Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Validation of the Polish version of the Unified Dyskinesia Rating Scale (UDysRS).

BACKGROUND: In 2008, the Movement Disorders Society published the Unified Dyskinesia Rating Scale (UDysRS). This has become the established tool for assessing the severity and disability associated with dyskinesia in patients with Parkinson's Disease (PD). We translated and validated the Polish version of the UDysRS, explored its dimensionality, and compared it to the Spanish version, which is the Reference Standard for UDysRS translations. MATERIAL AND METHODS: The UDysRS was translated into Polish by a team led by JS and GO. The back-translation, completed by colleagues fluent in both Polish and English who were not involved in the original translation, was reviewed and approved by the Executive Committee of the MDS Rating Scales Programme. Then the translated version of the UDysRS underwent cognitive pretesting, and the translation was modified based on the results. The approved version was considered to be the Official Working Document of the Polish UDysRS and was tested on 250 Polish PD patients recruited at movement disorder centres. Data was compared to the Reference Standard used for validating UDysRS translations. RESULTS: The overall factor structure of the Polish version was consistent with that of the Reference Standard version, as evidenced by the high Confirmatory Fit Index score (CFI = 0.98). The Polish UDysRS was thus confirmed to share a common factor structure with the Reference Standard. CONCLUSIONS: The Official Polish UDysRS translation is recommended for use in clinical and research settings. Worldwide use of uniform rating measures offers a common ground to study similarities and differences in disease manifestations and progression across cultures.

Validation of the Polish version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

BACKGROUND: In 2008, the Movement Disorders Society (MDS) published a new Unified Parkinson's Disease Rating Scale (MDS-UPDRS) as the official benchmark scale for Parkinson's Disease (PD). We have translated and validated the Polish version of the MDS-UPDRS, explored its dimensionality, and compared it to the original English one. METHODS: The MDS-UPDRS was translated into Polish by a team of Polish investigators led by JS and GO. The back-translation was completed by colleagues fluent in both languages (Polish and English) who were not involved in the original translation, and was reviewed by members of the MDS Rating Scales Programme. Then the translated version of the MDS-UPDRS underwent cognitive pretesting, and the translation was modified based on the results. The final translation was approved as the Official Working Document of the MDS-UPDRS Polish version, and was tested on 355 Polish PD patients recruited at movement disorders centres all over Poland (at Katowice, Gdansk, Lódz, Warsaw, Wroclaw, and Kraków). Confirmatory and explanatory factor analyses were applied to determine whether the factor structure of the English version could be confirmed in the Polish version. RESULTS: The Polish version of the MDS-UPDRS showed satisfactory clinimetric properties. The internal consistency of the Polish version was satisfactory. In the confirmatory factor analysis, all four parts had greater than 0.90 comparative fit index (CFI) compared to the original English MDS-UPDRS. Explanatory factor analysis suggested that the Polish version differed from the English version only within an acceptable range. CONCLUSIONS AND CLINICAL IMPLICATIONS: The Polish version of the MDS-UPDRS meets the requirements to be designated as the Official Polish Version of the MDS-UPDRS, and is available on the MDS web page. We strongly recommend using the MDS-UPDRS instead of the UPDRS for research purposes and in everyday clinical practice.

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.

Translation initiator EIF4G1 mutations in familial Parkinson disease.

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.

ALS-FTD complex disorder due to C9ORF72 gene mutation: description of first Polish family.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are complex neurodegenerative disorders that can be either sporadic or familial and can overlap clinically and pathologically. We present the first Central-Eastern European family with ALS-FTD syndrome due to a C9ORF72 repeat expansion. METHODS: We studied a family consisting of 37 family members, 6 of whom were genetically evaluated for C9ORF72 expansions. Family members were evaluated clinically, by history, and by chart review. RESULTS: Overall, 5 generations of the family were studied, and 6 affected family members were identified. All affected members were females and had a different clinical presentation, which was ALS, FTD or both. Among the genetically evaluated subjects, 5 carried a C9ORF72 expansion; 4 of these individuals remain clinically unaffected. CONCLUSION: Our report reveals that the hexanucleotide repeat expansion of C9ORF72, which is the most common genetic cause of ALS-FTD complex disorder, is also present in Central-Eastern Europe. Further studies are needed to assess the frequency of this expansion in the Polish population with familial as well as sporadic ALS, FTD and the ALS-FTD complex disorder.

