Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42

BACKGROUND: The antemortem diagnosis of Alzheimer disease (AD) requires time-consuming and costly procedures. Therefore, biochemical tests that can direct the physician rapidly to the correct diagnosis are highly desirable. Measurement of single biochemical markers in cerebrospinal fluid (CSF), such as total tau protein and beta-amyloid peptide42 (Abeta42), shows robust alterations that highly correlate with the clinical diagnosis of AD but generally lack sufficient diagnostic accuracy. OBJECTIVE: To study the combination of CSF phosphorylated tau protein (phospho-tau) and Abeta42 as biochemical markers for AD. METHODS: We combined CSF measurements of phospho-tau and Abeta42 in 100 consecutive patients who under-went diagnostic workup for dementia and in 31 healthy control subjects. RESULTS: We found that the calculated ratio of phospho-tau to Abeta42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%). CONCLUSION: The diagnostic usefulness of the CSF ratio of phospho-tau to Abeta42 is superior to either measure alone and can be recommended as an aid to evaluating individuals suspected of having dementia.     

Bioelectrical behaviour of hypoxic human neocortical tissue under the influence of nimodipine and dimethyl sulfoxide

Nimodipine and dimethyl sulfoxide (DMSO) have been shown to affect electrophysiological responses in rodent brain tissue in an vitro model of hypoxia. In the present study, the same agents were now examined for their effects on human neocortical brain slices under repeated hypoxic conditions. DMSO (0.4%), with and without addition of nimodipine (40 micromol/l), did not increase the latency of anoxic depolarization (AD). This finding is not in line with our previous observations of DMSO effects, with and without nimodipine, on brain slices of guinea pigs. AD latency was significantly longer in human neocortical brain slices compared with hippocampal slices of rodents even without any pharmacological influence. A possible acute effect of DMSO-nimodipine may therefore be masked by an interspecies difference of hypoxia resistance.     

Electrocardiographic changes at the onset of epileptic seizures

PURPOSE: We studied heart-rate (HR) changes at the transition from the preictal to the ictal state in patients with focal epilepsies to gain some insight into the mechanisms involved in the neuronal regulation of cardiovascular function. METHODS: We assessed ECG changes during 145 seizures recorded with scalp EEG in 58 patients who underwent video-EEG monitoring. Consecutive RR intervals were analyzed with a newly developed mathematical method for a total of 90 s. RESULTS: Ictal-onset tachycardia occurred in 86.9% of all seizures, whereas bradycardia was documented only in 1.4%. The incidence as well as the amount of ictal HR increase was significantly more pronounced in patients with mesial temporal lobe epilepsy (TLE) as compared with those with non-lesional TLE or extratemporal epilepsy. Moreover, right hemispheric seizures were associated with ictal-onset tachycardia. On average, ictal HR increase preceded EEG seizure onset by 13.7 s in TLE patients and 8.2 s in patients with extratemporal epilepsy. This difference was significant. Ictal HR changes could be classified according to their temporal evolution into two different patterns. These two patterns differed significantly between the temporal lobe and the extratemporal epilepsy patient group. CONCLUSIONS: Epileptic discharges directly influence areas of the central autonomic network, thus regulating HR and rhythm. Such changes occur before ictal discharges appear on surface electrodes. Our newly developed method may be of potential use for clinical applications such as automatic seizure-detection systems. Moreover, our method might help to clarify further the basic mechanisms of interactions between heart and brain.     

