects experienced falls. In the multivariable regression model the following variables were found to be independently associated with falls: disease duration; Hoehn and Yahr stage; absence of rest tremor; cardiovascular, arthritis, or “other” comorbidity; antidepressants; deep brain stimulation surgery; timed-up-and-go; and, semantic fluency. Conclusion: Disease duration but not age is independently associated with falls in Parkinson disease. Timed-up-and-go accurately reflects falls risk. Impaired semantic fluency is independently associated with falls, while verbal memory is not. Comorbidities, antidepressants, and deep brain stimulation also contribute to falls risk. Show more

Keywords: Parkinson disease, falls, cognitive dysfunction, antidepressants

DOI: 10.3233/JPD-130249

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 515-522, 2013

Authors: Visanji, Naomi P. | Collingwood, Joanna F. | Finnegan, Mary E. | Tandon, Anurag | House, Emily | Hazrati, Lili-Naz

Article Type: Research Article

Abstract: Alpha synuclein pathology is widespread and found in diverse cell types in multiple system atrophy (MSA) as compared to Parkinson's disease (PD). The reason for this differential distribution is unknown. Regional differences in the distribution of iron are associated with neurodegenerative diseases, and here we characterize the relationship between iron homeostasis proteins and regional concentration, distribution and form of iron in MSA and PD. In PD substantia nigra, tissue iron and expression of the iron export protein ferroportin increased, while the iron storage protein ferritin expression was unchanged. In the basis pontis of MSA cases, increased total iron concentration coupled …with a disproportionate increase in ferritin in dysmorphic microglia and a reduction in ferroportin expression. This is supported by isothermal remanent magnetisation evidence consistent with elevated concentrations of ferritin-bound iron in MSA basis pontis. Conventional opinion holds that excess iron is involved in neurodegeneration. Our data support that this may be the case in PD. While region-specific changes in iron are evident in both PD and MSA, the mechanisms of iron dysregulation appear quite distinct, with a failure to export iron from the MSA basis pontis coupling with significant intracellular accumulation of ferritin iron. This pattern also occurs, to a lesser extent, in the MSA putamen. Despite the excess tissue iron, the manner of iron dysregulation in MSA is reminiscent of changes in anemia of chronic disease, and our preliminary data, coupled with the widespread pathology and involvement of multiple cell types, may evidence a deficit in bioavailabile iron. Show more

Keywords: Parkinson's disease, multiple system atrophy, iron, ferritin, inflammation, ferroportin

DOI: 10.3233/JPD-130197

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 523-537, 2013

Authors: Cavanna, Andrea E. | Nani, Andrea | Williams, Adrian C.

Article Type: Research Article

Abstract: Pellagra is a complex systemic disease resulting from inadequate dietary intake of coenzyme precursors nicotinamide and tryptophan. Improved nutritional habits in most developed economies have led to a decrease in clinicians' and researchers' attention to this condition and its pathophysiological bases, although new cases of pellagra have recently been identified in association with alcohol abuse and HIV infection in Western countries. Pellagra is characterized by a complex clinical picture, which can include neuropsychiatric symptoms and Parkinsonian features. Interestingly, pellagra and Parkinson's disease could share some basic pathophysiological mechanisms at the level of nicotinamide metabolism, resulting in mitochondrial dysfunction and alterations …in dopaminergic pathways. Both neuropsychiatric and motor symptoms were mentioned in historical reports of pellagra cohorts. Here we present the English translation of the first detailed description of an original case of pellagra with Parkinsonian features, documented in a clinical note by Dr Giuseppe Paravicini one century ago. Show more

Keywords: Pellagra, Parkinson's disease, motor signs, historical description

DOI: 10.3233/JPD-130242

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 539-545, 2013

Authors: Peterson, Amie L. | Murchison, Charles | Zabetian, Cyrus | Leverenz, James B. | Watson, G. Stennis | Montine, Thomas | Carney, Natasha | Bowman, Gene L. | Edwards, Karen | Quinn, Joseph F.

Article Type: Research Article

Abstract: Background: Research in recent years has suggested a role of vitamin D in the central nervous system. The final converting enzyme and the vitamin D receptor are found throughout the human brain. From animal studies vitamin D appears important in neurodevelopment, up-regulation of neurotrophic factors, stabilization of mitochondrial function, and antioxidation. Objective: To examine the relationship between serum vitamin D and neuropsychiatric function in persons with Parkinson's disease (PD). Methods: This is an add-on study to a longitudinal study following neuropsychiatric function in persons with PD. Baseline neuropsychiatric performance and serum 25-hydroxyvitamin D were examined for 286 participants with PD. …Measures of global cognitive function (MMSE, MOCA, Mattis Dementia Scale), verbal memory (Hopkins Verbal Learning Test), fluency (animals, vegetables, and FAS words), visuospatial function (Benton Line Orientation), executive function (Trails Making Test and Digit-Symbol Substitution), PD severity (Hoehn & Yahr and Unified Parkinson's Disease Rating Scale) and depression (Geriatric Depression Scale (GDS)) were administered. Multivariate linear regression assessed the association between vitamin D concentration and neuropsychiatric function, in the entire cohort as well as the non-demented and demented subsets. Results: Using a multivariate model, higher vitamin D concentrations were associated with better performance on numerous neuropsychiatric tests in the non-demented subset of the cohort. Significant associations were specifically found between vitamin D concentration and verbal fluency and verbal memory (t = 4.31, p < 0.001 and t = 3.04, p = 0.0083). Vitamin D concentrations also correlated with depression scores (t = −3.08, p = 0.0083) in the non-demented subset. Conclusions: Higher plasma vitamin D is associated with better cognition and better mood in this sample of PD patients without dementia. Determination of causation will require a vitamin D intervention study. Show more

