Journal of Parkinson's Disease - Volume 7, issue s1

Authors: Patrik, Brundin

Article Type: Introduction

DOI: 10.3233/JPD-179008

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S1-S2, 2017

Authors: Hornykiewicz, Oleh

Article Type: Review Article

Abstract: Today we would find it difficult to place ourselves in the position of the physician or the patient prior to the L-DOPA era of Parkinson’s Disease (PD). David Marsden, the eminent British neurologist, neuroscientist and PD researcher of the second half of the last century and an eyewitness to that historical turning point, paints with few brush strokes, as it were, a vivid, telling picture of that period: “... Before the 1960s the clinical features and basic neuropathology of the disorder had been established, anticholinergic drugs and stereotaxic surgery were popular, but the illness progressed relentlessly and was the cause …of miserable disability... The discovery of selective striatal dopamine deficiency in the parkinsonian brain in the early 1960s changed everything [1 ]”. This paper by Oleh Hornykiewicz recounts the remarkable mixture of science, intrigue and politics behind the author’s work in the 1950s and early 1960s that triggered the modern era of Parkinson’s disease research: the discovery of the dopamine deficit in the brain of patients with Parkinson’s disease. Show more

DOI: 10.3233/JPD-179004

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S3-S10, 2017

Authors: Langston, J. William

Article Type: Review Article

Abstract: The identification of MPTP, a relatively simple compound which causes selective degeneration of the substantia nigra after systemic administration, has had an a significant impact on the understanding and treatment of Parkinson’s disease (PD) over the last 30 years. This article is prefaced by the intriguing “medical detective story” that lead to the discovery of the biological effects of MPTP in humans. The steps that lead to the unraveling its mechanism of action and their impact on research into pathways underlying nigrostriatal degeneration are reviewed. The impact of the animal models that have been developed utilizing MPTP is also described …with a focus on the translational implications of MPTP-related research. These include use of MAO-B inhibitors aimed at neuroprotection in PD and the importance of a stable primate model for PD which was utilized to better understand the circuitry of the basal ganglia, and the identification of the subthalamic nucleus as a target for deep brain stimulation. Finally, the results of a broad range of epidemiologic studies aimed as assessing the impact of environmental factors in PD that have been inspired by MPTP are summarized, including the discovery of other neurotoxicants (rotenone and paraquat) with parkinsonogenic effects. Overall, this article attempts to describe how the discovery of this nigral neurotoxicant began, where it is currently, and what the future may hold. Show more

DOI: 10.3233/JPD-179006

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S11-S19, 2017

Authors: Björklund, Anders | Lindvall, Olle

Article Type: Review Article

Abstract: The efforts to develop a dopamine cell replacement therapy for Parkinson’s disease have spanned over more than three decades. Based on almost 10 years of transplantation studies in animal models, the first patients receiving grafts of fetal-derived dopamine neuroblasts were operated in Lund in 1987. Over the following two decades, a total of 18 patients were transplanted and followed closely by our team with mixed but also very encouraging results. In this article we tell the story of how the preclinical and clinical transplantation program in Lund evolved. We recall the excitement when we obtained the first evidence for survival …and function of transplanted neurons in the diseased human brain. We also remember the setbacks that we have experienced during these 30 years and discuss the very interesting developments that are now taking place in this exciting field. Show more

Keywords: Transplantation, brain repair, fetal tissue, stem cells

DOI: 10.3233/JPD-179002

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S21-S31, 2017

Authors: Hariz, Marwan

Article Type: Review Article

Abstract: The year 2017 marks the 30th anniversary of the birth of modern deep brain stimulation (DBS), which was introduced by Benabid, Pollak et al. in 1987, initially targeting the motor thalamus to treat tremor, and subsequently targeting the subthalamic nucleus (STN) for treatment of symptoms of advanced Parkinson’s disease (PD). STN DBS is undoubtedly “the most important discovery since levodopa”, as stated by David Marsden in 1994. In 2014, The Lasker– DeBakey Clinical Medical Research Award to “honor two scientists who developed deep brain stimulation of the subthalamic nucleus”, was bestowed upon Benabid and DeLong. STN DBS remains today the …main surgical procedure for PD, due to its effectiveness in ameliorating PD symptoms and because it is the only surgical procedure for PD that allows a radical decrease in medication. Future improvements of DBS include the possibility to deliver a “closed-loop”, “on demand” stimulation, as highly preliminary studies suggest that it may improve both axial and appendicular symptoms and reduce side effects such as dysarthria. Even though DBS of the subthalamic nucleus is the main surgical procedure used today for patients with PD, all patients are not suitable for STN DBS; as a functional neurosurgeon performing since more than 25 years various surgical procedures the aim of which is not to save life but to improve the patient’s quality of life, I consider that the surgery should be tailored to the patient’s individual symptoms and needs, and that its safety is paramount. Show more

Keywords: Parkinson’s disease, deep brain stimulation, subthalamic nucleus, globus pallidus, thalamus, quality of life, pallidotomy, stereotactic neurosurgery, safety

DOI: 10.3233/JPD-179007

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S33-S41, 2017

Authors: Nussbaum, Robert L.

