Unified Parkinson's Disease Rating Scale

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant α-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.

/pdf/glucocerebrosidase-mutations-in-clinical-and-pathologically-3shbpwrwmz.pdf

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease

Background A clinical association has been reported between type 1 Gaucher's disease, which is caused by a glucocerebrosidase deficiency owing to mutations in the glucocerebrosidase gene (GBA), and parkinsonism. We examined whether mutations in the GBA gene are relevant to idiopathic Parkinson's disease. Methods A clinic-based case series of 99 Ashkenazi patients with idiopathic Parkinson's disease, 74 Ashkenazi patients with Alzheimer's disease, and 1543 healthy Ashkenazi Jews who underwent testing to identify heterozygosity for certain recessive diseases were screened for the six GBA mutations (N370S, L444P, 84GG, IVS+1, V394L, and R496H) that are most common among Ashkenazi Jews. Results Thirty-one patients with Parkinson's disease (31.3 percent; 95 percent confidence interval, 22.2 to 40.4 percent) had one or two mutant GBA alleles: 23 were heterozygous for N370S, 4 were heterozygous for 84GG, 3 were homozygous for N370S, and 1 was heterozygous for R496H. Among the 74 patients with Alzheimer's disease...

Mutations in the Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews

Mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme that is deficient in Gaucher's disease, are important and common risk factors for Parkinson's disease and related disorders. This association was first recognised in the clinic, where parkinsonism was noted, albeit rarely, in patients with Gaucher's disease and more frequently in relatives who were obligate carriers. Subsequently, findings from large studies showed that patients with Parkinson's disease and associated Lewy body disorders had an increased frequency of GBA mutations when compared with control individuals. Patients with GBA-associated parkinsonism exhibit varying parkinsonian phenotypes but tend to have an earlier age of onset and more associated cognitive changes than patients with parkinsonism without GBA mutations. Hypotheses proposed to explain this association include a gain-of-function due to mutations in glucocerebrosidase that promotes α-synuclein aggregation; substrate accumulation due to enzymatic loss-of-function, which affects α-synuclein processing and clearance; and a bidirectional feedback loop. Identification of the pathological mechanisms underlying GBA-associated parkinsonism will improve our understanding of the genetics, pathophysiology, and treatment for both rare and common neurological diseases.

/pdf/the-link-between-the-gba-gene-and-parkinsonism-yl7egvg3kd.pdf

The link between the GBA gene and parkinsonism

Summary Background Deep brain stimulation of the subthalamic nucleus (STN DBS) is an increasingly common treatment for Parkinson's disease. Qualitative reviews have concluded that diminished verbal fluency is common after STN DBS, but that changes in global cognitive abilities, attention, executive functions, and memory are only inconsistently observed and, when present, often nominal or transient. We did a quantitative meta-analysis to improve understanding of the variability and clinical significance of cognitive dysfunction after STN DBS. Methods We searched MedLine, PsycLIT, and ISI Web of Science electronic databases for articles published between 1990 and 2006, and extracted information about number of patients, exclusion criteria, confirmation of target by microelectrode recording, verification of electrode placement via radiographic means, stimulation parameters, assessment time points, assessment measures, whether patients were on levodopa or dopaminomimetics, and summary statistics needed for computation of effect sizes. We used the random-effects meta-analytical model to assess continuous outcomes before and after STN DBS. Findings Of 40 neuropsychological studies identified, 28 cohort studies (including 612 patients) were eligible for inclusion in the meta-analysis. After adjusting for heterogeneity of variance in study effect sizes, the random effects meta-analysis revealed significant, albeit small, declines in executive functions and verbal learning and memory. Moderate declines were only reported in semantic (Cohen's d 0·73) and phonemic verbal fluency (0·51). Changes in verbal fluency were not related to patient age, disease duration, stimulation parameters, or change in dopaminomimetic dose after surgery. Interpretation STN DBS, in selected patients, seems relatively safe from a cognitive standpoint. However, difficulty in identification of factors underlying changes in verbal fluency draws attention to the need for uniform and detailed reporting of patient selection, demographic, disease, treatment, surgical, stimulation, and clinical outcome parameters.

/pdf/cognitive-sequelae-of-subthalamic-nucleus-deep-brain-593p1oba1z.pdf

Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinson's disease: a meta-analysis

The aim of our study was to identify and quantify spatiotemporal and kinematic gait parameters obtained by 3D gait analysis (GA) in a group of Parkinson's disease (PD) patients compared with healthy subjects in order to investigate whether early PD patients could present an abnormal gait pattern. Forty-four patients affected by early-stage PD compared with a control group were analyzed. All participants were evaluated with 3D GA in the gait laboratory. The greatest significance in temporal parameters was found in cadence (102.46 ± 13.17 steps/min in parkinsonian patients vs 113.84 ± 4.30 steps/min in control subjects), followed by stride duration (1.19 ± 0.18 seconds right limb and 1.19 ± 0.19 seconds left limb in PD patients vs 0.426 ± 0.16 seconds right limb and 0.429 ± 0.23 seconds left limb in normal subjects) and stance duration. Marked differences were also found in the swing phase and in swing duration (p<0.05), while the stance phase was not significantly different in patients compared with healthy subjects. A statistically different velocity in PD patients (0.082 ± 0.29 m/s) vs healthy subjects (1.33 ± 0.06 m/s) was shown by spatial parameter analysis. Step width, stride length and swing velocity were highly significant parameters, as was average velocity. Our study highlighted some distinguishing characteristics of gait in early PD. Ambulation disorders may be present in the early stage of PD and their detection allows for early medical treatment and possible rehabilitation.

