Journal of Parkinson's Disease - Volume 5, issue 4

Authors: Mahlknecht, Philipp | Seppi, Klaus | Poewe, Werner

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific pathology prior to appearance of these classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to identify and validate markers …for the preclinical and prodromal stages of the illness. Currently, several nonmotor symptoms have been associated with an increased risk to develop PD in otherwise healthy individuals and ongoing research is aimed at validating a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. In fact, the recently defined MDS research criteria for prodromal PD have included combinations of risk and prodromal markers allowing to define target populations of future disease modification trials. Show more

Keywords: Parkinson’s disease (PD), biomarker, early diagnosis, premotor PD, nonmotor symptoms (NMS), neuroimaging, genetic and molecular biomarkers

DOI: 10.3233/JPD-150685

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 681-697, 2015

Authors: Burré, Jacqueline

Article Type: Review Article

Abstract: α-Synuclein is an abundant neuronal protein which localizes predominantly to presynaptic terminals, and is strongly linked genetically and pathologically to Parkinson’s disease and other neurodegenerative diseases. While the accumulation of α-synuclein in the form of misfolded oligomers and large aggregates defines multiple neurodegenerative diseases called “synucleinopathies”, its cellular function has remained largely unclear, and is the subject of intense investigation. In this review, I focus on the structural characteristics of α-synuclein, its cellular and subcellular localization, and discuss how this relates to its function in neurons, in particular at the neuronal synapse.

Keywords: α-synuclein, synapse, membranes, SNARE, neurotransmitter release, synaptic vesicles

DOI: 10.3233/JPD-150642

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 699-713, 2015

Authors: Armstrong, R.A.

Article Type: Review Article

Abstract: This review describes the oculo-visual problems likely to be encountered in Parkinson’s disease (PD) with special reference to three questions: (1) are there visual symptoms characteristic of the prodromal phase of PD, (2) is PD dementia associated with specific visual changes, and (3) can visual symptoms help in the differential diagnosis of the parkinsonian syndromes, viz. PD, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD)? Oculo-visual dysfunction in PD can involve visual acuity, dynamic contrast sensitivity, colour discrimination, pupil reactivity, eye movement, motion perception, and visual processing speeds. In addition, disturbance …of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations may be present. Prodromal features of PD may include autonomic system dysfunction potentially affecting pupil reactivity, abnormal colour vision, abnormal stereopsis associated with postural instability, defects in smooth pursuit eye movements, and deficits in visuo-motor adaptation, especially when accompanied by idiopathic rapid eye movement (REM) sleep behaviour disorder. PD dementia is associated with the exacerbation of many oculo-visual problems but those involving eye movements, visuo-spatial function, and visual hallucinations are most characteristic. Useful diagnostic features in differentiating the parkinsonian symptoms are the presence of visual hallucinations, visuo-spatial problems, and variation in saccadic eye movement dysfunction. Show more

Keywords: Parkinson’s disease (PD), oculo-visual dysfunction, prodromal phase, PD dementia, Parkinsonian syndromes, differential diagnosis

DOI: 10.3233/JPD-150686

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 715-726, 2015

Authors: Zach, Heidemarie | Gerrits, Wieneke L.J. | van de Warrenburg, Bart P. | Bloem, Bastiaan R.

Article Type: Letter

DOI: 10.3233/JPD-150638

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 727-729, 2015

Authors: Simon, David K. | Simuni, Tanya | Elm, Jordan | Clark-Matott, Joanne | Graebner, Allison K. | Baker, Liana | Dunlop, Susan R. | Emborg, Marina | Kamp, Cornelia | Morgan, John C. | Ross, G. Webster | Sharma, Saloni | Ravina, Bernard | On behalf of the NINDS NET-PD Investigators

Article Type: Short Communication

Abstract: Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson’s disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in …PD. Show more

Keywords: PGC-1alpha, oxidative stress, inflammation, Parkinson’s disease, biomarker, pioglitazone, 8-hydroxydeoxyguano sine, 8OHdG, IL-6, interleukin-6, cytokine

DOI: 10.3233/JPD-150666

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 731-736, 2015

Authors: Fauser, Mareike | Löhle, Matthias | Ebersbach, Georg | Odin, Per | Fuchs, Gerd | Jost, Wolfgang H. | Chaudhuri, K. Ray | Koch, Rainer | NoMoFlu-PD study group | Storch, Alexander

Article Type: Short Communication

Abstract: Nonmotor symptoms (NMS) fluctuate in conjunction with motor oscillations in advanced Parkinson’s disease (PD), though little is known about the variability of NMS fluctuations in individual patients. We aimed to assess within-patient variability in frequency and severity of NMS during a series of five patient-perceived motor On and Off periods in 38 fluctuating PD patients from the multicenter NonMotorFluctuations in PD study using a visual analogue scale. NMS frequency and severity appeared moderately variable in both motor states within individual patients. Symptom severity ranges between motor states showed high variability and were larger in motor Off states for most NMS.

Keywords: Nonmotor symptoms, nonmotor fluctuations, intraindividual variability, Parkinson’s disease, NMS domains

DOI: 10.3233/JPD-150656

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 737-741, 2015

Authors: Yarnall, Alison J. | Lawson, Rachael A. | Duncan, Gordon W. | Breen, David P. | Khoo, Tien K. | Brooks, David | Barker, Roger A. | Taylor, John-Paul | Burn, David J.

Article Type: Short Communication

Abstract: We evaluated the effect of anticholinergic burden on 219 participants with incident Parkinson’s disease (PD) and 99 controls at study baseline and 18 months. Anticholinergic burden for each individual was calculated and summed according to the Anticholinergic Drug Scale (ADS). Medication with anticholinergic activity was more commonly prescribed in PD compared to controls, although mean ADS scores were not significantly different. Cognitive scores did not differ in PD participants taking medications with anticholinergic activity compared to those who were not. Low overall ADS scores due to increased awareness of adverse effects of medications and brevity of follow-up are potential explanations.

