Michael Lawton

Michael Lawton
University of Bristol | UB · Population Health Sciences

About

150
Publications
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Introduction

Publications

Publications (150)
Preprint
Full-text available
The neuropathological process in Parkinson’s disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain which play crucial roles in the clinical expression and progression of these disorders. Here, we investigate the role of the macrostr...
Article
Background Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. Objectives To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. Methods We analyzed data from the Parkinson's Progression Markers Initi...
Article
Full-text available
There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a m...
Article
Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson’s disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Pa...
Preprint
Background: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. Objectives: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. Methods: We analyzed data from the Parkinson's Progression Markers Init...
Article
Background Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. Objectives To quantify the presence, severity, impact and associated factors for motor complications in PD. Methods Analysis of three large prospective cohort studies of recent‐onset...
Article
Full-text available
Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time—for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causa...
Article
The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of p...
Article
Background Clinical trials of disease‐modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. Objectives The objective is to select a patient‐centered primary outcome measure for disease‐modification trials over three or more years. Methods Experts in Parkinson's disease (PD), statistics, and...
Preprint
Full-text available
Up to 80% of Parkinsons disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinsons disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Park...
Article
Background: Many health systems are interested in increasing the number of uncomplicated and typical dementia diagnoses that are made in primary care, but the comparative accuracy of tests is unknown. Objective: Calculate diagnostic accuracy of brief cognitive tests in primary care. Methods: We did a diagnostic test accuracy study in general p...
Article
Full-text available
The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients...
Article
Full-text available
Background and Objectives The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and e...
Article
Full-text available
Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for...
Poster
Background Depression in individuals with Alzheimer’s disease (AD) is common, distressing, difficult to treat, may increase carer burden and is inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure. We aimed to ident...
Article
Full-text available
Background Treatment burden represents the work patients undertake because of their healthcare, and the impact of that effort on the patient. Most research has focused on older adults (65+) with multiple long-term conditions (MLTC-M) but there are more younger adults (18-65) living with MLTC-M and they may experience treatment burden differently. U...
Preprint
Full-text available
Importance: Forty percent of Parkinson ′s disease patients develop levodopa-induced-dyskinesia (LiD) within 4 years of starting levodopa. The genetic basis of LiD remains poorly understood, and there have been few well powered studies. Objective: To discover common genetic variants in the PD population that increase the probability of developing Li...
Preprint
Full-text available
Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time - for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying cau...
Article
Full-text available
The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore r...
Article
Full-text available
Background Depression in individuals with Alzheimer’s disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure. Objective We aimed to characterize depression...
Article
Full-text available
Background: Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly. Objective: To quantify dopamine transp...
Article
Full-text available
Biomarkers to aid diagnosis and delineate progression of Parkinson’s Disease are vital for targeting treatment in the early phases of disease. Here, we aim to discover a multi-protein panel representative of Parkinson’s and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. We used...
Article
Full-text available
Background There is large individual variation in both clinical presentation and progression between Parkinson’s disease patients. Generation of deeply and longitudinally phenotyped patient cohorts has enormous potential to identify disease subtypes for prognosis and therapeutic targeting. Methods Replicating across three large Parkinson’s cohorts...
Article
Full-text available
Parkinson’s disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson’s disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson’s disease patients, and the ge...
Article
Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the ge...
Preprint
Full-text available
Importance: There is a pressing need to understand the biology of Parkinson's disease (PD) progression and to identify biological pathways as possible therapeutic targets. Objective: To identify genomic variation associated with PD motor presentation and early stage progression. Design: GWAS meta-analysis of early PD motor progression, from multipl...
Article
Background: We recently showed that by employing an enhanced drug-delivery approach, repeated administration of glial cell line-derived neurotrophic factor (GDNF) can produce a spatially distributed increased 18 F-DOPA positron emission tomography (PET) uptake, suggesting sprouting of dopaminergic terminals throughout the putamen structure. Despit...
Article
