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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EUnderstanding the underlying pathology of Parkinson\u0027s disease (PD) is critical in identifying the disease early and developing novel treatments. This article discusses the role of a-synuclein in PD, the extranigral pathology and preclinical detection of PD, as well as how the updated understanding of PD pathology explains its clinical phenotype\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EExtrapyramidal \u0026amp; Movement Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDementias\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EExtrapyramidal \u0026amp; Movement Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENeurology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDementias\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EUnderstanding the underlying pathology of Parkinson\u0027s disease (PD) is critical in identifying the disease early and developing novel treatments. John Trojanowski, MD, PhD, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA, described the role of \u03b1-synuclein in PD. The misfolding of proteins, such as \u03b1-synuclein, can impart toxic properties. For example, intraneuronal Lewy bodies, which are composed of misfolded \u03b1-synuclein amyloid fibers, are present in the brains of patients with PD. In addition, the development of cognitive impairment is a feature of PD that coincides with the progression of Lewy bodies [Irwin DJ et al. \u003Cem\u003EAnn Neurol\u003C\/em\u003E 2012], and indeed, many patients with PD will develop dementia. In addition to Lewy body pathology, Alzheimer\u0027s pathology is observed in patients with PD.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EResearchers of a pilot study compared cerebrospinal fluid from patients with PD to spinal fluid from healthy controls to identify biomarkers for PD. Measurements of \u03b1-synuclein, \u03b2-amyloid\u003Csub\u003E1\u201342\u003C\/sub\u003E, total tau, and tau phosphorylated at threonine 181 were significantly lower in patients with PD compared with healthy controls (p\u0026lt;0.05) [Kang JH et al. \u003Cem\u003EJAMA Neurol\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EWith regard to animal studies, an \u03b1-synuclein transgenic mouse model showed normal spontaneous motor activity and cued fear conditioning but impaired contextual fear conditioning, indicating an effect on the hippocampus [Lim Y et al. \u003Cem\u003EJ Neurosci\u003C\/em\u003E 2011]. Additionally, a time-dependent increase in a rapidly progressive neurodegenerative \u03b1-synucleinopathy has been observed in mice that received an intracerebral inoculation of pathologic \u03b1-synuclein [Luk KC et al. \u003Cem\u003EJ Exp Med\u003C\/em\u003E 2012]. The pathology seen in these mice was similar to that observed in PD. In a third study, human corticobasal degeneration brain lysates of pathologic tau injected into healthy 3-month-old mice resulted in tau aggregate formation in hippocampal neurons and white matter [Iba M et al. \u003Cem\u003EJ Neurosci\u003C\/em\u003E 2013], which is similar to the pathology observed in Alzheimer\u0027s disease. These and other studies suggest a new understanding of PD, in that its transmission occurs from cell to cell, which could explain its progression in humans.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EVirginia Lee, PhD, MBA, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA, discussed how the updated understanding of PD pathology explains its clinical phenotype. Fibrillar \u03b1-synuclein acts as intracellular seeds that eventually form Lewy body\u2013like \u03b1-synuclein aggregates in the soma of the affected neuron. When preformed \u03b1-synuclein fibrils (PFFs) are administered to wild-type mice, they promote endogenous \u03b1-synuclein to form pathologic aggregates. As discussed above, intrastriatal injection of mouse PFFs into mice results in the formation of Lewy bodies [Luk KC et al. \u003Cem\u003EScience\u003C\/em\u003E 2012]. Additionally, a seeded pathology that resembles Lewy pathology can cause loss of synapses and synaptic proteins and impair normal cellular function in cultured neurons from wild-type mice [Volpicelli-Daley LA et al. \u003Cem\u003ENeuron\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EDifferent strains of PFFs have been generated from recombinant \u03b1-synuclein protein; one strain is able to recruit tau and the other cannot, in vitro and in mice [Guo JL et al. \u003Cem\u003ECell\u003C\/em\u003E 2013]. Biochemical and molecular analyses indicated that there are conformational differences between the \u03b1-synuclein strains and that more N- and C-termini are exposed in strain B. Strain-specific monoclonal antibodies support the theory of a conformation difference between the 2 \u03b1-synuclein strains by enzyme-linked immunosorbent assay [Guo JL et al. \u003Cem\u003ECell\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EDr. Lee suggested that if misfolded \u03b1-synuclein can be transmitted to healthy cells and cause disease, perhaps the uptake of misfolded \u03b1-synuclein can be blocked via immunotherapy. In vitro studies revealed that anti-\u03b1-synuclein monoclonal antibodies resulted in a decrease of PFF-induced insoluble pathologic \u03b1-synuclein aggregates in primary neurons, as well as synaptic loss and neuron death [Tran HT et al. \u003Cem\u003ECell Rep\u003C\/em\u003E 2014]. The antibodies also blocked the uptake of \u03b1-synuclein PFFs and prevented cell-to-cell transmission of misfolded \u03b1-synuclein. Also, the anti-\u03b1-synuclein antibody Syn303 has been observed to prevent the spread of Lewy pathology and decreased motor deficits and aggregate formation in mice that received an intrastriatal PFF injection.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003ECharles H. Adler, MD, PhD, Mayo Clinic College of Medicine, Scottsdale, Arizona, USA, discussed extranigral pathology and preclinical detection of PD. There are 4 proposed stages of Parkinson\u0027s at-risk syndrome: prephysiologic, preclinical, premotor, and prediagnostic [Siderowf A, Stern MD. \u003Cem\u003EAnn Neurol\u003C\/em\u003E 2008]. The prephysiologic stage is characterized by patients who have a genetic risk to develop PD, but no symptoms have yet developed; however, mutations or triplication of the synuclein gene and mutations of the leucine-rich repeat kinase 2 gene. In the preclinical phase, there are still no clinical signs of PD, but patients may be positive for biomarkers. While still being investigated, examples may include imaging studies such as transcranial ultrasound, \u003Csup\u003E123\u003C\/sup\u003EI-MIBG scintigraphy, radioligand tracers of presynaptic dopamine function, and magnetic resonance imaging\u2013diffusion tensor imaging.