Majority Of Parkinson's Disease Patients Research Articles

Parkinson's Disease is Predominantly aGenetic Disease.

The discovery of a pathogenic variant in the alpha-synuclein (SNCA) gene in the Contursi kindred in 1997 indisputably confirmed a genetic cause in a subset of Parkinson's disease (PD) patients. Currently, pathogenic variants in one of the seven established PD genes or the strongest known risk factor gene, GBA1, are identified in ∼15% of PD patients unselected for age at onset and family history. In this Debate article, we highlight multiple avenues of research that suggest an important - and in some cases even predominant - role for genetics in PD aetiology, including familial clustering, high rates of monogenic PD in selected populations, and complete penetrance with certain forms. At first sight, the steep increase in PD prevalence exceeding that of other neurodegenerative diseases may argue against a predominant genetic etiology. Notably, the principal genetic contribution in PD is conferred by pathogenic variants in LRRK2 and GBA1 and, in both cases, characterized by an overall late age of onset and age-related penetrance. In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.

Computerized analysis of hypomimia and hypokinetic dysarthria for improved diagnosis of Parkinson's disease

Background and ObjectiveAn aging society requires easy-to-use approaches for diagnosis and monitoring of neurodegenerative disorders, such as Parkinson's disease (PD), so that clinicians can effectively adjust a treatment policy and improve patients' quality of life. Current methods of PD diagnosis and monitoring usually require the patients to come to a hospital, where they undergo several neurological and neuropsychological examinations. These examinations are usually time-consuming, expensive, and performed just a few times per year. Hence, this study explores the possibility of fusing computerized analysis of hypomimia and hypokinetic dysarthria (two motor symptoms manifested in the majority of PD patients) with the goal of proposing a new methodology of PD diagnosis that could be easily integrated into mHealth systems. MethodsWe enrolled 73 PD patients and 46 age- and gender-matched healthy controls, who performed several speech/voice tasks while recorded by a microphone and a camera. Acoustic signals were parametrized in the fields of phonation, articulation and prosody. Video recordings of a face were analyzed in terms of facial landmarks movement. Both modalities were consequently modeled by the XGBoost algorithm. ResultsThe acoustic analysis enabled diagnosis of PD with 77% balanced accuracy, while in the case of the facial analysis, we observed 81% balanced accuracy. The fusion of both modalities increased the balanced accuracy to 83% (88% sensitivity and 78% specificity). The most informative speech exercise in the multimodality system turned out to be a tongue twister. Additionally, we identified muscle movements that are characteristic of hypomimia. ConclusionsThe introduced methodology, which is based on the myriad of speech exercises likewise audio and video modality, allows for the detection of PD with an accuracy of up to 83%. The speech exercise - tongue twisters occurred to be the most valuable from the clinical point of view. Additionally, the clinical interpretation of the created models is illustrated. The presented computer-supported methodology could serve as an extra tool for neurologists in PD detection and the proposed potential solution of mHealth will facilitate the patient's and doctor's life.

A story of the potential effect of non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease: beneficial or detrimental effects.

Parkinson's disease (PD) is an advanced neurodegenerative disease (NDD) caused by the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). As PD is an age-related disorder, the majority of PD patients are associated with musculoskeletal disorders with prolonged use of analgesic and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, NSAIDs can affect PD neuropathology in different ways. Thus, the objective of the present narrative review was to clarify the potential role of NSAIDs in PD according to the assorted view of preponderance. Inhibition of neuroinflammation and modulation of immune response by NSAIDs could be an effective way in preventing the development of NDD. NSAIDs affect PD neuropathology in different manners could be beneficial or detrimental effects. Inhibition of cyclooxygenase 2 (COX2) by NSAIDs may prevent the development of PD. NSAIDs afforded a neuroprotective role against the development and progression of PD neuropathology throughthe modulation of neuroinflammation. Though, NSAIDs may lead to neutral or harmful effects by inhibiting neuroprotective prostacyclin (PGI2) and accentuation of pro-inflammatory leukotrienes (LTs). In conclusion, there is still a potential conflict regarding the effect of NSAIDs on PD neuropathology.

