Exome-wide association study of levodopa-induced dyskinesia in Parkinson’s disease

AbstractLevodopa is the standard long-term dopamine replacement therapy to treat Parkinson’s disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.

Download Full-text

Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽

10.3390/genes12030430 ◽

2021 ◽

Vol 12 (3) ◽

pp. 430

Author(s):

Steven R. Bentley ◽

Ilaria Guella ◽

Holly E. Sherman ◽

Hannah M. Neuendorf ◽

Alex M. Sykes ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Rare Variants ◽

Strong Family History ◽

Disease Mutations ◽

Whole Exome ◽

History Of ◽

Functional Consequences ◽

Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

Download Full-text

Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00455-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Alessandro Gialluisi ◽

Mafalda Giovanna Reccia ◽

Nicola Modugno ◽

Teresa Nutile ◽

Alessia Lombardi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Candidate Genes ◽

Rare Variants ◽

Late Onset ◽

High Specificity ◽

Diagnostic Tools ◽

Multi Stage ◽

Whole Exome ◽

Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

Download Full-text

Social listening – revealing Parkinson’s disease over day and night

BMC Neurology ◽

10.1186/s12883-020-02024-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hui Zhang ◽

Fanwen Meng ◽

Xingyu Li ◽

Yali Ning ◽

Meng Cai

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Unmet Needs ◽

Unmet Need ◽

Motor Symptoms ◽

Motor Complications ◽

Sentiment Score ◽

Negative Sentiment ◽

Non Motor Symptoms ◽

Social Listening

Abstract Background Nocturnal symptoms in Parkinson’s disease are often treated after management of daytime manifestations. In order to better understand the unmet needs of nocturnal symptoms management, we analyzed the characteristics and burden of nocturnal symptoms from patients’ perspectives and explored their changes over time. Overall symptoms (occurring at day or night) were collected to compare whether the unmet needs related to nocturnal symptoms and to overall symptoms are different. Methods We used a Social Listening big-data technique to analyze large amounts of Parkinson’s disease symptoms in dialogues available from social media platforms in 2016 to 2018. These symptoms were classified as either overall symptoms or nocturnal symptoms. We used share of voice (SOV) of symptoms as a proportion of total dialogues per year to reflect the characteristics of symptoms. Negative sentiment score of symptoms was analyzed to find out their related burden. Results We found the SOV for overall motor symptoms was 79% and had not increased between 2016 and 2018 (79%, p = 0.5). The SOV for non-motor symptoms was 69% and had grown by 7% in 2018 (p < 0.01). The SOV for motor complications was 9% and had increased by 6% in 2018 (p < 0.01). The SOV of motor symptoms was larger than non-motor symptoms and motor complications (p < 0.01). The SOV of non-motor symptoms was larger than motor complications (p < 0.01). For nocturnal symptoms, 45% of the analyzed PD population reported nocturnal symptoms in 2018, growing by 6% (p < 0.01). The SOV for nocturnal-occurring motor symptoms was higher than most non-motor symptoms. However, non-motor symptoms had the higher increases and evoked higher negative sentiment regardless of whether they occurred during the day or night. For symptoms that can occur at either day or night, each nocturnal symptom was rated with a higher negative sentiment score than the same symptom during the day. Conclusions The growing SOV and the greater negative sentiment of nocturnal symptoms suggest management of nocturnal symptoms is an unmet need of patients. A greater emphasis on detecting and treating nocturnal symptoms with 24-h care is encouraged.

Download Full-text

Consistency and Stability of Motor Subtype Classifications in Patients With de novo Parkinson’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.637896 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jingru Ren ◽

Chenxi Pan ◽

Yuqian Li ◽

Lanting Li ◽

Ping Hua ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Classification Systems ◽

Motor Symptoms ◽

Chi Squared ◽

Baseline Evaluation ◽

The Stability ◽

First Time ◽

Non Motor Symptoms

ObjectivePatients with Parkinson’s disease (PD) are commonly classified into subtypes based on motor symptoms. The aims of the present study were to determine the consistency between PD motor subtypes, to assess the stability of PD motor subtypes over time, and to explore the variables influencing PD motor subtype stability.MethodsThis study was part of a longitudinal study of de novo PD patients at a single center. Based on three different motor subtype classification systems proposed by Jankovic, Schiess, and Kang, patients were respectively categorized as tremor-dominant/indeterminate/postural instability and gait difficulty (TD/indeterminate/PIGD), TDS/mixedS/akinetic-rigidS (ARS), or TDK/mixedK/ARK at baseline evaluation and then re-assessed 1 month later. Demographic and clinical characteristics were recorded at each evaluation. The consistency between subtypes at baseline evaluation was assessed using Cohen’s kappa coefficient (κ). Additional variables were compared between PD subtype groups using the two-sample t-test, Mann–Whitney U-test or Chi-squared test.ResultsOf 283 newly diagnosed, untreated PD patients, 79 were followed up at 1 month. There was fair agreement between the Jankovic, Schiess, and Kang classification systems (κS = 0.383 ± 0.044, κK = 0.360 ± 0.042, κSK = 0.368 ± 0.038). Among the three classification systems, the Schiess classification was the most stable and the Jankovic classification was the most unstable. The non-motor symptoms questionnaire (NMSQuest) scores differed significantly between PD patients with stable and unstable subtypes based on the Jankovic classification (p = 0.008), and patients with a consistent subtype had more severe NMSQuest scores than patients with an inconsistent subtype.ConclusionFair consistency was observed between the Jankovic, Schiess, and Kang classification systems. For the first time, non-motor symptoms (NMSs) scores were found to influence the stability of the TD/indeterminate/PIGD classification. Our findings support combining NMSs with motor symptoms to increase the effectiveness of PD subtypes.

