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Sara Ekmark-Lewén, Veronica Lindström, Astrid Gumucio, Elisabeth Ihse, Anish Behere, Philipp J Kahle, Eva Nordström, Maria Eriksson, Anna Erlandsson, Joakim Bergström, Martin Ingelsson
Introduction: Intraneuronal inclusions of alpha-synuclein are commonly found in the brain of patients with Parkinson's disease and other α-synucleinopathies. The correlation between alpha-synuclein pathology and symptoms has been studied in various animal models. In (Thy-1)-h[A30P] alpha-synuclein transgenic mice, behavioral and motor abnormalities were reported from 12 and 15 months, respectively. The aim of this study was to investigate whether these mice also display symptoms at earlier time points...
March 2018: Brain and Behavior
Ivan Martinez-Valbuena, Irene Amat-Villegas, Rafael Valenti-Azcarate, Maria Del Mar Carmona-Abellan, Irene Marcilla, Maria-Teresa Tuñon, Maria-Rosario Luquin
Parkinson's disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated α-synuclein in the peripheral nervous system. Pre-existing diabetes mellitus might be a risk factor for developing Parkinson's disease, and indeed, nearly 60% of Parkinson's disease patients are insulin resistant. Thus, we have investigated whether phosphorylated α-synuclein is deposited in pancreatic tissue of subjects with synucleinopathies. We studied pancreatic tissue from 39 subjects diagnosed with Parkinson's disease, Lewy body Dementia or incidental Lewy bodies disease, as well as that from 34 subjects with diabetes mellitus and a normal neuropathological examination, and 52 subjects with a normal neuropathological examination...
March 13, 2018: Acta Neuropathologica
Emma Robson, Clare Tweedy, Nelson Manzanza, John-Paul Taylor, Peter Atkinson, Fiona Randall, Amy Reeve, Gavin J Clowry, Fiona E N LeBeau
Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBD), including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P)...
March 7, 2018: Neuroscience
Morten Gersel Stokholm, Alex Iranzo, Karen Østergaard, Mónica Serradell, Marit Otto, Kristina Bacher Svendsen, Alicia Garrido, Dolores Vilas, Peter Parbo, Per Borghammer, Joan Santamaria, Arne Møller, Carles Gaig, David J Brooks, Eduardo Tolosa, Nicola Pavese
BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with18 F-DOPA and11 C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation...
March 6, 2018: Neurobiology of Disease
Kurt A Jellinger, Amos D Korczyn
BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD...
March 6, 2018: BMC Medicine
Viorica Chelban, Ekawat Vichayanrat, Lucia Schottlaende, Valeria Iodice, Henry Houlden
The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia...
March 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Jose-Alberto Palma, Horacio Kaufmann
Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully...
March 2018: Movement Disorders: Official Journal of the Movement Disorder Society
J William Langston, Jesse C Wiley, Michele Tagliati
The diagnosis of Parkinson's disease (PD) currently relies almost exclusively on the clinical judgment of an experienced neurologist, ideally a specialist in movement disorders. However, such clinical diagnosis is often incorrect in a large percentage of patients, particularly in the early stages of the disease. A commercially available, objective and quantitative marker of nigrostriatal neurodegeneration was recently provided by 123-iodine123 I-ioflupane SPECT imaging, which is however unable to differentiate PD from a variety of other parkinsonian syndromes associated with striatal dopamine deficiency...
2018: NPJ Parkinson's Disease
Esteban Luna, Samantha C Decker, Dawn M Riddle, Anna Caputo, Bin Zhang, Tracy Cole, Carrie Caswell, Sharon X Xie, Virginia M Y Lee, Kelvin C Luk
The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2-expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared...
March 3, 2018: Acta Neuropathologica
Lasse Reimer, Louise Buur Vesterager, Cristine Betzer, Jin Zheng, Lærke Dalsgaard Nielsen, Rikke Hahn Kofoed, Louise Berkhoudt Lassen, Ulrik Bølcho, Søren Riis Paludan, Karina Fog, Poul Henning Jensen
Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy comprise a group of neurodegenerative diseases termed synucleinopathies. Synucleinopathie are, characterized by presence of inclusion bodies in degenerating brain cells which contain aggregated α-synuclein phosphorylated on Ser129. Although the inflammation-associated serine-threonine kinase, PKR (EIF2AK2), promotes cellular protection against infection, we demonstrate a pro-degenerative role of activated PKR in an α-synuclein-dependent cell model of multiple system atrophy, where inhibition and silencing of PKR decrease cellular degeneration...
