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Zbigniew K Wszolek

Publications and source records attributed to Zbigniew K Wszolek.

At least 37 records · Page 2Linked to original sources
PubMed2006

Progressive supranuclear palsy: phenotypic sex differences in a clinical cohort.

We examined sex-based differences in phenotypic expression among a consecutive clinical series of 121 individuals diagnosed with probable progressive supranuclear palsy (PSP). For both men (44%) and women (56%), the age at symptomatic onset (66.2 and 68.5 years, respectively) and disease duration (4.6 and 4.3 years, respectively) were similar. The overwhelming majority of sex-based comparisons showed no significant difference on a variety of demographic, historical, and clinical characteristics, as well as measures of disease progression. The only differences observed were that men had significantly worse tremor as measured by the Unified Parkinson's Disease Rating Scale tremor subscore (0.9 for men and 0.3 for women, P<0.01) and men had a significantly higher mean body mass index (BMI; 28.2 for men and 25.1 for women, P=0.01), although these differences were not significant after Bonferroni correction. In general, the disease phenotype was similar between men and women, suggesting that sex may have little or no influence on the development, expression, or progression of the PSP phenotype.

Adult↗
PubMed2006

PARK8 LRRK2 parkinsonism.

Parkinson's disease (PD) is the most common form of parkinsonism, affecting nearly 2% of people older than 65 years of age. Symptomatic treatment has been available for decades, but to date there is no treatment retarding disease progression. Over the past decade several genes causing parkinsonism have been identified in families with a mendelian pattern of inheritance. The most recent is the leucine-rich repeat kinase 2 (LRRK2) gene. Pathogenic mutations in the LRRK2 gene cause a significant proportion of clinically typical, late-onset PD. This review summarizes the current knowledge on the contribution of LRRK2 mutations in understanding parkinsonism.

Aged↗
PubMed2006

Genetics of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder, although under-diagnosed, with a prevalence of up to 15% depending on the population sampled. Familial aggregation has been widely shown since Ekbom formerly described the condition in 1960; twin studies support a genetic contribution in the development of this disorder. Molecular genetic approaches have identified three genomic regions in RLS susceptibility, however no specific mutations have yet been identified. Herein, we review the current status of genetics in RLS, providing some methodological guidelines to help future research.

Gene Frequency↗
PubMed2006

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

Adult↗
PubMed2006

Speech characteristics of patients with pallido-ponto-nigral degeneration and their application to presymptomatic detection in at-risk relatives.

PURPOSE: This report describes the speech characteristics of individuals with a neurodegenerative syndrome called pallido-ponto-nigral degeneration (PPND) and examines the speech samples of at-risk, but asymptomatic, relatives for possible preclinical detection. METHOD: Speech samples of 9 members of a PPND kindred were subjected to perceptual characterization. Speech deterioration patterns were reported for 2 participants followed longitudinally at 6-month intervals. Cross-sectional findings were reported for 3 participants at various stages of disease. Longitudinal and cross-sectional findings were used to guide the examination of 4 at-risk, but asymptomatic, participants. RESULTS: Results revealed a progressive mixed dysarthria with hypokinetic, spastic, and flaccid features. It was characterized primarily by vocal tremor and high-frequency vocal flutter, speaking rate abnormalities most often in the direction of slowing, and a tendency toward monopitch. Dysarthria progression was marked by exacerbation and increasing severity of early features, progressive decrease in spontaneous speech output, verbal perseverations, and eventual mutism. Results for at-risk participants revealed preclinical speech abnormalities that preceded other motor signs. Speech results were examined in light of available autopsy findings for site of lesion associations. CONCLUSION: The dysarthria of PPND is an early harbinger of disease onset. It has a mixed presentation, with hypokinetic, spastic, and flaccid features.

Cross-Sectional Studies↗
PubMed2005

Lrrk2 pathogenic substitutions in Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) mutations have been implicated in autosomal dominant parkinsonism, consistent with typical levodopa-responsive Parkinson's disease. The gene maps to chromosome 12q12 and encodes a large, multifunctional protein. To identify novel LRRK2 mutations, we have sequenced 100 affected probands with family history of parkinsonism. Semiquantitative analysis was also performed in all probands to identify LRRK2 genomic multiplication or deletion. In these kindreds, referred from movement disorder clinics in many parts of Europe, Asia, and North America, parkinsonism segregates as an autosomal dominant trait. All 51 exons of the LRRK2 gene were analyzed and the frequency of all novel sequence variants was assessed within controls. The segregation of mutations with disease has been examined in larger, multiplex families. Our study identified 26 coding variants, including 15 nonsynonymous amino acid substitutions of which three affect the same codon (R1441C, R1441G, and R1441H). Seven of these coding changes seem to be pathogenic, as they segregate with disease and were not identified within controls. No multiplications or deletions were identified.

Adult↗
PubMed2005

Gender and the Parkinson's disease phenotype.