Gait analysis and clinical correlations in early Parkinson's disease.

The association between type 1 Gaucher disease and PD has been reported in the literature. The clinical picture is characterized by the predominance of bilateral akinetic-rigid signs and poor response to levodopa therapy. The authors describe four patients (two siblings) with type 1 Gaucher disease presenting with the following signs of typical PD: asymmetric onset of rigidity, resting tremor, bradykinesia, and a favorable response to Parkinson therapies.

Gaucher’s disease with Parkinson’s disease Clinical and pathological aspects

UNLABELLED Catechol-O-methyltransferase (COMT) inhibitors are drugs commonly used in the management of patients with Parkinson disease complicated by motor fluctuations. Among them, entacapone is the most commonly used. Tolcapone has been reintroduced in patients where entacapone has proved to be ineffective after being withdrawn from the market because of sporadic cases of hepatotoxicity. The last COMT inhibitor is nebicapone, which use in clinical practice is still under study. OBJECTIVES The objectives of this study were to analyze the clinical efficacy in reducing motor complications and to evaluate their use in clinical practice and the adverse events reported in the literature. METHODS Scientific articles of the main previously mentioned drugs have been reviewed. RESULTS All these 3 drugs have proved to be effective in improving wearing-off and significantly reduce the daily dose of levodopa at the number of daily intakes. Tolcapone is undoubtedly the most effective drug, although in clinical practice sporadic cases of hepatotoxicity have limited its use in patients unresponsive to entacapone. Nebicapone is effective, and its safety is still under evaluation. Entacapone is generally well tolerated, and no significant adverse events are reported. CONCLUSIONS To manage motor fluctuations, the use of COMT inhibitors is now consolidated in the common clinical practice. Tolcapone is used as a second choice in patients with severe motor fluctuations not responsive to entacapone.

A systematic review of catechol-0-methyltransferase inhibitors: efficacy and safety in clinical practice.

The aim of this study was to investigate and describe frequency and characteristics of sleep disorders in a large cohort of community dwelling persons with several degrees and typologies of cognitive disorders. 236 patients (78 men and 158 women) were enrolled with different subtypes of dementia: Alzheimer’s disease (AD), vascular dementia (VaD), mixed dementia, mild cognitive impairment (MCI), dementia with Lewy bodies (DLB), parkinson’s disease dementia (PDD), and frontotemporal lobar degeneration (FTLD), respectively. The sleep disturbances evaluated were: insomnia, excessive daytime sleepiness (EDS), REM behavior disorder (RBD), restless legs syndrome (RLS), and nightmares. Every type of sleep disorder was present in each type of dementia but with significant differences. Insomnia is found to be more present and specific for AD; EDS was associated with the presence of dementia in the elderly with LBD or PDD; RLS and nightmares that were recognized mainly in FTD, LBD, and PDD patients scores; patients with MCI had a frequency of sleep disturbances of any type equal to that of patients with AD presenting mostly insomnia, nightmares or RLS more frequently; nightmares were more frequent among LBD and PDD patients. Frequency of RDB was more frequent in FTD, AD, and VaD. Our findings demonstrate that sleep disturbance was related to dementia. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline.

Sleep disturbance and cognitive disorder: epidemiological analysis in a cohort of 263 patients

‘Speech Initiation Hesitation’ following Subthalamic Nucleus Stimulation in a Patient with Parkinson’s Disease R. Moretti a–c, P. Torre b, c, R.M. Antonellob, c, L. Capusb, M. Gioulisb, S. Zambito Marsalab, G. Cazzatob, A. Bava a aDipartimento di Fisiologia e Patologia, bDipartimento di Medicina Clinica e Neurologia, UCO di Clinica Neurologica, and cDipartimento di Medicina Clinica e Neurologia, UCO di Clinica Neurologica, Sezione Disturbi Cognitivi, Università degli Studi di Trieste, Trieste, Italy

Manuela Gioulis

Papers

Gait analysis and clinical correlations in early Parkinson's disease.

Gaucher’s disease with Parkinson’s disease Clinical and pathological aspects

A systematic review of catechol-0-methyltransferase inhibitors: efficacy and safety in clinical practice.

Sleep disturbance and cognitive disorder: epidemiological analysis in a cohort of 263 patients

‘Speech Initiation Hesitation’ following Subthalamic Nucleus Stimulation in a Patient with Parkinson’s Disease