We read with interest Uyar and colleagues' recent report on the association between diabetes, nondiabetic elevated gly-cated hemoglobin levels (HbA1c), and neuroaxonal damage in Parkinson's disease (PD) patients from the MARK-PD study. 1 The authors confirmed previously established findings of an inverse association between diabetes and cognitive a...
Preprint
Full-text available
Background There are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. Methods We studied 6,766 PD patients, over 15,340 visits with a mean follow-up o...
Article
Full-text available
OBJECTIVES Explore whether socioeconomic differences of patients affect the prioritisation of pre-existing research questions and explore the agreement between healthcare professionals (HCP) and patients in priority setting partnerships (PSPs). DESIGN AND SETTING Prospective, three centre survey across UK (400 participants), Tuebingen (176 partici...
Article
Full-text available
Objectives: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. Methods: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and le...
Article
Full-text available
Background: Type 2 diabetes (T2DM) is an established risk factor for developing Parkinson's disease (PD), but its effect on disease progression is not well understood. Objective: The aim of this study was to investigate the influence of T2DM on aspects of disease progression in PD. Methods: We analyzed data from the Tracking Parkinson's study...
Article
Background Hyposmia is an early feature in neurodegenerative diseases, most notably Parkinson’s Disease (PD). Using abbreviated smell tests could provide a cost-effective means for large-scale hyposmia screening. It is unclear whether short smell tests can effectively detect hyposmia in patient populations. Objectives To test the ability of short...
Preprint
Full-text available
Parkinson's disease (PD) is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of PD, particularly in the later stages of the disease. However, the rate of cognitive decline varies widely among PD patients, and the genetic basis for this h...
Article
Full-text available
Background: Patients with Parkinson's disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers. Objective:...
Preprint
Full-text available
Patient’s with Parkinson’s disease (PD) with coexistent type 2 diabetes (T2DM) can manifest with more severe motor and cognitive phenotypes. The precise reasons for this remain unclear though underlying pathophysiological differences are increasingly implicated. More severe neuroaxonal injury in PD patients with T2DM was recently proposed as a pote...
Article
Full-text available
Background: An unmet need remains for sensitive outcome measures in neuroprotective trials. The study aims to determine whether a composite clinical motor score, combining the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III motor examination score, Purdue Pegboard Test, and Timed Up and Go, provides greater sens...
Preprint
Full-text available
Biomarkers to aid diagnosis and delineate progression of Parkinsons Disease (PD) are vital for targeting treatment in the early phases of disease. Here, we aim to discover a multi-protein panel representative of PD and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. We used apta...
Article
Full-text available
Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson’s disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients...
Article
Background Alzheimer’s Disease and Parkinson’s Disease (PD) share similarities in phenotype and an overlap between disease subtypes and diagnostic testing which implies a link between some of the neurodegenerative processes. Here, we report the initial results for proteomic assays on two longitudinal PD cohorts demonstrating dementia‐like protein d...
Preprint
Full-text available
Background Patients with Parkinson disease (PD) have variable disease progression. More accurate prediction of progression could improve clinical trial design. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be improved by blood biomarkers. Objective To determine if serum n...
Preprint
Importance: Type 2 diabetes (T2DM) is an established risk factor for developing Parkinson's disease (PD) but its effect on disease progression is not well understood. Objective: To examine the effects of co-morbid T2DM on Parkinson's disease progression and quality of life. Design: We analysed data from the Tracking Parkinson's study, a large multi...
Article
Introduction Associations between measures of socio-economic position and cortisol remain controversial. We examined the association between social class and cortisol reactivity in an aging male population. Methods The Speedwell cohort study recruited 2,348 men aged 45-59 years from primary care between 1979-1982 (phase I) where occupational socia...
Article
Background: Parkinson's disease (PD) comorbid with rapid eye movement sleep behavior disorder (RBD) may show more severe motor and nonmotor symptoms, suggesting a distinct PD subtype. Objective: The aim of this study was to investigate the impact of RBD on the longitudinal change of motor and nonmotor symptoms in patients with PD. Methods: Pat...
Preprint
Full-text available
In their recent letter entitled “Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in parkinson’s disease”, Liu and colleagues report that in a genome-wide analysis of progression to dementia in parkinson’s disease (PD) the RIMS2 locus is a determinant of dementia in PD (1). In this study we...
Article
Full-text available
Objectives Hyposmia is a common feature of Parkinson's disease (PD), yet there is no standard method to define it. A comparison of four published methods was performed to explore and highlight differences. Materials and methods Olfactory testing was performed in 2097 cases of early PD in two prospective studies. Olfaction was assessed using variou...
Article
Full-text available
Objective Cognitive-driven activity of daily living (ADL) impairment in Parkinson’s disease (PD) is increasingly discussed as prodromal marker for dementia. Diagnostic properties of assessments for this specific ADL impairment are sparsely investigated in PD. The ability of the Functional Activities Questionnaire (FAQ) for differentiating between P...
Article
Full-text available