Keywords: Parkinson's disease, vitamin D, dementia, depression, cognition

DOI: 10.3233/JPD-130206

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 547-555, 2013

Authors: Antoniades, Chrystalina A. | Xu, Zheyu | Carpenter, R.H.S. | Barker, Roger A.

Article Type: Research Article

Abstract: Background: Clinicians normally use subjective rating scales to estimate the impairment of patients with Parkinson's disease (PD). More objective and quantitative methods of assessment would greatly aid our understanding of the disease. One promising approach is to measure reaction time: the large amount of data recorded in a short period provides precise, reproducible evaluation of the underlying neural decision processes. Manual evoked reaction times and repetitive tapping speed are often used, but differences of experimental design and analysis tend to obscure their interpretation. Saccadic latency, in many ways a simpler and more standardised task, is also normally affected in PD, …but its relation to the kind of movement impairment that affects patients' quality of life is less obvious. Objestive: The aim of this study was to evaluate these tasks in detail and also see whether their use in combination could provide a better measure than each in isolation. Methods: We compared three reaction time tasks: saccadometry, and evoked and spontaneous tapping, using protocols as similar as possible, correlating the measurements within a group of PD patients and of age-matched controls. Results: Surprisingly, manual and saccadic performance is uncorrelated in the normal population; but both are similarly affected by PD. The differences between groups are strengthened when the three measures are combined. Conclusions: Saccadic latency can be regarded as an appropriate surrogate for more general kinds of motor impairment. The combination of saccadic and manual parameters enhances their potential use in quantifying disease status and evaluating treatments. Show more

Keywords: Saccadic eye movements, manual reaction times, Parkinson's disease, evoked motor response

DOI: 10.3233/JPD-120126

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 557-563, 2013

Authors: Eberling, Jamie L. | Dave, Kuldip D. | Frasier, Mark A.

Article Type: Research Article

Abstract: The development of an α-synuclein imaging agent could be transformative for Parkinson's disease research and drug development. The ability to image α-synuclein in the brain would enable tracking of the degree and location of pathology over time and monitoring of therapies aimed at reducing α-synuclein levels. The Michael J. Fox Foundation has assembled a consortium of researchers to develop an α-synuclein radiotracer for use in positron emission tomography (PET) imaging studies. While this poses a number of challenges they should not be insurmountable and lessons learned from the development of tau radiotracers should provide valuable insights.

Keywords: α-synuclein, positron emission tomography, radiopharmaceutical, biomarker, β-amyloid, tau

DOI: 10.3233/JPD-130247

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 565-567, 2013

Authors: Spiros, Athan | Roberts, Patrick | Geerts, Hugo

Article Type: Research Article

Abstract: Background: Possible solutions for the low success rate in CNS Drug discovery and development in CNS diseases include drug repurposing. Objectives: As a possible alternative to prohibitively expensive systematic testing in animal models, we propose to use a humanized quantitative systems pharmacology (QSP) platform as an example of a well-validated phenotypic assay in Parkinson's disease (PD) tremor for filtering out possible interesting molecules that then can be tested in preclinical animal models. This will significantly reduce discovery time and costs, while at the same time providing a better predictability to the human clinical outcome. The method will be applied to …the Prestwick library, a library of FDA approved and off-patent medications. Methods: The platform contains 30 CNS physiologically implemented targets and simulates biophysically realistic neuronal network interactions between supplemental motor cortex and motor striatum based on preclinical neurophysiology and human electrophysiology data. Importantly, the platform is further calibrated using retrospective clinical data on Parkinsonian side-effects with antipsychotics. Results: We use this QSP platform to screen pharmacological profiles of serotonergic drugs in the Prestwick library. We identified five interesting multi-pharmacology agents, including trazodone that in a previously reported study improved clinical PD scales as augmentation strategy. Conclusion: The Quantitative Systems Pharmacology platform is a powerful modeling and simulation tool with a relevant human clinical scale as output, where multi-target drugs effect can be simulated and promising candidates for further study in pharmacological profiling or animal models can be identified. Show more

Keywords: Systems pharmacology, Parkinson's disease, drug repurposing, tremor

DOI: 10.3233/JPD-130211

Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 569-580, 2013