Keywords: Parkinson disease, dementia, mild cognitive impairment, anticholinergics, amyloid

DOI: 10.3233/JPD-150664

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 743-747, 2015

Authors: Kelm-Nelson, Cynthia A. | Yang, Katie M. | Ciucci, Michelle R.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a complex neurodegenerative disease with vocal communication deficits that manifest early, progress, and are largely resistant to medical interventions; however, they do respond to exercise-based speech and voice therapies. Objective and Methods: To study how exercise-based vocal treatment can affect the progression of communication deficits related to PD, we studied ultrasonic vocalizations (USVs) in rats with homozygous knockout (-/-) of PINK1 , a gene mutation known to cause PD, under the manipulation of a behavioral vocal exercise paradigm that allows us to precisely control dose and timing of exercise in the prodromal (prior …to diagnosis) stages. Results: We show that intensive vocal-training rescues frequency range and intensity deficits as well as leads to an increase in call complexity and duration of calls compared to sham-training; however, over time this training regime loses significant effect as the disease progresses. We also show effects of frequent handling and conspecific (male-female) interaction in the sham-training group as they demonstrated significantly higher call rate, intensity, frequency range, and call complexity compared to rats without any form of training and consequently less handling/interaction. Further, we confirm that this model exhibits progressive gross motor deficits that indicate neurodegeneration. Discussion: This study suggests that the evolving nature of vocal communication deficits requires an adjustment of therapy targets and more intensive training over the course of this progressive disease and demonstrates the importance of frequent social experiences. Show more

Keywords: Parkinson’s disease, PINK1, ultrasonic vocalization, cranial sensorimotor, exercise, rat, communication

DOI: 10.3233/JPD-150688

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 749-763, 2015

Authors: Preterre, Cécile | Corbillé, Anne-Gaëlle | Balloy, Gaëlle | Letournel, Franck | Neunlist, Michel | Derkinderen, Pascal

Article Type: Research Article

Abstract: Background: Alpha-synuclein containing inclusions in neurons, the characteristic pathological lesions of Parkinson’s disease (PD), are not limited to the central nervous system, but also affect the enteric nervous system (ENS). This suggests that the ENS offer some potential as a surrogate of central nervous system pathology and that it may represent an original source of biomarkers for PD. However, the usefulness of α -synuclein detection in gastrointestinal biopsies as a biomarker for PD is still unclear, as the different immunohistochemical methods employed to date have led to conflicting results. Objective: Our aim is to propose an optimized immunoblotting …method for the detection of endogenous α -synuclein in the healthy ENS that may be used to supplement the immunohistochemical analysis. Methods: Primary culture of rat ENS and homogenates of human small intestine were analyzed by Western Blot using seven different α -synuclein and phospho-α -synuclein antibodies along with two methods that increase α -synuclein retention on blot membranes, namely incubation of the membranes with paraformaldehyde (PFA) or treatment of samples with the crosslinker dithiobis[succinimidylpropionate] (DSP). Results: A moderate improvement in the detection of endogenous enteric α -synuclein was observed following membrane fixation with PFA for only two of the seven antibodies we tested. Immunodetection of total and phosphorylated α -synuclein in the ENS was markedly improved when samples were treated with DSP, regardless of the antibody used. Conclusions: Our results demonstrate that the detection of α -synuclein in the gut by Western Blot can be optimized by using methods for enhanced membrane retention of the protein along with the appropriate antibody. Such an optimized protocol opens the way to the development of novel biomarkers for PD that will enable a quantification of α -synuclein in gastrointestinal biopsies. Show more

Keywords: Alpha-synuclein, enteric nervous system, Western Blot, Parkinson’s disease

DOI: 10.3233/JPD-150670

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 765-772, 2015

Authors: Bega, Danny | Kim, Soeun | Zhang, Yunxi | Elm, Jordan | Schneider, Jay | Hauser, Robert | Fraser, Andy | Simuni, Tanya | on behalf of the NET-PD LS1 Investigators

Article Type: Research Article

Abstract: Background: Data on predictors of decline in PD are largely based on de-novo populations and limited to the use of motor outcomes that fail to capture the full scope of disease. Objective: Determine the clinical predictors of decline in early treated PD using a novel multi-domain measure. Methods: Data from NINDS Exploratory Trials in PD Long-Term Study 1 (NET-PD LS1), a multicenter Phase 3 study of creatine in early treated PD, were analyzed. Functional decline was defined by a global outcome metric (GO) that consisted of: Schwab and England ADL scale, PD 39-item Questionnaire, Unified PD …Rating Scale, Ambulatory Capacity Score, Symbol Digit Modalities Test, and Modified Rankin Scale. Univariate and multivariate models were used to test the association of predictors of interest with a standardized rank-sum of the GO. Results: 765 of 1741 participants completed five-year assessments and were included. Older age at disease onset (p  <  0.0001), higher baseline levodopa equivalent dose (p  = 0.01), and worse Scales for Outcomes of Parkinson’s Disease Cognition score (p  = 0.001) at baseline were the strongest predictors of functional decline in multivariate analysis. PD symptom subtype was not a significant predictor of outcome (p  = 0.42). The full model was only a modest predictor of change in GO (R2  = 0.186). Conclusions: This is the largest study to systematically assess predictors of functional decline in early treated PD over several years, and the first to use a multi-domain outcome measure of decline. Older age at disease onset and worse cognition, and not PD subtype, were predictors of decline. Show more

Keywords: Parkinson’s disease, NET-PD

DOI: 10.3233/JPD-150668

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 773-782, 2015