CSF neurogranin levels as a biomarker in Alzheimer's disease and frontotemporal lobar degeneration: a cross-sectional analysis.

BACKGROUND: There is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer's disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum. METHODS: Participants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism. RESULTS: Ng levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p < .001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p = .029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p = .034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p = .001) and AD-dementia (F[1, 100] = 20.90, p < .001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p = .491) or FTLD-dementia (F[1, 62]= 2.27, p = .051). The main effect of diagnosis across the diagnostic subgroups on Aß1-42/Ng ratio was significant too (F[4, 263]=, p < .001). We found a non-significant association between Ng levels and memory scores overall (ß=-0.25, p = .154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (ß=-0.32, p = .358). CONCLUSIONS: In this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aß1-42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits.

The bleeding risk during warfarin therapy is associated with the number of variant alleles of CYP2C9 and VKORC1 genes.

BACKGROUND: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. AIM: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. METHODS: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. RESULTS: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p < 0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B < CYP2C9 *1/*1 + VKORC1 A/B < CYP2C9 *1/*2 + VKORC1 B/B. CONCLUSION: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.

Pharmacogenetic algorithm for predicting daily dose of warfarin in Caucasian patients of Czech origin.

OBJECTIVES: Warfarin use is limited by a low therapeutic index and significant interindividual variability of the daily dose. The most important factor predicting daily warfarin dose is individual genotype, polymorphisms of genes CYP2C9 (warfarin metabolism) and VKORC1 (sensitivity for warfarin). Algorithms using clinical and genetic variables could predict the daily dose before the initiation of therapy. The aim of this study was to develop and validate an algorithm for the prediction of warfarin daily dose in Czech patients. METHODS: Detailed clinical data of patients with known and stable warfarin daily dose were collected. All patients were genotyped for polymorphisms in genes CYP2C9 and VKORC1. RESULTS: Included patients were divided into derivation (n=175) and validation (n=223) cohorts. The final algorithm includes the following variables: Age, height, weight, treatment with amiodarone and presence of variant alleles of genes CYP2C9 and VKORC1. The adjusted coefficient of determination is 72.4% in the derivation and 62.3% in the validation cohort (p<0.001). CONCLUSIONS: Our validated algorithm for warfarin daily dose prediction in our Czech cohort had higher precision than other currently published algorithms. Pharmacogenetics of warfarin has the potential in the clinical practice in specialized centers.