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EPatients begin to develop nonmotor signs or symptoms of PD in the premotor phase. Researchers of a longitudinal clinicopathologic study [AZSAND; Adler C et al. \u003Cem\u003ENeurology\u003C\/em\u003E 2014] evaluated annual movement, neuropsychology, sleep, autonomic function, as well as performance on the University of Pennsylvania Smell Test (UPSIT) every third year, following subjects until death and autopsy.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EFocusing on preclinical detection of PD, Dr. Adler next reviewed incidental Lewy body disease (iLBD), which is characterized by the presence of Lewy bodies without parkinsonism or dementia. The prevalence of iLBD increases with age, as \u226412% of individuals aged \u0026gt;60 years and \u226430% of autopsied elderly patients have iLBD. Dr. Adler suggested that these patients with iLBD may actually have preclinical PD or dementia with Lewy bodies (DLB). Patients with iLBD have a lower level of tyrosine hydroxylase (TH) compared with healthy controls (p=0.01) [Beach TG et al. \u003Cem\u003EActa Neuropathol\u003C\/em\u003E 2008]. In addition, striatal and epicardial levels of TH are between those of healthy controls and patients with PD (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Dickson DW et al. \u003Cem\u003EActa Neurophathol\u003C\/em\u003E 2008].\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/15\/25\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Tyrosine Hydroxylase Levels in the Striatum and Epicardium in iLBD\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-625882873\u0022 data-figure-caption=\u0022Tyrosine Hydroxylase Levels in the Striatum and Epicardium in iLBD\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/15\/25\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/15\/25\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/15\/25\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14562\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003ETyrosine Hydroxylase Levels in the Striatum and Epicardium in iLBD\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EiLBD=incidental Lewy body disease; PD=Parkinson\u0027s disease; TH=tyrosine hydroxylase.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced from Dickson DW et al. Evidence that incidental Lewy body disease is presymptomatic Parkinson\u0027s disease. \u003Cem\u003EActa Neuropathol\u003C\/em\u003E 2008;115:437\u2013444. With permission from Springer Verlag.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EIn a case-control study, patients with iLBD also had significantly lower UPSIT and Trails B scores compared with patients without iLBD (p\u22640.001) [Adler CH et al. \u003Cem\u003EMov Disord\u003C\/em\u003E 2010]. Last, patients with iLBD score lower in the 12-odor Cross-Cultural Smell Identification Test compared with controls [Ross GW et al. \u003Cem\u003EMov Disord\u003C\/em\u003E 2006].\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EHyposmia is well documented in patients with PD but is not specific for it. In the Parkinson At-Risk Study, \u223c5000 patients without PD performed UPSIT, and 13.4% were found to be hyposmic [Siderowf A et al. \u003Cem\u003EMov Disord\u003C\/em\u003E 2012]. In addition, constipation, depression, anxiety, and rapid eye movement (REM) sleep behavior disorder (RBD) were associated with hyposmia. Data of the conversion rate to PD are expected in the future. RBD is present in the majority of patients with PD, and the majority of patients with idiopathic RBD develop PD or DLB. In addition, pathologic data suggest that RBD is a synucleinopathy. Reduced olfactory function and color vision in patients with RDB is associated with neurodegeneration [Iranzo A et al. \u003Cem\u003EParkinsonism Relat Disord\u003C\/em\u003E 2013; Postuma RB et al. \u003Cem\u003EAnn Neurol\u003C\/em\u003E 2011]. In addition, in a longitudinal study, 20 of 78 patients with RBD developed parkinsonism with motor findings preceding the diagnosis of parkinsonism by \u22645 years [Postuma RB et al. \u003Cem\u003EBrain\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EAlthough it has low specificity, constipation is a highly sensitive indicator of PD [Postuma RB et al. \u003Cem\u003EMov Disord\u003C\/em\u003E 2012], as men with \u0026lt;1 bowel movement a day had a \u22654-fold risk of developing PD compared with men who had \u22652 bowel movements a day [Abbott RD et al. \u003Cem\u003ENeurology\u003C\/em\u003E 2001]. In addition, 24% of men with iLBD had \u0026lt;1 bowel movement a day, compared with 6.5% of men with \u0026gt;1 bowel movement a day [Abbott RD et al. \u003Cem\u003EMov Disord\u003C\/em\u003E 2007]. Lewy bodies have been found in the myenteric plexus of the esophagus and colon, and accumulation of \u03b1-synuclein in the bowel of patients with PD and preclinical PD has been reported [Beach et al. \u003Cem\u003EActa Neuropathol\u003C\/em\u003E 2010; Hilton D et al. \u003Cem\u003EActa Neuropathol\u003C\/em\u003E 2014; Shannon KM et al. \u003Cem\u003EMov Disord\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EIn conclusion, PD is a progressive disorder that begins before the onset of symptoms. As reviewed, misfolded \u03b1-synuclein, a hallmark of PD, can be transmitted from cell to cell and cause aggregation of \u03b1-synuclein and tau protein in healthy neurons. Mutations in the synuclein, leucine-rich repeat kinase 2, Parkinson protein 2, PTEN-induced putative kinase 1, and glucosidase beta acid genes, among others, can result in the development of PD. Ideally, as preclinical pathology and symptoms are clarified, this can open up avenues for optimizing early diagnosis and treatment.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/15\/25.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzp4jq\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzp4jq\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}