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. METHODS: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. RESULTS: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Independent and joint effects of the MAPT and SNCA genes in Parkinson disease.

OBJECTIVE: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. METHODS: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. RESULTS: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. INTERPRETATION: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.

Percutaneous closure of the left atrial appendage to prevent ischaemic stroke in patients with atrial fibrillation who require but have contraindications to oral anticoagulation.

Atrial fibrillation (AF) is associated with a five-fold increased risk for stroke due to cardioembolic events. Most strokes in patients with AF arise from thrombus formation in the left atrial appendage (LAA). Oral anticoagulation is a standard treatment of AF patients with high risk of stroke. However, the main drawbacks of oral anticoagulation are high risk of major bleeding and imperfect effectiveness dependent on a very narrow therapeutic range. In this article, based on two case reports, we describe a method of percutaneous closure of the LAA. We discuss indications, describe the procedure and mention possible complications. LAA closure seems to be a promising tool to prevent AF-related strokes in a selected group of patients.

The influence of visual control on postural stability in Parkinson disease.

BACKGROUND AND PURPOSE: The aim of the study was to evaluate the influence of visual control on parameters of postural stability among patients with Parkinson disease (PD) in comparison with control subjects. MATERIAL AND METHODS: Fifty patients diagnosed with idiopathic PD and 50 control subjects without features of central nervous system injury were selected for the study. The clinical diagnosis of idiopathic PD was established according to the clinical criteria of the United Kingdom Parkinson's Disease Society Brain Bank. Only patients in stages I-III according to the Hoehn-Yahr scale were included. The range of sway of the centre of foot pressure (COP) in the frontal plane (COPx) and in the sagittal plane (COPy), as well as the total path length in both axes (COPxy), was tested during quiet standing with and without visual control. RESULTS: COPxy with and without visual control was the smallest in the group of patients in stage II in comparison with patients in stage I and III according to Hoehn-Yahr and in comparison with the control group. CONCLUSIONS: Visual control significantly affects the parameters of postural stability in PD patients.

Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe.

INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed.

Decompressive hemicraniectomy in ischaemic stroke.

BACKGROUND AND PURPOSE: Hemispheric ischaemic stroke complicated by oedema is associated with high mortality. The results of randomized studies showed that decompressive hemicraniectomy performed in this group of patients could be beneficial. First experiences with implementation of hemi-craniectomy in patients with brain infarct in our stroke centre are presented. MATERIAL AND METHODS: Between August 2007 and July 2008, four patients with hemispheric brain infarcts complicated by malignant oedema underwent decompressive hemicraniectomy within 72 hours from symptoms onset. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Clinical outcome was assessed 3, 6 and 12 months after the event using the modified Rankin scale (mRS). RESULTS: In the first patient, the neurosurgical procedure included only decompressive hemicraniectomy, whereas in the other three duraplasty was performed additionally. The first patient died 23 days after the stroke onset due to acute respiratory failure. Another died at four months after the event, due to infectious complications. The remaining two patients presented severe functional disability 12 months after the procedure (mRS score 4). CONCLUSIONS: Decompressive surgery with duraplasty can be a life-saving procedure for patients with brain oedema. To our knowledge, the presented cases are among the first reported cases of hemispheric ischaemic stroke treated with decompressive hemicraniectomy in Poland. Extended follow-up with a larger group of patients is necessary to assess long-term outcome.

Middle cerebral artery vasospasm: transcranial color-coded duplex sonography versus conventional nonimaging transcranial Doppler sonography.

