Parkinsonism syndrome in heterozygotes for Niemann-Pick C1.

Niemann-Pick C (NPC) disease is a rare autosomal recessive lipid storage disorder. We report here the unique occurrence of three adult heterozygous carriers of mutations in the NPC1 gene who also have a parkinsonism syndrome. This suggests the possibility that mutations in NPC1 could be a risk factor for Parkinson's disease similar to the phenomenon that is now recognized with Gaucher disease and the glucocerebrosidase (GBA) gene. This report should be a stimulus for larger more detailed epidemiological studies.

Implementation of a cost-effective HPLC/UV-approach for medical routine quantification of donepezil in human serum.

A novel, simple, specific and sensitive high performance liquid chromatography (HPLC) assay for the detection and quantification of donepezil in serum of demented patients has been developed and validated. The analytical procedure involves an offline serum preextraction using solid phase extraction (SPE) cartridges (Oasis® HLB, Waters Co). The chromatographic analyses were performed on a Dionex HPLC system with a Phenomenex Luna Phenyl-Hexyl analytical column, and a mobile phase with the two components 0.02 mol/l phosphate buffer and acetonitrile. The flow rate was 0.4 ml/min. For the detection of donepezil three different UV wavelengths were used as an interference-control check. Interference tests between donepezil and 100 of the most commonly used concomitant medications allow quantification of donepezil under the polypharmaceutical conditions of the daily clinical routine. The retention time for donepezil was 12.1 min. The method was validated according to the guidelines of the Society of Toxicology and Forensic Chemistry (GTFCh): The calibration curve was linear over a concentration range from 5 to 160 ng/ml (n=8/r²>0.999). No endogenous compounds were found to interfere with the analyte, which was shown by retention times for the comedication most often prescribed to demented patients. The method had an accuracy of >85%. Intra- and inter-assay coefficients of variation were <6% and <8%, respectively, at three different concentrations. The limit of quantification (LOQ) and the limit of detection (LOD) were found to be 6.1 and 1.7 ng/ml for donepezil. Application of the method to patient serum samples discovered that concentrations suggested as "therapeutic" in the literature may only be reached either by high, off-label dosages or by utilization of inhibitory metabolic effects of the comedication.

Cerebrospinal fluid tau and beta-amyloid in Alzheimer patients, disease controls and an age-matched random sample.

We prospectively evaluated the diagnostic accuracy of cerebrospinal fluid (CSF)-beta-amyloid1-42 (Abeta42), -total-tau (tau) and -phosphorylated-tau181 (p-tau181) as measured by sandwich ELISAs in the clinical routine of a community state hospital to discriminate between patients with Alzheimer's disease (AD), healthy controls (HC), non-AD-dementias, a group composed of various psychiatric disorders (non-AD-dementias, mental diseases) and an age-matched random sample (RS) (total N=219). By comparing patients with AD to HC as reference, tau revealed sensitivity (sens)/specificity (spec) of 88%/80%, p-tau(181) 88%/80%, tau/Abeta42-ratio 81%/85% and phospho-tau(181)/Abeta42-ratio 81%/78%. Discriminative power between HC and all dementias under investigation was estimated lower for tau (78%/77%) and p-tau(181) (73%/79%). Relative to patients with AD, ROC analysis for the RS revealed highest sens/spec for p-tau181 (79%/77%) and p-tau181/Abeta42 ratio (78%/75%). Differentiation between AD versus a group made of patients with various psychiatric disorders was optimised by using CSF-p-tau181 (80%/77%). Under clinical routine conditions current CSF-biomarkers show a substantial capacity to discriminate between AD and HC as reference and to mark off AD patients from RS and heterogeneous diagnostic groups composed of non-AD dementias and other psychiatric conditions. Despite a residual substantial overlap between the groups, we conclude that current CSF markers are well suited to support AD-related diagnostic procedures in every-day clinics.