Download Full-text

Schizophrenia as Potential Trigger for Melanoma Development and Progression! The Psycho-Neuro-Endocrine-Oncology (P.N.E.O) Network!

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2018.276 ◽

2018 ◽

Vol 6 (8) ◽

pp. 1442-1445

Author(s):

Georgi Tchernev ◽

Ilia Lozev ◽

Ivanka Temelkova ◽

Svetoslav Chernin ◽

Irina Yungareva

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous Tissue ◽

World Literature ◽

Careful Analysis ◽

Potential Trigger ◽

Patient Groups ◽

Neuroectodermal Origin ◽

High Level ◽

First Time

BACKGROUND: Skin, nervous tissue, dopamine and melanoma share a common neuroectodermal origin. Hence, processes that modulate nervous tissue formation, patient mental status, motor regulation of individuals, and skin cancerogenesis are inextricably linked. Psycho-neuro-endocrine oncology (or dermato-oncology), i.e. P.N.E.O., is a new model or trend in medicine and science presented for the first time in the world literature by us, that aims to examine the relationship between the mental state, the hormones and the malignant transformation. Schizophrenia and Parkinson’s disease are the two main patterns of disease where the main symptoms are related to dopamine levels in the human body. According to our analyses of the available literature, the amount of dopamine is related to the incidence of melanocytic or non-melanocytic cutaneous tumours in patients with central nervous system diseases and those affecting the motor function and coordination. Such patterns of interaction are extremely indicative of the elucidation of the ubiquitous hypothesis or statement: “My illness is on a mental basis, caused by stress ...”CASE PRESENTATION: We present a 44-year-old patient with untreated schizophrenia for approximately 25 years, associated with advanced acral localised melanoma. Schizophrenia is generally associated with a higher level of dopamine, which is also a key precursor to melanin synthesis. After a careful analysis of all literature on melanoma in patients with 1) treated and untreated schizophrenia, 2) those with untreated and untreated forms of Parkinson’s disease, it would be logical to conclude that the high level of dopamine in the described patient groups is a risk factor for the development of melanoma.CONCLUSIONS: The possible mechanisms for the occurrence of malignant melanoma within the so-called psycho/neuro/endocrine oncology (P.N.E.O.), as well as the effective methods of prevention, are under discussion.

Download Full-text

Emerging targets for the diagnosis of Parkinson’s disease: examination of systemic biomarkers

Biomarkers in Medicine ◽

10.2217/bmm-2020-0654 ◽

2021 ◽

Author(s):

Lara Cheslow ◽

Adam E Snook ◽

Scott A Waldman

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Unmet Need ◽

Multiple Organ ◽

The Body ◽

Organ Systems ◽

Diagnostic Approaches ◽

New Biomarkers

Parkinson’s disease (PD) is a highly prevalent and irreversible neurodegenerative disorder that is typically diagnosed in an advanced stage. Currently, there are no approved biomarkers that reliably identify PD patients before they have undergone extensive neuronal damage, eliminating the opportunity for future disease-modifying therapies to intervene in disease progression. This unmet need for diagnostic and therapeutic biomarkers has fueled PD research for decades, but these efforts have not yet yielded actionable results. Recently, studies exploring mechanisms underlying PD progression have offered insights into multisystemic contributions to pathology, challenging the classic perspective of PD as a disease isolated to the brain. This shift in understanding has opened the door to potential new biomarkers from multiple sites in the body. This review focuses on emerging candidates for PD biomarkers in the context of current diagnostic approaches and multiple organ systems that contribute to disease.