OBJECTIVES: To determine whether there are gender differences in the Parkinson's disease (PD) phenotype using a large clinic-based cohort. METHODS: We examined gender differences in demographic, historical and clinical characteristics in a consecutive clinical series of 1,264 individuals diagnosed with PD. RESULTS: The majority of individuals in the sample were male (67 %). Comparative analyses showed males and females were not significantly different on most demographic and historical characteristics. For both genders, the mean age and the mean age at symptomatic onset were about 70 and 63 years, respectively and, thus, disease duration was not significantly different between genders. The proportion of individuals with a positive family history of PD (15 %) was similar for both genders. A positive history of depression was significantly higher in females (35 % vs. 24 %). The UPDRS instability score was significantly worse among females, whereas the rigidity score was significantly worse for males. Females showed significantly worse ADL capacity and a more advanced H&Y stage. The proportion of individuals receiving antiparkinsonian medication (about 66 %) and time between the last dose and the clinical evaluation (about 4 hours) was similar for both genders. There was a trend for lower daily levodopa equivalence dosage and more severe dyskinesia score among females but these differences did not reach statistical significance after Bonferroni correction. CONCLUSIONS: The majority of comparisons tended to highlight the commonalities in the PD phenotype between genders, particularly in reference to historical and early disease stage characteristics. However, gender may be an important factor related to the expression of PD features during the symptomatic disease course.

Activities of Daily Living↗
PubMed2005

Alterations of T-lymphocyte populations in Parkinson disease.

Immune reaction-related inflammation may be important in the pathogenesis of Parkinson disease (PD). To elucidate peripheral immunologic alterations in PD, we characterized extended peripheral T-lymphocyte populations in 33 patients with PD and 34 normal subjects. Patients with PD had significantly decreased CD4+:CD8(+)T-cell ratios (P<0.001), fewer CD4(+)CD25(+)T cells (P<0.01), and significantly increased ratios of IFN-gamma-producing to IL-4-producing T cells (P<0.001). The characteristics of predominant expression of CD8(+)T cells, depletion of CD4(+)CD25(high) cells, and a shift to a T(H)1-type immune response in the peripheral immune system in PD patients may reflect an immune reaction-associated inflammatory process in the brain.

Aged↗
PubMed2005

PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation.

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Adult↗
PubMed2005

Severe vascular disturbance in a case of familial brain calcinosis.

Here we present the first neuropathological study of a case of autosomal dominant brain calcinosis in a family followed through five generations. The 71-year-old female who came to autopsy had unusually severe and extensive bilateral brain calcifications. The process appeared to start with deposition of minute calcium-positive spheroids of less than 1 mum in diameter in capillaries that otherwise appeared normal. These could be observed extending to areas distant from the main pathology. In more advanced stages, larger spheroids completely covered some capillaries while sparing others. In heavily affected regions, ghost capillaries were observed where only calcium spheroids remained after endothelial cells and basement membranes had disappeared. Vessels of all sizes were affected, and large accretions were observed in the basal ganglia, thalamus and cerebellum. Combined scanning electron microscopy and X-ray spectrometry of these large deposits revealed a dominant presence of calcium and phosphorous, plus carbon and oxygen indicative of organic material, and small amounts of sodium, potassium, sulfur, and magnesium. Reactive astrocytes and reactive microglia accumulated around the calcified deposits, indicating a mild ongoing inflammatory process. The results suggest that severe vascular impairment and mild inflammation contribute to the slow but inexorable progression of hereditary brain calcinosis.

Aged↗
PubMed2005

Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.

Age Factors↗
PubMed2005

Parkinsonism, FXTAS, and FMR1 premutations.

The presence of late-onset neurological symptoms in male carriers of premutation expansions of the fragile X mental retardation 1 (FMR1) gene has been described recently. One of the clinical symptoms in this fragile X-associated tremor/ataxia syndrome (FXTAS) is parkinsonism. To test the possible association between expanded FMR1 alleles and Parkinson's disease (PD), we determined the size of the FMR1 CGG repeat in 414 male cases of clinically diagnosed parkinsonism, the majority of whom had PD. None of our patients had expanded FMR1 repeats within the premutation range (55-200 CGG repeats). Five patients (1.2%) carry intermediate-size alleles (41-54 CGG repeats). Expansions within the FMR1 gene are not associated with PD in our study.

Adolescent↗
PubMed2005

Body mass index is reduced early in Parkinson's disease.

Mean body mass index (BMI) in 100 cases of idiopathic Parkinson's disease (PD) was found to be 9% reduced in comparison to that in patients with either essential tremor or no neurologic disease. A similar reduction in BMI was also discovered among the 24 cases of PD in whom retrospective BMI data were available from their presymptomatic years. These results suggest that alterations in nutrient intake or metabolism could reflect early changes in the central autonomic network preceding the emergence of classical extrapyramidal manifestations of PD.

Aged↗
PubMed2005

Defining the Parkinson's disease phenotype: initial symptoms and baseline characteristics in a clinical cohort.

OBJECTIVES: Examine the demographic and historical characteristics of a large Parkinson's disease (PD) clinical cohort and determine the pattern and relationship between initial symptoms of PD and physical examination ratings at the initial subspecialty clinic visit. METHODS: A clinical series of 1244 consecutive individuals diagnosed with PD. Baseline characteristics were examined. RESULTS: The overall sample was predominantly right-handed (92%) male (67%), with a mean age of 70 years and symptomatic disease duration of about 7 years. About 25% of the sample reported a positive family history of a neurodegenerative disorder. Tremor (47%) and bradykinesia (29%) were the two most common initial symptoms of PD and occurred primarily in the upper extremities (68%). Tremor, bradykinesia, and postural instability showed a significant correspondence between the initial self-reported symptom and clinical signs at the first exam p < 0.05. However, rigidity did not show a significant correspondence. CONCLUSION: The demographic and clinical characteristics of the sample are thought to be phenotypically representative of 'typical' PD and were comparable to other clinic- and population-based cohorts. Initial symptoms reported by patients, including type and body location correlate tightly with initial examination findings for all cardinal symptoms of parkinsonism except rigidity. This corroboration may substantiate inclusion of such data in studies of longitudinal progression in PD.

Age of Onset↗