Background In Parkinson’s disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their...
Article
Objective: We sought to identify an abbreviated test of impaired olfaction, amenable for use in busy clinical environments in prodromal (isolated REM sleep Behavior Disorder (iRBD)) and manifest Parkinson's disease (PD). Methods: 890 PD and 313 control participants in the Discovery cohort study underwent Sniffin' stick odour identification asses...
Article
Full-text available
Background There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case–control genome‐wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression. Methods We analyzed...
Conference Paper
Parkinson's disease (PD) is a neurodegenerative disorder with marked variation in motor and non-motor baseline phenotype and subsequent progression. Biomarkers can help stratify patients in clinical trials. Diabetes has been described as a risk factor for PD; glucose dysregulation facilitating glycation, aggregation, and subsequent -synuclein toxic...
Article
Full-text available
Purpose The Oxford Parkinson’s Disease Centre (OPDC) Discovery Cohort MRI substudy (OPDC-MRI) collects high-quality multimodal brain MRI together with deep longitudinal clinical phenotyping in patients with Parkinson’s, at-risk individuals and healthy elderly participants. The primary aim is to detect pathological changes in brain structure and fun...
Preprint
Full-text available
Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies (GWASs) have identified variants associated with disease risk, but not progression. Objective: To identify genetic variants associated with PD progression in GWASs. Methods: We analysed three larg...
Article
Full-text available
Background Hyposmia is an early feature in neurodegenerative diseases, most notably Parkinson's disease (PD). Using abbreviated smell tests could provide a cost‐effective means for large‐scale hyposmia screening. It is unclear whether short smell tests can effectively detect hyposmia in patient populations. Objectives To test the ability of short...
Article
Full-text available
Background: Predicting prognosis in Parkinson's disease (PD) has important implications for individual prognostication and clinical trials design and targeting novel treatments. Blood biomarkers could help in this endeavor. Methods: We identified 4 blood biomarkers that might predict prognosis: apolipoprotein A1, C-reactive protein, uric acid an...
Preprint
Full-text available
Purpose: The Oxford Parkinson's Disease Centre (OPDC) Discovery Cohort magnetic resonance imaging (MRI) sub-study (OPDC-MRI) collects high quality multimodal brain MRI together with deep longitudinal clinical phenotyping in patients with Parkinson's, at-risk individuals and healthy elderly participants. The primary aim is to detect pathological cha...
Article
Full-text available
Objective: We recently demonstrated that 998 features derived from a simple 7-minute smartphone test could distinguish between controls, people with Parkinson's and people with idiopathic Rapid Eye Movement sleep behavior disorder, with mean sensitivity/specificity values of 84.6-91.9%. Here, we investigate whether the same smartphone features can...
Article
Full-text available
Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Asses...
Article
Full-text available
Objective: To describe the prevalence, natural history, and risk factors for impulse control behaviors (ICBs) among people with Parkinson disease (PD), those with REM sleep behavior disorder (RBD), and controls. Methods: Participants with early PD (within 3.5 years of diagnosis), those with RBD, and controls were clinically phenotyped and screen...
Article
Full-text available
Objective: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. Methods: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete...
Preprint
Full-text available
The generation of deeply phenotyped patient cohorts offers an enormous potential to identify disease subtypes with prognostic and therapeutic utility. Here, we quantify diverse Parkinson's disease patient phenotypes on continuous scales by identifying the underlying axes of phenotypic variation using a Bayesian multiple phenotype mixed model that i...
Article
Background L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined. Methods Patients were assessed before and after their usual morning L-dopa dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited resp...
Presentation
Background L-dopa responsiveness is embodied in diagnostic criteria for PD, but the extent of variation is not well defined. Objective To quantify L-dopa responsiveness in early PD, and explore the relationship with motor complications. Methods An examination of data from the Parkinson’s Progression Markers Initiative (PPMI), using MDS UPDRS scor...
Article
Full-text available
Background Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (E...
Article
Full-text available
Objective: We sought to identify motor features that would allow the delineation of individuals with sleep study-confirmed idiopathic REM sleep behavior disorder (iRBD) from controls and Parkinson disease (PD) using a customized smartphone application. Methods: A total of 334 PD, 104 iRBD, and 84 control participants performed 7 tasks to evaluat...
Article
Full-text available
Objectives To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson’s disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. Methods 1601 and 944 patients with idiopathic PD, from Tracking Parkinson’s and Discovery cohorts, respectively, were evaluated in motor...
Article
Full-text available
Introduction: The causes of pain in early/moderate Parkinson's disease (PD) are not well understood. Although peripheral factors such as rigidity, reduced joint movements and poor posture may contribute towards the development of pain, central mechanisms including altered nociceptive processing may also be involved. Methods: We performed a large...
Article
Objectives: To examine the influence of GBA mutation carrier state on age at onset of PD, the motor phenotype and cognitive function at baseline assessment in a large cohort of United Kingdom patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. Methods: We prospectively r...