OBJECTIVE: To prospectively compare accuracies of transcranial color-coded duplex sonography (TCCS) and transcranial Doppler sonography (TCD) in the diagnosis of middle cerebral artery (MCA) vasospasm. DESIGN: Prospective blinded head-to-head comparison TCD and TCCS methods using digital subtraction angiography (DSA) as the reference standard. SETTING: Department of Radiology in a tertiary university health center in a metropolitan area. PATIENTS: Eighty-one consecutive patients (mean age, 53.9 +/- 13.9 years; 48 women). The indication for DSA was subarachnoid hemorrhage in 71 patients (87.6%), stroke or transient ischemic attack in five patients (6.2%), and other reasons in five patients (6.2%). INTERVENTIONS: The MCA was graded as normal, narrowed <50%, and >50% using DSA. The accuracy of ultrasound methods was estimated by total area (Az) under receiver operator characteristic curve. To compare sensitivities of ultrasound methods, McNemar's test was used with mean velocity thresholds of 120 cm/sec for the detection of less advanced, and 200 cm/sec for the more advanced MCA narrowing. MEASUREMENTS AND MAIN RESULTS: Angiographic MCA narrowing 50% in 10 of 135 arteries. Accuracy of TCCS was insignificantly higher than that of TCD in the detection of 50% narrowing, total Az for mean velocity being 0.83 +/- 0.05, 0.77 +/- 0.05, and 0.95 +/- 0.02, 0.86 +/- 0.08, respectively. Sensitivity of TCCS at commonly used threshold of 120 cm/sec for less advanced MCA spasm was significantly better than that of TCD at similar specificity, 55% vs. 39%, p = 0.038, whereas at a threshold of 200 cm/sec used for more advanced spasm, sensitivities and specificities of both methods were not different. CONCLUSION: The accuracy of TCCS and TCD is similar, but TCCS is more sensitive than TCD in the detection of MCA spasm. Sensitivity of both techniques in the detection of mild and more advanced spasm using 120 cm/sec and 200 cm/sec thresholds, respectively, is poor; however, a larger sample is required to increase precision of our sensitivity estimates.

Perfusion computed tomography in prediction of functional outcome in patients with acute ischaemic stroke.

PURPOSE: To determine the value of perfusion computed tomography (CT) in prediction of the clinical course and late functional outcome in patients with acute ischaemic stroke who had unremarkable initial brain CT examination. MATERIAL AND METHODS: Single slice perfusion CT was performed in 55 consecutive patients (27 women, mean age 67 +/- 11 years) with acute ischaemic stroke within 6 hours (median 2.26 hours) from onset of symptoms. Values of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) obtained from affected hemisphere were compared to respective values in non-affected hemisphere (relative parameters). Initial neurological deficits were estimated using NIH Stroke Scale (NIHSS) score and correlated with perfusion CT values, employing Spearman rank correlation coefficient (r). Values of perfusion CT parameters in prediction of functional outcome were determined by comparing against scores on modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS) after three months of onset of stroke. RESULTS: All perfusion CT parameters significantly correlated with initial neurological deficit. The highest correlation with the NIHSS was found for relative CBF, which correlated better than absolute CBF (rCBF r = 0.69; CBF r = 0.50, P < 0.001). In prediction of favourable outcome (mRS

From mild cognitive impairment to Alzheimer's disease - influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up.

BACKGROUND AND PURPOSE: People with mild cognitive impairment (MCI) have higher risk of developing dementia than the general population. Currently known risk factors for dementia include older age, low education level, gait disorders, hippocampal atrophy, and apolipoprotein E allele. Vascular risk factors may modify the neurodegenerative process. The aim of this study was therefore to assess the influence of vascular (genetic and environmental) risk factors on progression to dementia in an MCI group during a one-year period. MATERIAL AND METHODS: Fifty-five MCI patients (30 men and 25 women) and 44 controls (25 men and 19 women) matched for age, gender and education were studied. Mild cognitive impairment was diagnosed according to Petersen criteria (Mayo Clinic Group). Neuropsychological evaluation was made. Assessed vascular risk factors included hypertension, cardiovascular disease, diabetes, cigarette smoking, hyperlipidaemia, hyperhomocysteinaemia with vitamin B12 and folate deficiency. Genetic risk factors (APOE polymorphism, C677T and A1298C MTHFR polymorphisms) were also assessed. RESULTS: Vascular risk factors were found significantly more often in the MCI group (p = 0.041), including APOE4 allele (p = 0.018), hyperhomocysteinaemia (p = 0.012) and folate deficiency (p = 0.023). Discriminant function analysis showed that only age and hypertension are potential factors which may have an influence on progression to dementia in the MCI group within one year of prospective observation. CONCLUSION: Vascular risk factors are associated with cognitive impairment but do not have a significant influence on progression to dementia in the MCI group.

