Papers by Caroline H Williams-Gray
The role of high-field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward
Movement disorders : official journal of the Movement Disorder Society, Jan 28, 2017
Historically, magnetic resonance imaging (MRI) has contributed little to the study of Parkinson&#... more Historically, magnetic resonance imaging (MRI) has contributed little to the study of Parkinson's disease (PD), but modern MRI approaches have unveiled several complementary markers that are useful for research and clinical applications. Iron- and neuromelanin-sensitive MRI detect qualitative changes in the substantia nigra. Quantitative MRI markers can be derived from diffusion weighted and iron-sensitive imaging or volumetry. Functional brain alterations at rest or during task performance have been captured with functional and arterial spin labeling perfusion MRI. These markers are useful for the diagnosis of PD and atypical parkinsonism, to track disease progression from the premotor stages of these diseases and to better understand the neurobiological basis of clinical deficits. A current research goal using MRI is to generate time-dependent models of the evolution of PD biomarkers that can help understand neurodegeneration and provide reliable markers for therapeutic trials...
Parkinson's disease
Medicine, 2016
A new biomarker for Parkinson's disease?
Movement Disorders, 2015
Stability of mild cognitive impairment in newly diagnosed Parkinson's disease
Journal of neurology, neurosurgery, and psychiatry, 2017
Mild cognitive impairment (MCI) is common in early Parkinson's disease (PD). We evaluated the... more Mild cognitive impairment (MCI) is common in early Parkinson's disease (PD). We evaluated the stability of PD-MCI over time to determine its clinical utility as a marker of disease. 212 newly diagnosed participants with PD were recruited into a longitudinal study and reassessed after 18 and 36 months. Participants completed a range of clinical and neuropsychological assessments. PD-MCI was classified using Movement Disorders Society Task Force level I (Montreal Cognitive Assessment <26) and level II (using cut-offs of 1, 1.5 and 2SD) criteria. After 36 months, 75% of participants returned; 8% of patients had developed a dementia all of which were previously PD-MCI. Applying level I criteria, 70% were cognitively stable, 19% cognitively declined and 11% improved over 36 months. Applying level II criteria (1, 1.5 and 2SD), 25% were cognitively stable, 41% cognitively declined, 15% improved and 19% fluctuated over 36 months. 18% of participants reverted to normal cognition from ...
Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts
The Lancet. Neurology, Jan 16, 2017
Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disea... more Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generate...
α-Synuclein pre-formed fibrils impair tight junction protein expression without affecting cerebral endothelial cell function
Experimental neurology, 2016
Recently it has been shown that there is impaired cerebral endothelial function in many chronic n... more Recently it has been shown that there is impaired cerebral endothelial function in many chronic neurodegenerative disorders including Alzheimer's and Huntington's disease. Such problems have also been reported in Parkinson's disease, in which α-synuclein aggregation is the pathological hallmark. However, little is known about the relationship between misfolded α-synuclein and endothelial function. In the present study, we therefore examined whether α-synuclein preformed fibrils affect endothelial function in vitro. Using a well-established endothelial cell model, we found that the expression of tight junction proteins, in particular zona occludens-1 and occludin, was significantly perturbed in the presence of fibril-seeded neurotoxicity. Disrupted expression of these proteins was also found in the postmortem brains of patients dying with Parkinson's disease. There was though little evidence in vitro of functional impairments in endothelial cell function in terms of t...
Neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's
Annals of neurology, Jan 22, 2016
We hypothesized that mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher... more We hypothesized that mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes will be associated with aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, while mutations associated with non-neuropathic GD will confer intermediate progression rates. 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HR) for global cognitive impairment of 3.17 (95% CI, 1.60 - 6.25) and a hastened decline in Mini Mental State Exam scores compared to non-carriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had HR of 3.22...
