Currently, there is no biochemical marker clinically available to test for the presence of Alzheimer's disease (AD). Recent studies suggest that the core component of AD-associated neurofibrillary tangles (NFTs), the microtubule-associated protein tau, might be present in CSF. This study focuses on establishing both the presence of tau in CSF and its potential utility in the diagnosis of AD. We obtained CSF from 181 individuals; 71 of these were diagnosed as having probable AD by NINCDS-ADRDA criteria. The remaining 110 individuals were divided into three groups: (1) age-matched demented non-AD patients (n = 25), (2) neurologic controls (n = 59), and (3) other controls (n = 26). We developed a sensitive enzyme-linked immunosorbent tau assay using monoclonal antibodies prepared against recombinant human tau. We confirmed specificity of the antibodies by a combination of immunoprecipitation and immunoblot results. By this assay we measured that the AD population has a mean level of tau 50% greater than the non-AD dementia patients. Comparing AD patients with all other groups, the difference in tau levels as analyzed by one-way ANOVA is highly statistically significant (p < 0.001). Postmortem analysis of two AD patients with high levels of CSF tau revealed a high density of NFTs in the hippocampus. There was no significant correlation between tau and age in the non-AD groups. This study suggests that CSF tau is elevated in AD and might be a useful aid in antemortem diagnosis.

A questionnaire designed to screen Parkinson's disease (PD) in literate populations has been developed. It consists of nine questions, self-administered at medical facilities or by mail, and a scale of weights for ascribing scores to specific questions when the answer is positive. The questions were chosen to be symptom specific for PD and the weights were determined from answers provided by 37 PD patients in a neurological outpatient clinic. The questionnaire sensitivity was tested on a different PD population from the same outpatient clinic--50 individuals--and the specificity on a group of 100 ophthalmological patients. The sensitivity was 100% and the specificity was 100%. Three individuals who screened positive among the 100 ophthalmological patients were assessed and given a new diagnosis of PD. This questionnaire therefore constitutes an instrument that should prove valuable as the first stage of a door-to-door survey. It has high sensitivity and specificity.

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

VPA-induced coma with hyperammonemia and without evidence of hepatic failure should be considered in patients being treated with PHT or PB when VPA is administered concomitantly. This case report shows the importance of clinical monitoring and immediate drug discontinuation when drowsiness, gastrointestinal symptoms, or lethargy occur.

To obtain accurate estimates of the prevalence of age-associated memory impairment, dementia, and Alzheimer's disease, a population study was carried out in Turegano, a rural community of 1011 inhabitants in the Segovia province of Spain. The study was divided into two phases: a door to door survey of the entire population aged 40 years and over (503 persons), followed by a clinical examination of suspected cases for positive and differential diagnosis of dementia and cognitive impairment. The prevalence of age-associated memory impairment was 3*6% in individuals of 40 years and over and 7l1% in individuals of 65 years and over, whereas dementia was found in 2-6% and 5-2%, respectively.The prevalence rates of both clinical conditions increased with age. The most prevalent clinical category of dementia was dementia of Alzheimer type, which represented 1-8% and 3-8% of these two age groups. The corresponding figures for vascular dementia were 0 4% and 0.90/o and for secondary dementia 044% and 0*5%. Age-associated memory impairment is an age-dependent disorder with a high prevalence among the elderly; some of these patients may represent an early stage of Alzheimer's disease, suggesting that the prevalence of this disorder may be higher than previously estimated. ( Neurol Neurosurg Psychiatry 1993;56:973-976) Memory impairment and dementia are among the most frequent neurological disorders of the elderly; Alzheimer's disease accounts for most of these cases.' As a consequence of the projected shift in the age distribution of the population in developed countries, it is expected that the prevalence of these disorders will increase in the future.' This has renewed an interest in epidemiological studies to assess their socioeconomic con-