Journal of Parkinson's Disease - Volume 7, issue 3

Article Type: Obituary

DOI: 10.3233/JPD-179010

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 409-410, 2017

Authors: O’Regan, Grace | deSouza, Ruth-Mary | Balestrino, Roberta | Schapira, Anthony H.

Article Type: Review Article

Abstract: Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it …is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD. Show more

Keywords: Parkinson disease, glucocerebrocidase, lysosome, alpha synuclein, ambroxol, autophagy

DOI: 10.3233/JPD-171092

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 411-422, 2017

Authors: Heinzel, Sebastian | Lerche, Stefanie | Maetzler, Walter | Berg, Daniela

Article Type: Review Article

Abstract: Background: Parkinson’s disease (PD) is characterized by heterogeneity and multifactorial longitudinal changes. To identify PD subtypes and factors influencing the disease course, multiple cohort studies have been designed globally. Knowledge about existing cohorts is pivotal to foster collaboration, which may help to advance the understanding of PD. Objective: To raise the awareness about PD cohorts and potential global collaboration opportunities. Methods: Observational cohort studies in clinical PD were identified by a European working group (JPND BioLoC-PD) and through literature search. Using a structured survey investigators of 44 cohorts provided basic information on cohorts and assessments performed. …Results: For the 44 cohorts (32% on early/de-novo PD), 14.666 participants (cohorts’ median: 138; range: 23–3.090), a median 1.5-year follow-up interval (0.5–4 years) and a median (planned) observational period of 5 years (1–20 years) were indicated. All studies have assessed motor functions often using rating scales (UPDRS-III; 93% of studies) and less frequently quantitative gait/balance (25%) or fine motor assessments (27%). Cognitive (100%), neuropsychiatric (91%), daily living (78%), sleep (70%), sensory (63%), and gastrointestinal/autonomic (55%) assessments were common and often comparable. Neuroimaging data (82%) and biomaterial (69%) have been collected in many studies. Surprisingly, possible disease modifiers, such as sport/physical activity (11%), have rarely been assessed. Conclusions: Existing data of PD cohorts provide vast collaboration opportunities. We propose to establish a comprehensive, up-to-date, open-access internet platform with easy-to-use search tools of PD cohort descriptions and potentially available data. Bringing researchers together to enable collaborative joint, meta- and replication analyses is timely and necessary to advance PD research ultimately required for an understanding of PD that can be translated into more effective therapies. Show more

Keywords: Parkinson Disease, cohort studies, symptom assessment, biomarkers, information dissemination, social networking, biomedical research

DOI: 10.3233/JPD-171100

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 423-432, 2017

Authors: Galvagnion, Céline

Article Type: Review Article

Abstract: α-synuclein is a small protein abundantly expressed in the brain and mainly located in synaptic terminals. The conversion of α-synuclein into oligomers and fibrils is the hallmark of a range of neurodegenerative disorders including Parkinson’s disease and dementia with Lewy bodies. α-synuclein is disordered in solution but can adopt an α-helical conformation upon binding to lipid membranes. This lipid-protein interaction plays an important role in its proposed biological function, i.e., synaptic plasticity, but can also entail the aggregation of the protein. Both the chemical properties of the lipids and the lipid-to-protein-ratio have been reported to modulate the aggregation propensity of …α-synuclein. In this review, the influence of changes in the nature and levels of lipids on the aggregation propensity of α-synuclein in vivo and in vitro will be discussed within a common general framework. In particular, while biophysical measurements and kinetic analyses of the time courses of α-synuclein aggregation in the presence of different types of lipid vesicles allow a mechanistic dissection of the influence of the lipids on α-synuclein aggregation, biological studies of cellular and animal models of Parkinson’s disease allow the determination of changes in lipid levels and properties associated with the disease. Show more

Keywords: α-synuclein, amyloid, cholesterol, fatty acids, glucocerebrosidase, kinetic analysis, lipids, Parkinson’s disease, sphingolipid

DOI: 10.3233/JPD-171103

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 433-450, 2017

Authors: Athauda, Dilan | Wyse, Richard | Brundin, Patrik | Foltynie, Thomas

Article Type: Article Commentary

Abstract: There is growing interest in the use of glucagon-like peptide-1 agonists as treatments for Parkinson’s disease following the recent publication of the results of the Exenatide-PD trial. In this randomized, double-blind, placebo controlled trial, patients with moderate stage Parkinson’s disease treated with once-weekly subcutaneous injections of exenatide 2 mg (Bydureon) for 48 weeks, had a 3.5-point advantage over the placebo group in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (Part 3) in the practically defined OFF medication state, 12 weeks after cessation of the trial drug. In this article, we discuss some of the important issues …of relevance to this trial, with regards to trial design, patient selection, choice of outcome measure and also place into context the implications these results have for patients with Parkinson’s disease and the wider research community. Show more