Dementia & Neuropsychologia, 2008
Neurobehavioural and psychiatric symptoms are common in a range of neurodegenerative disorders wi... more Neurobehavioural and psychiatric symptoms are common in a range of neurodegenerative disorders with distinct profiles which are helpful in the diagnosis and monitoring of these disorders. The Cambridge Behavioural Inventory (CBI) has been shown to distinguish frontotemporal dementia (FTD), Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD), but it is lengthy. Objective: To develop a shorter version of the 81 item CBI. Methods: CBI data from 450 participants with behavioural variant frontotemporal dementia (bv-FTD) (64), AD (96), PD (215) and HD (75) were analysed using Principal Components Analysis and measures of internal consistency (Cronbach alpha). Results: A reduced 45-item questionnaire was developed. The instrument identified distinct behavioural profiles and performed as well as the original version. Conclusions: A shorter (45 item) version of the CBI is capable of differentiating bv-FTD and AD from PD and HD. It may be useful in delineating the type and extent of problems in these disorders as well as monitoring therapeutic interventions. O Inventário Comportamental de Cambridge revisado Resumo -Sintomas psiquiátricos e de comportamento são comuns em várias doenças neurodegenerativas, com perfis distintos que são úteis no diagnóstico e no acompanhamento destas doenças. O Inventário Comportamental de Cambridge (CBI) tem mostrado como distinguir entre demência frontotemporal (DFT), doença de Alzheimer (DA), doença de Huntington (DH) e doença de Parkinson (DP), mas é um instrumento longo. Objetivo: Desenvolver uma versão curta do CBI de 81 itens. Métodos: Dados de 450 participantes com a variante comportamental (VC) da DFT (64), DA (96), DP (215) e DH (75) foram analisados usando análise de componentes principais (PCA) e medidas de consistência interna (Cronbach alpha). Resultados: Uma versão reduzida de 45 itens do questionário foi desenvolvida. O instrumento identificou perfis distintos de comportamento e seu desempenho foi tão bom quanto a versão original. Conclusões: Uma versão curta (45 itens) do CBI é capaz de diferenciar VC-DFT e DA de DP e DH, e pode ser útil em identificar o tipo e extensão de problemas nestas doenças e também no monitoramento de intervenções terapêuticas. Palavras-chave: Inventário Comportamental de Cambridge, sintomas neuropsiquiátricos, diagnóstico diferencial de demência, demência frontotemporal, doença de Alzheimer, doença de Huntington, doença de Parkinson.
Cognitive decline and quality of life in incident Parkinson's disease: The role of attention
Parkinsonism & Related Disorders, 2016
Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease demen... more Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease dementia (PDD) is associated with poorer quality of life (QoL). Prior to the onset of PDD, many patients experience progressive cognitive impairment. There is a paucity of longitudinal studies investigating the effects of cognitive decline on QoL. This study aimed to determine the longitudinal impact of cognitive change on QoL in an incident PD cohort. Recently diagnosed patients with PD (n = 212) completed a schedule of neuropsychological assessments and QoL measures; these were repeated after 18 (n = 190) and 36 months (n = 158). Mild cognitive impairment (PD-MCI) was classified with reference to the Movement Disorder Society criteria. Principal component analysis was used to reduce 10 neuropsychological tests to three cognitive factors: attention, memory/executive function, and global cognition. Baseline PD-MCI was a significant contributor to QoL (β = 0.2, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). For those subjects (9%) who developed dementia, cognitive function had a much greater impact on QoL (β = 10.3, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Multivariate modelling showed attentional deficits had the strongest predictive power (β = -2.3, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01); brief global tests only modestly predicted decline in QoL (β = -0.4, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). PD-MCI was associated with poorer QoL over three years follow up. Cognitive impairment had a greater impact on QoL in individuals who developed dementia over follow-up. Impaired attention was a significant determinant of QoL in PD. Interventions which improve concentration and attention in those with PD could potentially improve QoL.
Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data
The Lancet. Neurology, Jan 23, 2016
Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 d... more Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with…
Comparative epidemiology of incident Parkinson's disease in Cambridgeshire, UK
Journal of neurology, neurosurgery, and psychiatry, Jan 22, 2016
The spectrum of clinical features seen with alpha synuclein pathology
Neuropathology and Applied Neurobiology, 2016
Precompetitive Data Sharing as a Catalyst to Address Unmet Needs in Parkinson's Disease1
Journal of Parkinson's disease, Jan 14, 2015
Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifyin... more Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contr...
The pathophysiological and prognostic heterogeneity of mild cognitive impairment in Parkinson’s disease
Cognitive Impairment and Dementia in Parkinson's Disease, 2015
Movement disorders : official journal of the Movement Disorder Society, 2006
The genetics of behavior and cognition in Parkinson’s disease
Diagnosis and Management, 2013
Mild cognitive impairment and Parkinson's disease--something to remember
Journal of Parkinson's disease, 2014
Cognitive impairment is common in Parkinson's disease (PD), and many patients will eventually... more Cognitive impairment is common in Parkinson's disease (PD), and many patients will eventually develop a dementia, which has a devastating impact on the patient and their family. As such, there has been much interest in identifying a prodromal state to inform prognosis and facilitate earlier management, similar to the concept of 'MCI' in the Alzheimer's field. However, grouping the early cognitive deficits of PD together as 'PD-MCI' may not be the best way forward as it implies a single aetiological basis with one clinical consequence. In this review, we argue that cognitive deficits in PD arise from a number of different pathological pathways, only some of which herald a dementing process. This has important implications both for treatment of individual patients, and for the design of future disease-modifying therapy trials.
Which patients with Parkinson's disease participate in clinical trials? One centre's experiences with a new cell based therapy trial (TRANSEURO)
Journal of Parkinson's disease, 2014
There is currently little evidence regarding the selection of patients for clinical trials in Par... more There is currently little evidence regarding the selection of patients for clinical trials in Parkinson's Disease (PD), especially those involving experimental therapies delivered using invasive techniques. Understanding which patients are recruited will increase awareness of issues regarding parity of access to clinical trials and have an impact on the wider applicability of results, as well as provoking discussion regarding future improvements in the enrolment process. TRANSEURO is an open label multi-centre surgical transplant trial which seeks to investigate the feasibility and efficacy of grafts of human foetal ventral mesencephalic tissue in patients with PD. The Cambridge based cohort of TRANSEURO participants (n = 26) was compared with a population representative sample of patients with PD eligible for, but not enrolled in, TRANSEURO (n = 33). Measurements were available in both populations for demographics, neuropsychological tests, tests of motor and non-motor function...
The factor structure of the UPDRS as an index of disease progression in Parkinson's disease
Journal of Parkinson's disease, 2011
The optimum method for evaluating disease progression in Parkinson's disease (PD) has not bee... more The optimum method for evaluating disease progression in Parkinson's disease (PD) has not been established, and this has implications for clinical trials. The majority of previous studies have utilized change on the Unified Parkinson's disease Rating Scale (UPDRS) as an index of progression. However, the UPDRS has not been validated for this purpose. We utilized exploratory factor analysis (EFA) to evaluate the longitudinal properties of the UPDRS as an index of disease progression in PD. Data was derived from a representative cohort of 122 PD patients followed from diagnosis and assessed every 18-24 months for up to 7.9 years. For each subject the rate of change of each item on the UPDRS-3 was calculated and an EFA was performed using this data. Results were compared with those of previously published EFAs in cross-sectional PD cohorts. The UPDRS-3 retains a stable factor structure when used as an index of disease evolution. The 27 items reduced to 6 factors which accounted...
Neuropsychological Features of Early Cognitive Impairment in Parkinson’s Disease
Advances in Biological Psychiatry, 2012
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Papers by Caroline H Williams-Gray