Showing papers by "Thomas Foltynie published in 2006"

Cognitive deficits and psychosis in Parkinson's disease: a review of pathophysiology and therapeutic options.

Abstract: Parkinson's disease is a neurodegenerative disorder causing not only motor dysfunction but also cognitive, psychiatric, autonomic and sensory disturbances. Symptoms of dementia and psychosis are common: longitudinal studies suggest that up to 75% of patients with Parkinson's disease may eventually develop dementia, and the prevalence of hallucinations ranges from 16-17% in population-based surveys to 30-40% in hospital-based series. These cognitive and behavioural features are important in terms of prognosis, nursing home placement and mortality. The pattern of cognitive deficits in Parkinson's disease is variable, but often includes executive impairment similar to that seen in patients with frontal lesions, as well as episodic memory impairment, visuospatial dysfunction and impaired verbal fluency. The most common manifestation of psychosis in Parkinson's disease is visual hallucinations, but delusions, paranoid beliefs, agitation and florid psychosis can also occur. An understanding of the pathophysiology underlying these symptoms is essential to the development of targeted therapeutic strategies. Post-mortem studies suggest an association between Lewy body deposition and dementia in Parkinson's disease, and indeed Parkinson's disease and dementia with Lewy bodies may form part of the same disease spectrum. Whether Lewy bodies actually play a causative role in cognitive dysfunction, however, is unknown. Deficits in neurotransmitter systems provide more obvious therapeutic targets and dysfunction of dopaminergic, cholinergic, noradrenergic and serotonergic systems have all been implicated; these may each underlie different features of Parkinson's disease dementia, perhaps explaining some of the heterogeneity of the syndrome. Psychosis has traditionally been considered as a dopaminergic drug-induced phenomenon, but factors intrinsic to the disease process itself also cause hallucinations and delusions. These factors may include Lewy body deposition in the limbic system, cholinergic deficits and impairments of primary visual processing. Therapeutic intervention for cognitive and behavioural symptoms in Parkinson's disease currently focuses on two main groups of drugs: cholinesterase inhibitors and atypical antipsychotics. A recent large, randomised, controlled trial suggests that cholinesterase inhibitors can produce a modest improvement in cognitive function, as well as psychotic symptoms, generally without an adverse effect on motor function. Certain atypical antipsychotics allow hallucinations, delusions and behavioural problems to be brought under control with minimal deleterious effects on motor function and cognition, but their safety in elderly patients has recently been called into question. Deep brain stimulation does not appear to be a useful treatment for cognitive and psychiatric dysfunction in patients with Parkinson's disease. Modafinil improves alertness in Parkinson's disease and warrants further investigation to establish its effects on cognitive performance.

UCHL-1 is not a Parkinson's disease susceptibility gene

Abstract: OBJECTIVE: The UCHL-1 gene is widely cited as a susceptibility factor for sporadic Parkinson's disease (PD). The strongest evidence comes from a meta-analysis of small studies that reported the S18Y polymorphism as protective against PD, after pooling studies of white and Asian subjects. Here, we present data that challenge this association. METHODS: In a new large case-control study in white individuals (3,023 subjects), the S18Y variant was not protective against PD under any genetic model of inheritance. Similarly, a more powerful haplotype-tagging approach did not detect other associated variants. RESULTS: Finally, in an updated S18Y-PD meta-analysis (6,594 subjects), no significant association was observed under additive, recessive, or dominant models (odds ratio = 1.00 [95% confidence interval: 0.74-1.33]; odds ratio = 1.01 [95% confidence interval: 0.76-1.35]; and odds ratio = 0.96 [95% confidence interval: 0.86-1.08], respectively), and a cumulative meta-analysis showed a trend toward a null effect. INTERPRETATION: Based on the current evidence, the UCHL-1 gene does not exhibit a protective effect in PD.