Dopamine beta-hydroxylase -1021C>T association and Parkinson's disease.

A single nucleotide polymorphism in the promoter region of the dopamine beta-hydroxylase gene (DBH -1021C>T; rs1611115) is reported to regulate plasma enzyme activity levels. This variant has also been the focus of two large association studies in Parkinson's disease yielding conflicting results. We examined this association in four Caucasian patient-control series (n=2696). A modest protective association was observed in the Norwegian series (OR=0.81, p=0.03; n=1676), however, the effect was in the opposite direction in the Polish series (OR=2.01, p=0.01; n=224). No association was observed for DBH -1021C>T with disease susceptibility in the US and Irish series, or combining all four series (OR=0.91, p=0.16, n=2696). We observed a modest association between DBH -1021C>T and AAO in the combined series (p=0.01). Taken together, these findings indicate that DBH -1021C>T does not play a major role in the pathogenesis of Parkinson's disease.

Genetic variation of Omi/HtrA2 and Parkinson's disease.

Variants in the Omi/HtrA2 gene have been nominated as a cause of Parkinson's disease. This sequencing study of Omi/HtrA2 in 95 probands with apparent autosomal dominant inheritance of Parkinson's disease did not identify any pathogenic mutations. In addition, there was no association between common variations in the Omi/HtrA2 gene and susceptibility to Parkinson's disease in any of our four patient-control series (n=2373). Taken together our results do not support a role for Omi/HtrA2 variants in the pathogenesis of Parkinson's disease.

Apolipoprotein E gene polymorphism, total plasma cholesterol level, and Parkinson disease dementia.

BACKGROUND: Apolipoprotein E gene (APOE) polymorphism is an important determinant for the development of various cardiovascular and neurodegenerative disorders. There have been conflicting reports of association of APOE polymorphism with dementia in Parkinson disease (PD). OBJECTIVE: To determine the relationship between APOE polymorphisms and plasma cholesterol concentration, and PD with dementia (PDD). DESIGN: Four-year (1999-2002) case-control study. SETTING: Academic medical center with inpatient and outpatient movement disorders services. Patients Consecutive white patients of the same ethnic background with PD. INTERVENTIONS: Strict clinical, neuropsychological, and neuroimaging criteria were used to exclude dementia with Lewy bodies, Alzheimer disease, and vascular dementia. Findings were compared in 2 clinical groups, including 98 patients (47 men and 51 women; mean age, 71 years) with PDD and 100 patients (52 men and 48 women; mean age, 62 years) with PD without dementia. MAIN OUTCOME MEASURES: Analysis of APOE genotypes and allelic frequency (polymerase chain reaction) and plasma cholesterol concentration (enzymatic assay) were evaluated by a clinician blinded to the clinical diagnosis, and findings were compared between the groups with PDD or PD without dementia. Multiple stepwise regression analysis and the Spearman rank correlation coefficient were used to evaluate relationships between dementia and both APOE polymorphism and cholesterol concentration. Statistical significance was set at P<.05. RESULTS: Epsilon4 allele frequencies were similar in PDD and PD without dementia (16.8% vs 19%, respectively). Cholesterol concentration, APOE genotypes, and allelic frequencies did not relate to PDD. CONCLUSIONS: In contrast to Alzheimer disease, when PDD is carefully defined, it is clearly not associated with APOE polymorphisms or with a distinctive plasma cholesterol profile. Ongoing longitudinal follow-up with emphasis on autopsy recruitment will enable further analyses of biochemical alterations underlying PDD.