Keywords: Clinical trial, disease modification, exenatide, glucagon-like peptide-1 agonist, insulin resistance, neuroprotection, Parkinson’s disease

DOI: 10.3233/JPD-171192

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 451-458, 2017

Authors: Vilas, Dolores | Fernández-Santiago, Rubén | Sanchez, Elena | Azcona, Luis J. | Santos-Montes, Meritxell | Casquero, Pilar | Argandoña, Lucía | Tolosa, Eduardo | Paisán-Ruiz, Coro

Article Type: Short Communication

Abstract: Background: Common genetic variability in the ACMSD gene has been associated with increased risk for Parkinson’s disease (PD) but ACMSD mutations in clinical cases of PD have so far not been reported. Objective: To describe a case of sporadic PD carrying a novel ACMSD mutation. Methods: As part of a genetic study to identify potential pathogenic gene defects related to PD in the Mediterranean island Menorca, an initial group of 62 PD patients underwent mutational screening using a panel-based sequencing approach. Results: We report a 74-years-old man with sporadic PD who …developed tremor in his right hand and slowness. On examination, moderate rigidity, asymmetric bradykinesia, and bilateral action tremor were present. He was started on levodopa with significant improvement. Two years later, he developed wearing off phenomena. The genetic study in the patient identified a novel ACMSD mutation resulting in p.Glu298Lys amino-acid change which was not present in neurologically normal population. Conclusions: Our data suggest that not only common genetic variability but also rare variants in ACMSD alone or in combination with other risk factors might increase the risk of PD. Show more

Keywords: ACMSD, Parkinson’s, genetic, kynurenine

DOI: 10.3233/JPD-171146

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 459-463, 2017

Authors: O’Dowd, Seán | Galna, Brook | Morris, Rosie | Lawson, Rachael A. | McDonald, Claire | Yarnall, Alison J. | Burn, David J. | Rochester, Lynn | Anderson, Kirstie N.

Article Type: Short Communication

Abstract: Abnormal sleep may associate with cognitive decline in Parkinson’s disease (PD). Furthermore, sleep dysfunction may associate with worse motor outcome. We hypothesised that PD patients with poor quality sleep would have greater progression in gait dysfunction, due to structural and functional overlap in networks subserving sleep and gait regulation. 12 PD patients and 12 age-matched controls completed longitudinal follow-up over 36 months. Poor sleep efficiency and greater sleep fragmentation correlated significantly with progression of step-width variability, a gait characteristic mediated by postural control, providing evidence that poor sleep in PD is associated with a more rapid deterioration in gait.

Keywords: Gait, pedunculopontine nucleus, Parkinson’s disease, postural control, sleep quality

DOI: 10.3233/JPD-161062

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 465-470, 2017

Authors: Knudsen, Karoline | Haase, Anne-Mette | Fedorova, Tatyana D. | Bekker, Anne Charlotte | Østergaard, Karen | Krogh, Klaus | Borghammer, Per

Article Type: Research Article

Abstract: Background: Symptoms from the gastrointestinal tract are highly prevalent in Parkinson’s disease (PD), but knowledge of the underlying pathology is incomplete and valid objective markers on regional gastrointestinal function are limited. Objective: The aims were to evaluate gastrointestinal transit time and motility in PD patients and controls. Methods: Twenty-two PD patients and 15 controls were included. Gastric-, small intestinal-, and caecum-ascending colonic transit times as well as colonic motility, defined as mass- and fast movements, were performed using the ambulatory 3D-Transit system. Gastrointestinal transit time with radio opaque markers, gastric emptying scintigraphy, and subjective non-motor symptoms …were also evaluated. Results: Using the 3D-Transit system, the patient group displayed significantly longer small intestinal- and caecum-ascending transit times (p  = 0.030 and p  = 0.0063). No between-group difference was seen in gastric transit time (p  = 0.91). Time to first mass- and fast colonic movement were significantly increased in PD (p  = 0.023 and p  = 0.006). Radio opaque marker gastrointestinal transit time was significantly increased in the patient group (p  < 0.0001), whereas no difference was seen in scintigraphic gastric emptying time (p  = 0.68). Prevalence of constipation symptoms on the NMSQuest was 41% in PD and 7% in controls. Conclusions: Significantly increased small intestinal- and caecum-ascending 3D-Transit times were detected in PD patients. Also, time to first propagating colonic movement was increased. Radio opaque marker gastrointestinal transit time was significantly delayed, but no difference was seen in gastric transit time and gastric emptying time. The present findings highlight widespread intestinal involvement in PD increasing throughout the gastrointestinal tract. Show more

Keywords: Constipation, gastrointestinal, non-motor symptom, Parkinson’s disease, transit time