Saccadic latency distributions in Parkinson’s disease and the effects of l -dopa

Abstract: Parkinson's disease (PD) is associated with a loss of central dopaminergic pathways in the brain leading to an abnormality of movement, including saccades. In PD, analysis of saccadic latency distributions, rather than mean latencies, can provide much more information about how the neural decision process that precedes movement is affected by disease or medication. Subject to the constraints of intersubject variation and reproducibility, latency distribution may represent an attractive potential biomarker of PD. Here we report two studies that provide information about these parameters, and demonstrate a novel effect of dopamine on saccadic latency, implying that it influences the neural decision process itself. We performed a detailed cross-sectional study of saccadic latency distributions during a simple step task in 22 medicated patients and 27 age-matched controls. This revealed high intersubject variability and an overlap of PD and control distributions. A second study was undertaken on a different population specifically to investigate the effects of dopamine on saccadic latency distributions in 15 PD patients. L-dopa was found to prolong latency, although the magnitude of the effect varied between subjects. The implications of these observations for the use of saccadic latency distributions as a potential biomarker of PD are discussed, as are the effects of L-dopa on neural decision making, where it is postulated to increase the criterion level of evidence required before the decision to move is made.

No evidence for association with Parkinson disease for 13 single-nucleotide polymorphisms identified by whole-genome association screening.

Abstract: To the Editor: The 13 SNPs identified by Maraganore et al.1 as being potentially associated with Parkinson disease (PD [MIM 168600]) represent some of the first fruit produced by the whole-genome association screening era and are clearly worthy of follow-up. To further explore these exciting candidates, we typed each SNP in 538 patients with idiopathic PD and in 516 control individuals from the United Kingdom. Cases included 160 patients involved in a community-based epidemiological study of incident PD and 378 consecutive patients with prevalent PD attending our research clinic. All cases met United Kingdom Parkinson's Disease Society Brain Bank criteria for the diagnosis of PD. The mean age at disease onset was 63 years (range 25–91 years); 2% of patients had early-onset disease (⩽40 years), and 14% of patients reported a family history of one or more first-degree relatives with parkinsonian symptoms or tremor. The control group consisted of 146 spouses of patients with PD and 370 blood donors. All individuals were white, except for four patients and one spouse. All gave written informed consent and a blood sample from which DNA was extracted using standard methods. Genotyping was performed using Taqman Assay-on-Demand (rs2245218) and Assays-by-Design products on a 7900HT Sequence Detection System (Applied Biosystems). Only samples that typed successfully for at least one-third of markers were included in the analysis (520 cases and 499 controls). Genotyping success rates were all ⩾97%, and no marker showed evidence of deviation from Hardy-Weinberg equilibrium. Two pairs of SNPs (rs2313982 and rs1509269; rs682705 and rs7520966) were found to be in strong linkage disequilibrium (D′=1.0, r2>0.69), which reduced the number of independent tests to 11. Allele frequencies in cases and controls were compared using the COCAPHASE program in the UNPHASED package.2 Our study provides, on average, 85% power (range 68%–96%) to detect the case-control differences averaged over tier 1 and tier 2, as observed by Maraganore et al.1 In our data set, none of the 13 SNPs showed any evidence of association, all P values being >.25, even without correction for multiple testing (tables 1 and ​and2).2). Fewer than half of the SNPs (46%) showed allele frequency differences between cases and controls in the same direction as that reported by Maraganore et al.1 The combination of our data with those from the original report, with the use of the Mantel-Haenszel test statistic (Statsdirect) and correction for the 11 independent tests performed, revealed that only three markers (rs10200894, ss46548856, and rs7702187) retain any evidence of significance at the 5% level in the total data (table 1). In summary, our study suggests that none of the 13 markers identified by Maraganore et al.1 is associated with PD. Table 1 Thirteen SNPs Reported by Maraganore et al.,1 Ranked in Accordance with Evidence for Association in a Meta-Analysis Combined with Data from This Study Table 2 Genotype Counts for 13 SNPs Studied Under the null hypothesis that there are no genes influencing susceptibility to PD, a follow-up of 1.4% (2,734) of the 198,345 markers included in the screening stage, as performed by Maraganore et al.,1 would be expected to identify 27–28 markers showing P<.01 in the replication stage, with half of these—that is, 13–14—showing an allele frequency difference in the same direction as that seen in the screening stage. The number of markers identified by Maraganore et al.1 is, thus, in keeping with that expected under the null hypothesis. However, since such screens are not intended to identify all susceptibility genes and, indeed, would be considered successful if they identified even a single such locus, we would not expect to see a striking excess of markers above the predicted 13. In short, it could be anticipated that most of the 13 markers identified by Maraganore et al.1 would be false positives. However, our failure to replicate results for any of the 13 markers identified by Maraganore et al.1 suggests that their screen lacked power in one or more critical dimensions. Although typing 200,000 markers in 450 cases and controls is a substantial effort, it is clear that this will adequately interrogate only a part of the common variation in the genome. Increasing the density of markers and the number of samples studied would be the most effective way to increase the power of the study but, in practice, would be the most difficult. It must remain possible that a more generous threshold (such as P<.1) would have captured relevant loci currently lying high in the ranking of markers provided by the screening stage performed by Maraganore et al.1 but falling outside their stringent threshold. On the downside, this approach would greatly increase the number of markers requiring follow-up, generating a list of nearly 1,000 instead of just 13 potentially associated loci. Various strategies for multistage whole-genome association studies have been proposed,3–6 and the importance of setting an appropriate threshold for following up first-stage results has been stressed. We feel that the present observations, regarding one of the first whole-genome association screens performed, strengthen the importance of these theoretical recommendations. To ensure that replication and follow-up phases are not overwhelmingly large, it is essential to ensure high power in the screening phase. If thresholds as stringent as P<.01 are to be used, the screening phase in future PD screens will need to be very much larger than that performed by Maraganore et al.1

Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort

Abstract: The LRRK2 G2019S mutation is the commonest genetic cause of Parkinson's disease (PD) identified to date, although estimates of its prevalence in idiopathic disease vary considerably. Our objectives were to determine G2019S mutation frequency in an unselected, community based cohort of idiopathic PD cases from the UK and to describe phenotypic characteristics among carriers. The mutation was present in two of 519 cases (0.4%) and none of 887 control individuals. The true prevalence of the mutation in idiopathic disease, its penetrance, and the phenotypic heterogeneity of associated cases have important implications for genetic screening in the clinical field.

A case of voltage-gated potassium channel antibody-related limbic encephalitis

Abstract: Background A 56-year-old man presented to hospital with a 6-month history of recurrent episodes of altered behavior and 'odd' episodes. He had become apathetic and uninterested in his family. He had no relevant past medical or family history. General and physical neurological examinations were unremarkable, as was bedside cognitive testing. Investigations Brain MRI scan, 24-h electroencephalogram, serum and cerebrospinal fluid testing for voltage-gated potassium channel antibodies, blood screening for tumors, CT scans of the chest, abdomen and pelvis, whole-body PET scan, neuropsychological examination, brain 18F-fluorodeoxyglucose-PET scan. Diagnosis Voltage-gated potassium channel antibody-related limbic encephalitis. Management Antiepileptic drugs, immunomodulatory therapy, oral steroids, plasma exchange.

The frequency and validity of self-reported diagnosis of Parkinson's Disease in the UK elderly: MRC CFAS cohort

Abstract: Background: Estimates of the incidence and prevalence of chronic diseases can be made using established cohort studies but these estimates may have lower reliability if based purely on selfreported diagnosis. Methods: The MRC Cognitive Function & Ageing Study (MRC CFAS) has collected longitudinal data from a population-based random sample of 13004 individuals over the age of 65 years from 5 centres within the UK. Participants were asked at baseline and after a two-year follow-up whether they had received a diagnosis of Parkinson's disease. Our aim was to make estimates of the incidence and prevalence of PD using self-reporting, and then investigate the validity of selfreported diagnosis using other data sources where available, namely death certification and neuropathological examination. Results: The self-reported prevalence of Parkinson's disease (PD) amongst these individuals increases with age from 0.7% (95%CI 0.5–0.9) for 65–75, 1.4% (95%CI 1.0–1.7) for 75–85, and 1.6% (95%CI 1.0–2.3) for 85+ age groups respectively. The overall incidence of self reported PD in this cohort was 200/100,000 per year (95%CI 144–278). Only 40% of the deceased individuals reporting prevalent PD and 35% of those reporting incident PD had diagnoses of PD recorded on their death certificates. Neuropathological examination of individuals reporting PD also showed typical PD changes in only 40%, with the remainder showing basal ganglia pathologies causing parkinsonism rather than true PD pathology. Conclusion: Self-reporting of PD status may be used as a screening tool to identify patients for epidemiological study, but inevitably identifies a heterogeneous group of movement disorders patients. Within this group, age, male sex, a family history of PD and reduced cigarette smoking appear to act as independent risk factors for self-reported PD.

No alterations in α‐synuclein gene dosage observed in sporadic Parkinson's disease

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