March 1, 2018: Neurobiology of Disease
Rizwan S Akhtar, Joseph P Licata, Kelvin C Luk, Leslie M Shaw, John Q Trojanowski, Virginia M-Y Lee
Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples...
March 3, 2018: Journal of Neurochemistry
Hiroyuki Honda, Naokazu Sasagasako, Chang Shen, Masahiro Shijo, Hideomi Hamasaki, Satoshi O Suzuki, Yoshio Tsuboi, Naoki Fujii, Toru Iwaki
INTRODUCTION: Perry syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry syndrome. A novel F52L DCTN1 mutation case of Perry syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy. METHODS: A Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance...
February 23, 2018: Parkinsonism & related Disorders
Alan J Fowler, Charbel E-H Moussa
Parkinson's disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson's disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson's disease...
February 28, 2018: CNS Drugs
Oscar S Gershanik
Current understanding of the pathophysiology of Parkinson's disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson's disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies...
February 2018: Arquivos de Neuro-psiquiatria
Genesys Giraldo, Mieu Brooks, Benoit I Giasson, Christopher Janus
Parkinson's disease manifests as a progressive movement disorder with underlying degeneration of dopaminergic neurons in the substantia nigra, consequent depletion of dopamine levels, and the accumulation of Lewy bodies in the brain. Because α-synuclein (α-Syn) protein is the major component of Lewy bodies, mouse models expressing wild-type or mutant SNCA/α-Syn genes provide a useful tool to investigate canonical characteristics of the disease. We evaluated a mouse model (denoted M20) that expresses human wild-type SNCA gene...
February 6, 2018: Neurobiology of Aging
David J Irwin, Sharon X Xie, David Coughlin, Naomi Nevler, Rizwan S Akhtar, Corey T McMillan, Edward B Lee, David A Wolk, Daniel Weintraub, Alice Chen-Plotkin, John E Duda, Meredith Spindler, Andrew Siderowf, Howard I Hurtig, Leslie M Shaw, Murray Grossman, John Q Trojanowski
OBJECTIVE: To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). METHODS: Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology...
February 21, 2018: Neurology
David A Bennett, Brian A Gordon
No abstract text is available yet for this article.
February 21, 2018: Neurology
Kari Anne Bjørnarå, Lasse Pihlstrøm, Espen Dietrichs, Mathias Toft
BACKGROUND: Parkinson's disease is a heterogeneous disorder where genetic factors may underlie clinical variability. Rapid eye movement sleep behavior disorder (RBD) is a parasomnia strongly linked to synucleinopathies, including Parkinson's disease. We hypothesized that SNCA variants conferring risk of Parkinson's disease would also predispose to an RBD phenotype. METHODS: We assessed possible RBD (pRBD) status using the RBD screening questionnaire and investigated known susceptibility variants for Parkinson's disease located in the α-synuclein (SNCA) and tau (MAPT) gene loci in 325 Parkinson's disease patients...
February 21, 2018: BMC Neurology
Rodolfo Savica, Boeve F Bradley, Michelle M Mielke
Importance: This article reviews the epidemiological evidence of features of α-synucleinopathies that precede clinical onset of disease, proposes a clinical timeline, and attempts to define the different premotor and clinical phenotypes associated with α-synucleinopathies. Observations: The pathological hallmarks of the α-synucleinopathies (Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, and multisystem atrophy) begin years before a clinical diagnosis...
February 19, 2018: JAMA Neurology
Janin Lautenschläger, Amberley D Stephens, Giuliana Fusco, Florian Ströhl, Nathan Curry, Maria Zacharopoulou, Claire H Michel, Romain Laine, Nadezhda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan J Phillips, Alfonso De Simone, Clemens F Kaminski, Gabriele S Kaminski Schierle
Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium...
February 19, 2018: Nature Communications
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