Small-scale pattern formation in a cortical area of the embryonic chicken telencephalon

The parahippocampal area is a cortical region of the avian dorsomedial telencephalon. In the chicken embryo, it contains discrete clusters of cadherin-7-positive cells, which are embedded in a cadherin-7-negative matrix. In the present work, the development and spatial distribution of these clusters is studied in whole-mount specimens. The clusters form a complex, coherent pattern of patches of variable size, spacing, and staining intensity. The pattern is especially prominent and regularly spaced in the rostral part of the caudolateral parahippocampal area. Here, it consists of stripes and connecting bridges with an average periodicity of approximately 0.3 mm. This pattern vaguely resembles some animal fur patterns and the ocular dominance domain of the mammalian visual cortex. The cadherin-7-positive patches also differ from their surrounding area by their cytoarchitecture and their increased acetylcholinesterase activity, suggesting that they represent functionally specialized subregions within the parahippocampal area. During development, the patchiness is first observed between 9 and 10 days of incubation and gradually becomes more prominent until 15 days of incubation. Our results indicate that the patchy organization of cortical gray matter on a small scale of periodicity (below 1 mm), which is well studied in the mammalian neocortex, is also found in the avian telencephalon.     

Increased expression of GABA(A) receptor beta-subunits in the hippocampus of patients with temporal lobe epilepsy

It has been postulated that dysfunction of the GABA-ergic transmission is causatively related to the development of epilepsy. Animal models of temporal lobe epilepsy (TLE) revealed considerable changes in the expression of GABA(A) receptor subunits in the hippocampus. Using immunocytochemistry, we investigated the expression of GABA(A) receptor subunits alpha1, alpha3, beta1-3, and gamma2 in hippocampal specimens obtained at surgery from TLE patients with and without hippocampal sclerosis and in autopsy controls. Consistent with the severe neurodegeneration in the CA1 sector, significant decreases in alpha1-, alpha3-, beta3-, and gamma2-subunit immunoreactivity (IR) were detected in sclerotic but not in nonsclerosic specimens. In contrast, pronounced increases in IR of all 3 beta-subunits were observed in most sectors of the hippocampal formation both in sclerotic and nonsclerotic specimens, being especially pronounced in the dentate molecular layer and in the subiculum where subunit alpha3- and gamma2-IR were also elevated. Using in situ hybridization for subunits beta2 and beta3, increased expression of the respective mRNAs was detected in dentate granule cells of patients with and without hippocampal sclerosis. Beta-subunits are important constituents of the GABA(A) receptor and contribute to the binding site of GABA. Our data indicate pronounced adaptive changes in the expression of these GABA(A) receptor subunits related to seizure activity and indicate altered assembly of GABA(A) receptors in TLE.     

Detecting panic disorder in medical and psychosomatic outpatients: comparative validation of the Hospital Anxiety and Depression Scale, the Patient Health Questionnaire, a screening question, and physicians' diagnosis

OBJECTIVES: To compare the validity of detecting panic disorder using the Hospital Anxiety and Depression Scale (HADS), the Patient Health Questionnaire (PHQ), a screening question, and physicians' diagnosis, and to test whether modified evaluation algorithms improve the operating characteristics of these questionnaires. Additionally, patient and physician acceptability of the screening questionnaires was investigated. METHODS: The total sample of 499 patients comprised 348 medical outpatients and 151 psychosomatic outpatients. The Structured Clinical Interview for DSM-IV (SCID) was the criterion standard for the presence of a panic disorder. Sensitivity, specificity, predictive values, and overall accuracy were compared for the different measures. The conditional test characteristics were calculated based on the observed prevalence of panic disorder in the medical and psychosomatic subsample, respectively. RESULTS: Panic disorder was diagnosed in 4.3% of the medical outpatients and in 19.2% of the psychosomatic outpatients. The HADS, PHQ, and screening question achieved good operating characteristics. In contrast, physicians detected only 15% of cases with panic disorder. Modified evaluation algorithms of the questionnaires lead to an improvement of test characteristics. Of all measures, the PHQ had the best operating characteristics. The use of screening questionnaires was accepted by 96% of the patients and 97% of the physicians. CONCLUSIONS: The questionnaires as well as the screening question performed well in detecting panic disorder. Thus, the integration of these highly accepted measures into clinical evaluation is suggested. Recommendations for the selection of specific evaluation algorithms are given.     