Download Full-text

Complex Parkinson's disease: review and experiences

British Journal of Neuroscience Nursing ◽

10.12968/bjnn.2019.15.3.140 ◽

2019 ◽

Vol 15 (3) ◽

pp. 140-145

Author(s):

Phil Cotterell ◽

Debbie Weight ◽

Sharon Joseph ◽

Paul Joseph

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Progression ◽

Unmet Need ◽

Motor Fluctuations ◽

Financial Problems ◽

Care Environment ◽

Psychological Issues ◽

Palliative Approach ◽

The Impact

The rate of Parkinson's disease progression is highly individual. It is important to identify those in the complex stage of the disease. Non-oral therapies may be appropriate for those in the complex stage of the disease who experience motor fluctuations, but there can be reasons for a failure to explore these options. Complex Parkinson's disease is a challenging time for the patient, their carer/s and for Parkinson's specialists. Changes to independence can be difficult to deal with, and the disease has an impact both physically and psychologically. For carers, the impact of Parkinson's can also result in physical and psychological issues as well as social and financial problems. Consideration often turns to moving into a care environment, dealing with neuropsychiatric issues and challenging unmet need. Dealing with symptoms and problems using a team and a palliative approach is required.

Download Full-text

Novel ATP13A2 and PINK1 variants identified in Chinese patients with Parkinson’s disease by whole-exome sequencing

Neuroscience Letters ◽

10.1016/j.neulet.2020.135075 ◽

2020 ◽

Vol 733 ◽

pp. 135075 ◽

Cited By ~ 2

Author(s):

Hui Chen ◽

Yu-Hua Jin ◽

Yan-Yan Xue ◽

Yu-Lan Chen ◽

Yi-Jun Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Patients ◽

Whole Exome

Download Full-text

A New Perspective in the Treatment of Parkinson’s Disease Psychosis

US Neurology ◽

10.17925/usn.2016.12.02.93 ◽

2016 ◽

Vol 12 (02) ◽

pp. 93

Author(s):

Rajesh Pahwa ◽

Kelly E Lyons ◽

◽

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuropsychiatric Symptoms ◽

Unmet Need ◽

Controlled Study ◽

Psychotic Symptoms ◽

Dopamine Antagonists ◽

Motor Symptoms ◽

Double Blind ◽

Good Tolerability

Neuropsychiatric symptoms, such as psychosis, are well described in Parkinson’s disease (PD); most appear to be due to disease pathology with exacerbation caused by dopaminergic treatment. More than 50% of patients with PD develop psychosis at some point throughout their disease course. Clinicians need to routinely assess patients with PD for psychotic symptoms, particularly hallucinations. Treatment of psychotic symptoms in PD is an unmet need as there are currently no US Food and Drug Administration (FDA) approved medications specifically for PD psychosis (PDP). Current treatments for PDP have been adapted from dopamine antagonists used to treat psychosis in other conditions, such as schizophrenia. Typical antipsychotics, as well as some atypical antipsychotics, worsen PD motor symptoms due to blockade of dopamine D2 receptors. Quetiapine and clozapine have been studied in PDP and are the most commonly used treatments for PDP. Clozapine has been shown to be effective; however, regular bloodwork is required, while data for quetiapine are inconsistent. Pimavanserin, a highly selective serotonin (5HT2A subtype) receptor inverse agonist, is not associated with motor worsening in PDP patients due to the absence of dopamine blockade. In a double-blind, placebo-controlled study, pimavanserin showed significant improvement in moderate to severe psychosis compared to placebo, with good tolerability and without worsening of PD motor symptoms. These data suggest that pimavanserin is a safe and efficacious treatment for PDP psychosis and could be a potential new treatment option for PDP.

Download Full-text

Mindfulness Training among Individuals with Parkinson’s Disease: Neurobehavioral Effects

Parkinson s Disease ◽

10.1155/2015/816404 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 15

Author(s):

Barbara Pickut ◽

Sven Vanneste ◽

Mark A. Hirsch ◽

Wim Van Hecke ◽

Eric Kerckhofs ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Complementary Medicine ◽

Stress Reduction ◽

Unmet Need ◽

Mindfulness Training ◽

Five Facet Mindfulness Questionnaire ◽

Alternative And Complementary Medicine ◽

Point Increase ◽

Neurobehavioral Effects

Objective. To investigate possible neurobehavioral changes secondary to a mindfulness based intervention (MBI) training for individuals living with Parkinson’s disease (PD).Background. In the context of complementary medicine, MBIs are increasingly being used for stress reduction and in patient populations coping with chronic illness. The use of alternative and complementary medicine may be higher in patients with chronic conditions such as PD. However, behavioral effects of mindfulness training in PD have not yet been reported in the literature and this points to an unmet need and warrants further examination.Methods. A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Questionnaires and the UPDRS I–IV were obtained at baseline and 8-week follow-up.Results. Significant changes after the MBI were found including a 5.5 point decrease on the UPDRS motor score, an increase of 0.79 points on Parkinson’s disease questionnaire (PDQ-39) pain item, and a 3.15 point increase in the Five Facet Mindfulness Questionnaire observe facet.Conclusions. To the best of our knowledge, this is the first quantitative analysis of neurobehavioral effects of MBI in PD.

Download Full-text