Genetic variants of TAS2R38 bitter taste receptor associate with distinct gut microbiota traits in Parkinson's disease: A pilot study

The non-tasting form of the bitter taste receptor, TAS2R38, has been shown as a genetic risk factor associated with the development of Parkinson's disease (PD). Specific taste receptors that are expressed in the lower gastrointestinal tract may respond to alteration in gut microbiota composition, detecting bacterial molecules, and regulate immune responses. Given the importance of brain-gut-microbiota axis and gene-environment interactions in PD, we investigate the associations between the genetic variants of TAS2R38 and gut microbiota composition in 39 PD patients. The results confirm that the majority of PD patients have reduced sensitivity to 6-n-propylthiouracil (PROP) and are carriers of at least one non-functional TAS2R38 AVI haplotype. Moreover, we found this correlation to be associated with a reduction in bacteria alpha-diversity with a predominant reduction of Clostridium genus. We hypothesised that the high frequency of the non-taster form of TAS2R38 associated with a diminuition of Clostridium bacteria in PD might determine a reduction in the activation of protective signalling-molecules useful in preserving gut homeostasis. This pilot study, by identifying a decrease in specific bacteria associated with a reduced sensitivity to PROP, adds essential information that opens new avenues of research into the association of PD microbiota composition and sensory modification.

L-DOPA-Induced Dyskinesia in a Genetic Drosophila Model of Parkinson's Disease.

Motor symptoms in Parkinson’s disease (PD) are directly related to the reduction of a neurotransmitter dopamine. Therefore, its precursor L-DOPA became the gold standard for PD treatment. However, chronic use of L-DOPA causes uncontrollable, involuntary movements, called L-DOPA-induced dyskinesia (LID) in the majority of PD patients. LID is complicated and very difficult to manage. Current rodent and non-human primate models have been developed to study LID mainly using neurotoxins. Therefore, it is necessary to develop a LID animal model with defects in genetic factors causing PD in order to study the relation between LID and PD genes such as α-synuclein. In this study, we first showed that a low concentration of L-DOPA (100 µM) rescues locomotion defects (i.e., speed, angular velocity, pause time) in Drosophila larvae expressing human mutant α-synuclein (A53T). This A53T larval model of PD was used to further examine dyskinetic behaviors. High concentrations of L-DOPA (5 or 10 mM) causes hyperactivity such as body bending behavior (BBB) in A53T larva, which resembles axial dyskinesia in rodents. Using ImageJ plugins and other third party software, dyskinetic BBB has been accurately and efficiently quantified. Further, we showed that a dopamine agonist pramipexole (PRX) partially rescues BBB caused by high L-DOPA. Our Drosophila genetic LID model will provide an important experimental platform to examine molecular and cellular mechanisms underlying LID, to study the role of PD causing genes in the development of LID, and to identify potential targets to slow/reverse LID pathology.

Neuropsychiatric symptoms and cognitive abilities over the initial quinquennium of Parkinson disease.

ObjectiveTo determine the evolution of numerous neuropsychiatric symptoms and cognitive abilities in Parkinson disease from disease onset.MethodsProspectively collected, longitudinal (untreated, disease onset to year 5), observational data from Parkinson's Progression Markers Initiative annual visits was used to evaluate prevalence, correlates, and treatment of 10 neuropsychiatric symptoms and cognitive impairment in Parkinson disease participants and matched healthy controls.ResultsOf 423 Parkinson disease participants evaluated at baseline, 315 (74.5%) were assessed at year 5. Eight neuropsychiatric symptoms studied increased in absolute prevalence by 6.2–20.9% at year 5 relative to baseline, and cognitive impairment increased by 2.7–6.2%. In comparison, the frequency of neuropsychiatric symptoms in healthy controls remained stable or declined over time. Antidepressant and anxiolytic/hypnotic use in Parkinson disease were common at baseline and increased over time (18% to 27% for the former; 13% to 24% for the latter); antipsychotic and cognitive‐enhancing medication use was uncommon throughout (2% and 5% of patients at year 5); and potentially harmful anticholinergic medication use was common and increased over time. At year 5 the cross‐sectional prevalence for having three or more neuropsychiatric disorders/cognitive impairment was 56% for Parkinson disease participants versus 13% for healthy controls, and by then seven of the examined disorders had either occurred or been treated at some time point in the majority of Parkinson disease patients. Principal component analysis suggested an affective disorder subtype only.InterpretationNeuropsychiatric features in Parkinson disease are common from the onset, increase over time, are frequently comorbid, and fluctuate in severity.

Research advances on L-DOPA-induced dyskinesia: from animal models to human disease.