Article Type: Review Article

Abstract: In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work. Although alpha-synuclein mutations are a rare cause of hereditary PD, the importance of …this finding goes far beyond the rare families with hereditary disease because it pinpointed alpha-synuclein as a key contributor to the far more common sporadic form of Parkinson disease. This work confirms William Harvey’s observation from 350 years ago that studying rarer forms of a disease is an excellent way to understand the more common forms of that disease. The identification of synuclein’s role in hereditary Parkinson disease has opened new avenues of research into the pathogenesis and potential treatments of the common form of Parkinson disease that affects many millions of Americans and tens of millions of human beings worldwide. Show more

Keywords: Alpha-synuclein, hereditary Parkinson disease, gene mapping, positional cloning

DOI: 10.3233/JPD-179003

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S43-S49, 2017

Authors: Goedert, Michel | Jakes, Ross | Spillantini, Maria Grazia

Article Type: Review Article

Abstract: In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson’s disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, VMY …Lee and JQ Trojanowski. Show more

Keywords: Alpha-synuclein, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, protein aggregation, aggregate propagation, neurodegeneration

DOI: 10.3233/JPD-179005

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S51-S69, 2017

Authors: Braak, Heiko | Del Tredici, Kelly

Article Type: Review Article

Abstract: A relatively small number of especially susceptible nerve cell types within multiple neurotransmitter systems of the human central, peripheral, and enteric nervous systems (CNS, PNS, ENS) become involved in the degenerative process underlying sporadic Parkinson’s disease (sPD). The six-stage model we proposed for brain pathology related to sPD (Neurobiol Aging 2003) was a retrospective study of incidental and clinically diagnosed cases performed on unconventionally thick tissue sections (100 μm) from a large number of brain regions.The staging model emphasized what we perceived to be a sequential development of increasing degrees of Lewy pathology in anatomically interconnected regions together with …the loss of aminergic projection neurons in, but not limited to, the locus coeruleus and substantia nigra. The same weight was assigned to axonal and somatodendritic Lewy pathology, and the olfactory bulb was included for the first time in a sPD staging system. After years of research, it now appears that the earliest lesions could develop at nonnigral (dopamine agonist nonresponsive) sites, where the surrounding environment is potentially hostile: the olfactory bulb and, possibly, the ENS. The current lack of knowledge regarding the development of Lewy pathology within the peripheral autonomic nervous system, however, means that alternative extra-CNS sites of origin cannot be disregarded as possible candidates. The PD staging system not only caused controversy but contributed a framework for (1) assessing pathology in the spinal cord, ENS, and PNS in relationship to that evolving in the brain, (2) defining prodromal disease and cohorts of at-risk individuals, (3) developing potential prognostic biomarkers for very early disease, (4) testing novel hypotheses and experimental models of α-synuclein propagation and disease progression, and (5) finding causally-oriented therapies that intervene before the substantia nigra becomes involved. The identification of new disease mechanisms at the molecular and cellular levels indicates that physical contacts (transsynaptic) and transneuronal transmission between vulnerable nerve cells are somehow crucial to the pathogenesis of sPD. Show more

Keywords: α-synuclein, autonomic nervous system, cell-to-cell transfer, central nervous system, dorsal motor nucleus of the vagal nerve, enteric nervous system, Lewy body disease, locus coeruleus, Parkinson’s disease, olfactory bulb, peripheral nervous system, prion-like, protein aggregation, protein misfolding, spinal cord, substantia nigra

DOI: 10.3233/JPD-179001

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S71-S85, 2017

Authors: Singleton, Andrew B. | Hardy, John A. | Gasser, Thomas

Article Type: Review Article

Abstract: Genetic understanding in Parkinson’s disease (PD) has followed a path of hard won evolution occasionally punctuated by revolution. While it was suggested early on by both Leroux and Gowers that heredity had a role to play in PD, this was a view that wasn’t widely enough held to even be unpopular. The dogma was that the disease was one of environmental provenance and while the evidence for this is still rather scarce, this view pervades in the minds of patients, clinicians, and scientists. Conversely the evidence linking genetics to PD is both overwhelming and growing. Here we describe the growth …of genetics in PD from backwater to driving force, and the structure and shape of its future. Show more

DOI: 10.3233/JPD-179009

Citation: Journal of Parkinson's Disease, vol. 7, no. s1, pp. S87-S93, 2017