DOI: 10.3233/JPD-171131

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 471-479, 2017

Authors: Skorvanek, Matej | Ladomirjakova, Zuzana | Han, Vladimir | Lesko, Norbert | Feketeova, Eva | Jarcuskova, Dominika | Repkova, Barbora | Spisak, Peter | Urbancikova, Zuzana | Vargova, Adriana | Gombosova, Laura | Zakuciova, Maria | Veseliny, Eduard | Trebuna, Frantisek | Mechirova, Eva | Gdovinova, Zuzana

Article Type: Research Article

Abstract: Background: Gastrointestinal symptoms are a well-recognized and common premotor feature of Parkinson’s disease (PD). Moreover, multiple studies have assessed the value of colonic α-synuclein as a potential marker of prodromal PD. Recently, the International Parkinson and Movement Disorders Society (MDS) defined research criteria for prodromal PD. Objective: The aim of our study was to test the MDS research criteria in patients undergoing diagnostic colonoscopies as potential candidates for inclusion in prospective trials evaluating colonic biopsies as a potential biomarker of prodromal PD. Methods: We evaluated elderly patients without manifest parkinsonism undergoing diagnostic colonoscopies. During the study …we assessed all risks and prodromal markers of the MDS research criteria, excluding radiotracer imaging and genetic testing. Results: The mean age of the 100 enrolled patients was 61.6±9.7 years; 42 were men. The most common prodromal marker in our cohort was constipation (40%), followed by MDS-UPDRS part III scores of >6 points, excluding action tremor items (39%) and hyposmia (37%). Substantia nigra hyperechogenicity was identified in 9%, and polysomnography confirmed REM sleep behavior disorder in 2% of the patients. Five of the 100 enrolled patients (5%) fulfilled the criteria for probable prodromal PD, while another 3 patients met the 50% probability threshold. Conclusions: Our findings suggest, that the prevalence of prodromal PD in patients undergoing diagnostic colonoscopies may be higher compared to the general elderly population, although this should be confirmed in further studies including also matched controls not undergoing colonoscopy. The real prevalence of prodromal PD in this cohort will have to be confirmed in longitudinal follow-up. Patients undergoing diagnostic colonoscopies may be good candidates for multistep screening and inclusion in prospective trials. Show more

Keywords: Parkinson’s disease, prodromal, screening, risk factors, colonoscopy

DOI: 10.3233/JPD-161036

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 481-489, 2017

Authors: Fabbri, Margherita | Reimão, Sofia | Carvalho, Miguel | Nunes, Rita G. | Abreu, Daisy | Guedes, Leonor Correia | Bouça, Raquel | Lobo, Patricia P. | Godinho, Catarina | Coelho, Miguel | Gonçalves, Nilza C. | Rosa, Mario Miguel | Antonini, Angelo | Ferreira, Joaquim J.

Article Type: Research Article

Abstract: Background: A specific T1-weighted magnetic resonance imaging (MRI) sequence has been shown to detect substantia nigra (SN) neuromelanin (NM) signal changes that accurately discriminate Parkinson’s disease (PD) patients from controls, even in early disease stages. However, it is unclear what happens to these SN changes in later disease stages and if they can be a marker of disease progression. Objective: to investigate the pattern of SN-NM area loss and contrast ratio (CR) intensity changes in late-stage PD (LSPD) compared to earlier disease stages. Methods: A comparative cross-sectional study was performed, analyzing SN-NM MRI signal in LSPD …(Schwab and England Activities of Daily Living Scale score <50 or Hoehn Yahr Stage [HY] >3), comparing this group with de novo , 2–5 year PD and controls. SN-NM signal area and CR values for the internal and lateral SN regions were obtained with semi-automated methods. Results: 13 LSPD, 12 de novo patients with PD, 10 PD patients with a 2–5 year disease duration, and 10 controls were included. NM signal area was significantly decreased in LSPD compared to de novo PD (P-value  = 0.005; sensitivity: 75%; specificity 92% and AUC: 0.86). In the lateral SN region, a decrease in the CR was detected in all PD groups compared to controls; despite not reaching statistical significance, a slight increment was observed comparing LSPD to 2–5 year PD. NM signal area significantly correlated with HY (R = –0.37; P  < 0.05) and Movement disorder Society Unified Parkinson’s Disease Rating Scale part II (MDS-UPDRS) (R = –0.4; P  < 0.05) while a weak correlation was found with MDS-UPDRS part III (R = –0.26; P : 0.1). Conclusion: SN area evaluated by NM-sensitive MRI may be a promising biomarker of nigral degeneration and disease progression in PD patients. Show more

Keywords: Neuromelanin, Parkinson’s disease, late-stage, disease progression, biomarker

DOI: 10.3233/JPD-171135

Citation: Journal of Parkinson's Disease, vol. 7, no. 3, pp. 491-501, 2017