L-3,4-dihydroxyphenylalanine (L-DOPA) was introduced about half a century ago and is still the most effective medicine for the treatment of Parkinson's disease (PD). However, such chronic treatment eventually leads to L-DOPA-induced dyskinesia (LID) on the majority of PD patients. Besides L-DOPA, dopamine agonists are able to induce dyskinesia as well. So far no drug is yet claimed to effectively curb LID, and amantadine has only a modest benefit on LID patients. Thus, understanding the molecular mechanisms behind LID is urgently needed, and developing new antiparkinsonian medications with low dyskinesia potential is necessarily required. In the last decades, several animal models have been generated for these aims. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned monkey models always considered as gold standard of PD studies are also applied well for the research of LID. Additionally, several rodent models were developed for such clinical needs. Of them, 6-hydroxydopamine (OHDA)-lesioned rats or mice exhibiting countable abnormal involuntary movements (AIMs) after L-DOPA treatments have becoming widely applicable tools for LID pathogenesis studies. Under investigating these models for years, multiple potential LID-associated genes and pathways have been innovatively identified, which largely advance the therapeutic and preventative strategies for the disease. In this review, we attempt to update the recent findings represented in LID animal models and trial studies, which may facilitate the mechanistic understanding, drug development, and clinical evaluation of this movement disorder.

Depression symptomatology correlates with event-related potentials in Parkinson's disease: An affective priming study

BackgroundDepression is a predominant non-motor symptom of Parkinson's disease (PD), which is often under recognised and undertreated. To improve identification of depression in PD it is imperative to examine objective brain-related markers. The present study addresses this gap by using electroencephalography (EEG) to evaluate the processing of emotionally valanced words in PD. MethodsFifty non-demented PD patients, unmedicated for depression or anxiety, completed an affective priming task while EEG was simultaneously recorded. Prime and target word pairs of negative or neutral valence were presented at a short 250 ms stimulus onset asynchrony. Participants were asked to evaluate the valence of the target word by button press. Depression was measured using an established rating scale. Repeated measures analysis of covariance and correlational analyses were performed to examine whether event-related potentials (ERP) varied as a function of depression scores. ResultsKey ERP findings reveal reduced responses in parietal midline P300, N400 and Late Positive Potential (LPP) difference waves between congruent and incongruent neutral targets in patients with higher depression scores. LimitationsComparisons of ERPs were limited by insufficient classification of participants with and without clinical depression. A majority of PD patients who had high depression scores were excluded from the analysis as they were receiving antidepressant and/or anxiolytic medications which could interfere with ERP sensitivity. ConclusionsThe present study suggests that the Pz-P300, N400 and LPP are ERP markers relates to emotional dysfunction in PD. These findings thus advance current knowledge regarding the neurophysiological markers of a common neuropsychiatric deficit in PD.

Long-term PEG-J Tube for Treatment Delivery in Patients With Advanced Parkinsonʼs Disease

Introduction: Duodopa® is a modern treatment for advanced stages of Parkinson's disease (PD) administrated via PEG-J by means of a tube connected to an external pump. Duodopa® is delivered continuously in small quanta preventing large plasma level fluctuations and thus suppressing disabling motor complications related to oral treatment in advanced stages of PD. Methods: We retrospectively analyzed records from 51 PD patients (23 males; mean age 66 (SD) 8 years) treated in the Movement Disorders Center in Prague with Duodopa® PEG-J. Time on PEG-J, weight, Duodopa® dose and adverse effects were analyzed. Results: The mean time on PEG-J was 3.7 (IQR 0.6 - 3.2) years. Adverse effects occurred in 36 (71%) patients commonly manifested by inflammation around the PEG-J stoma (17 pts). Other common side effects were technical problems with the pump (13 pts), excessive tissue granulation (7 pts) or tube dislocation (6 pts). The overall mortality was 24%, with no relationship to PEG-J complications. Out of the surviving patients, treatment was stopped in 11 (23%) due to lack of efficacy and in 4 (8%) due to intolerable side effects related to the PEG-J. In addition, there was an interaction between the change of the Duodopa® dose, change in body weight and PEG-J duration (p=0.023) (Figure 1).FigureConclusion: Despite the relatively high frequency of side effects during Duodopa® treatment, the PEG-J was well tolerated in the majority of PD patients during a relatively long follow-up. Surprisingly, the Duodopa daily consumption co-varied with body weight in different ways according to various durations of the treatment.