Nonconscious formation and reactivation of semantic associations by way of the medial temporal lobe

A successful strategy to memorize unrelated items is to associate them semantically. This learning method is typical for declarative memory and depends on the medial temporal lobe (MTL). Yet, only a small fraction of perceived items emerge into conscious awareness and receive the status of representations in declarative memory. This functional magnetic resonance imaging (fMRI) study tackled the mnemonic fate of unrelated item pairs processed without conscious awareness. Stimuli consisted of a face and a written profession (experimental condition) or of a face (control condition) exposed very briefly between pattern masks. Although the participants were unaware of the stimuli, activity in the hippocampus and perirhinal cortex was changed in the experimental versus the control condition; perirhinal activity changes correlated with the reaction time measure of the later nonconscious retrieval. For retrieval, the previously presented faces were shown again, this time for conscious inspection. The task was to guess the professional category of each face. This task was to induce a nonconscious retrieval of previously formed face-profession associations. Remarkably, activity in the hippocampus and perirhinal cortex was enhanced when subjects were confronted with faces from the experimental versus the control condition. The degree of hippocampal and perirhinal activation changes correlated with the reaction time measure of nonconscious retrieval. Together, our findings suggest that new semantic associations can be formed and retrieved by way of the medial temporal lobe without awareness of the associations or its components at encoding or any awareness that one is remembering at retrieval.     

Hemostatic markers with bolus versus prolonged heparin after carotid artery stenting

BACKGROUND: The evolving technique of carotid stenting (CS) requires optimal antithrombotic strategies to reduce periinterventional thromboembolic risk. In animal models of balloon injury, tissue factor (TF) was shown to be the major procoagulant of the atherosclerotic plaque mediating prolonged procoagulant activity. METHODS: We analyzed TF and TF-dependent hemostatic markers before and 2, 6 and 24 h after CS with two antithrombotic drug regimens. Group A (n=20) received prolonged unfractionated heparin (UFH) for 18-20 h starting at intervention next to aspirin and thienopyridine. In group B (n=16), single bolus UFH was administered next to combined antiplatelet therapy. Natural anticoagulants were determined at baseline. RESULTS: Patients with symptomatic and asymptomatic cerebrovascular disease did not differ in plasma TF levels. Furthermore, no statistically significant difference for TF, TFPI/Xa-complex and prothrombin fragment F1.2 was observed between bolus and prolonged heparin treatment. No significant change was found in time course for these parameters. Two patients (5.5%; one in each treatment group) suffered periinterventional minor stroke associated with increased levels of F1.2 and TFPI/Xa-complex. Both were resistant to activated protein C (APC ratio<1.9) due to heterozygous factor V Leiden mutation. CONCLUSIONS: No significant activation of the TF pathway was seen with both antithrombotic regimens suggesting that single bolus UFH combined with antiplatelet therapy is generally sufficient to control TF-dependent procoagulant activity after CS. However, patients with resistance to activated protein C may be at increased periinterventional stroke risk.     

Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats

There is a concern that increased paternal age may be associated with altered fertility and an increased incidence of birth defects in man. In previous studies of aged male rats, we have found abnormalities in the fertility and in the embryos sired by older males. Aging in mammals is associated with alterations in the content and patterns of DNA methylation in somatic cells; however, little is known in regard to germ cells. A systematic search for global and gene-specific alterations of DNA methylation in germ cells and liver of male rats was done. Restriction landmark genomic scanning, a method used to determine specific methylation patterns of CpG island sequences, has revealed a region of the ribosomal DNA locus that is preferentially hypermethylated with age in both spermatozoa and liver. In contrast, all single copy CpG island sequences in spermatozoa and in liver remain unaltered with age. We further demonstrate that a large proportion of rat ribosomal DNA is normally methylated and that regional and site-specific differences exist in the patterns of methylation between spermatozoa and liver. We conclude that patterns of ribosomal DNA methylation in spermatozoa are vulnerable to the same age-dependent alterations that we observe in normal aging liver. Failure to maintain normal DNA methylation patterns in male germ cells could be one of the mechanisms underlying age-related abnormalities in fertility and progeny outcome.