The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements

Although l-DOPA alleviates the motor symptoms of Parkinson's disease (PD), it elicits troublesome l-DOPA-induced dyskinesia (LID) in a majority of PD patients after prolonged treatment. This is likely due to conversion of l-DOPA to dopamine as a ‘false neurotransmitter’ from serotoninergic neurons. The highly selective and efficacious 5-HT1A receptor agonist, NLX-112 (befiradol or F13640) shows potent activity in a rat model of LID (suppression of Abnormal Involuntary Movements, AIMs) but its anti-AIMs effects have not previously been investigated following repeated administration.Acute administration of NLX-112 (0.04 and 0.16 mg/kg i.p.) reversed l-DOPA (6 mg/kg)-induced AIMs in hemiparkinsonian rats with established dyskinesia. The activity of NLX-112 was maintained following repeated daily i.p. administration over 14 days and was accompanied by pronounced decrease of striatal 5-HT extracellular levels, as measured by in vivo microdialysis, indicative of the inhibition of serotonergic activity. A concurrent blunting of l-DOPA-induced surge in dopamine levels on the lesioned side of the brain was observed upon NLX-112 administration and these neurochemical responses were also seen after 14 days of treatment.NLX-112 also suppressed the expression of AIMs in rats that were being primed for dyskinesia by repeated l-DOPA administration. However, when treatment of these rats with NLX-112 was stopped, l-DOPA then induced AIMs with scores that resembled those of control rats.The present study shows that the potent anti-AIMs activity of NLX-112 is maintained upon repeated administration and supports the ongoing clinical development of NLX-112 as a novel antidyskinetic agent for PD patients receiving l-DOPA treatment.

Neurological applications for myocardial MIBG scintigraphy

Signs or symptoms of impaired autonomic regulation of circulation are typically present in patients affected by Parkinson's disease (PD), in agreement with the cardiac sympathetic denervation discovered by Goldstein more than 15 yrs. ago. In particular, the majority of PD patients have a diffuse left ventricular myocardial sympathetic denervation, being a normal neurological condition present only in a small number of affected subjects. Actually MIBG cardiac imaging is a universally accepted method to estimate cardiac sympathetic innervations. This review covers the role of MIBG cardiac imaging in PD as well as in other parkinsonisms, focusing the attention on technical problems and pathophysiological premises for cardiac denervation. In particular new emerging data support the role of MIBG as biomarker of PD, also before motor symptoms became clinically evident. Therefore the timing of cardiac noradrenergic denervation in PD is a key issue and we want to update the analysis of autonomic cardiovascular abnormalities studied with MIBG in PD and related disorders.

Identifying prodromal Parkinson's disease: Pre‐Motor disorders in Parkinson's disease

Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.

Stem Cell Therapy for Parkinson’s Disease: A Road Map for a Successful Future

Cell transplant therapy for Parkinson's disease (PD) has been in use for over 2 decades as an experimental treatment. Different cell types have been proposed as better therapeutic alternatives. However, source availability and therapeutic value of the transplants as compared to current pharmacological options have precluded the use of this kind of surgery in the majority of PD patients. In this article, we discuss the suitability of different types of stem cells for PD therapy, the requirements that the donor cells should fulfill in order to improve upon current methods, and propose alternatives for evaluating the efficacy of PD cell therapy.

Alpha‐synuclein and Parkinson's disease: Implications from the screening of more than 1,900 patients

Data on the frequency of alpha-synuclein mutations in Parkinson's disease (PD) are limited. Screening the entire coding region in 1,921 PD patients with denaturing high performance liquid chromatography and subsequent sequencing we only detected silent mutations (g.2654A>G, g.10151G>A, and g.15986A>T) and the c.209G>A substitution corresponding to the p.A53T mutation. These results demonstrate that mutations in the alpha-synuclein gene are rare and suggest that other factors contribute to alpha-synuclein aggregation in the majority of PD patients.

Short-Term Memory in Parkinsonʼs Disease After Withdrawal of Long-Term Anticholinergic Therapy

We assessed the short-term memory (STM) using the Visual Paired Associates and the Verbal Paired Associates test, and the motor status at the end of 7.8 +/- 3.7 years of anticholinergic therapy in 22 nondemented patients with Parkinson's disease (PD). Eighteen patients managed to stop anticholinergic therapy. During anticholinergic therapy, STM in PD is significantly worse than in normal controls (CS). Two months after the withdrawal of anticholinergic drugs, the STM retest gain is significantly greater in PD than in CS, and at that time STM in PD did equal CS levels. After withdrawal of anticholinergic therapy, thirteen patients noticed a deterioration of motor function; the dose of levodopa had to be increased in seven patients. We conclude that in nondemented PD patients, long-term anticholinergic therapy probably does not result in irreversible damage to STM, and withdrawal of long-term anticholinergic therapy is feasible in the majority of PD patients.