Johannes Kornhuber

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimers disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimers disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).

Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease

We undertook a two-stage genome-wide association study (GWAS) of Alzheimers disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimers disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

Background Late Onset Alzheimers disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimers disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents — preclinical studies

Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-D-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinsons patients. The issue of whether NMDA antagonism plays a role in the symptomatological antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinsons disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and memantine which show neuroprotective activity in animals at therapeutically relevant doses.

Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt–Jakob disease

Creutzfeldt-Jakob disease (CJD) is a rare, fatal, neurodegenerative disease caused by a transmissible agent designated as proteinaceous infectious agent (prion). Searching for biochemical markers of CJD, we analysed cerebrospinal fluid (CSF) samples of 53 patients for tau-protein using an enzyme linked immunoassay (ELISA). In a group of 21 patients with definite CJD seen in the German case control study for CJD, tau-protein concentrations in CSF were significantly higher than in two control-groups of patients with other diseases (median 13,153 pg/ml, range 1,533-27,648 pg/ml; P = 0.0001). One group comprised 19 patients who were seen in the same study and were diagnosed as having other dementing diseases (tau concentration: median 558 pg/ml, range 233-1,769 pg/ml). The second control group comprised 13 patients from our hospital with no dementing disease (tau concentration: median 296 pg/ml, range 109-640 pg/ml). We conclude that determination of tau protein levels in CSF is a useful marker for laboratory diagnosis of CJD.

Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study

Recent studies from our laboratory have provided evidence that the 1-amino-adamantane derivative memantine (1-amino-3,5-dimethyl-adamantane) binds to the MK-801-binding site of the N-methyl-D-aspartate (NMDA)-receptor-gated ion channel. This action has been suggested to account for the antiparkinsonian and antispastic activity of the drug. In the present investigation we have extended our work by testing a series of 1-amino-adamantanes, including amantadine (1-amino-adamantane) and memantine, for their ability to compete with [3H]MK-801 binding in membrane homogenates of postmortem human frontal cortex. The most potent substance (1-amino-3,5-diethyl-adamantane) had a Ki-value of 0.19 +/- 0.06 microM while the weakest substance (1-N-methyl-amino-adamantane) had a Ki-value of 21.72 +/- 1.63 microM. The Ki-value of amantadine was 10.50 +/- 6.10 microM. In agreement with our earlier investigation, the Ki-value of memantine was 0.54 +/- 0.23 microM. The results indicate that 1-amino-adamantanes, in general, may produce their pharmacological effects through an interaction with the NMDA-receptor-gated ion channel. The displacement of [3H]MK-801 binding thus may provide the basis to predict the antiparkinsonian and antispastic activity of novel substituted 1-amino-adamantanes and possibly of other drugs.

[3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients

[3H]MK-801 binding was used as a marker for the NMDA receptor-ion channel complex in postmortem brain samples from the frontal cortex, hippocampus, putamen, entorhinal region, and amygdala of schizophrenic patients and controls. In schizophrenia [3H]MK-801 binding levels were increased in all brain regions investigated reaching significance in the putamen.

Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex

It has recently been shown that MK-801 ((+ )5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), a NMDA antagonist, has therapeutic activity in an animal model of Parkinsons disease. MK-801 reversed the reduced locomotor activity in the reserpineand amethyl-paratyrosine-pretreated mouse, indicating a mechanism independent of dopamine or noradrenaline release (Carlsson and Carlsson, 1989). This suggests that NMDA antagonists might be useful in the treatment of Parkinsons disease . Conversely, antiparkinson drugs might have NMDA antagonistic activity (Olney et al ., 1987) . The present investigation demonstrates that the long known antiparkinson and antipastic substance, memantine (1-amino-3,5-dimethyladamantane), inhibits the binding of [ 3H]MK-801 to postmortem human brain homogenates at therapeutic concentrations . Tissue from the frontal cortex was taken at autopsy from 3 subjects with no apparent history of neurological or psychiatric disorders . There were 2 males, aged 36 and 60, and 1 female aged 85 years. The postmortem interval was between 24 and 48 h. All details of the experimental procedures were identical to those previously described (Kornhuber et al., 1989) . MK-801 and memantine were investigated within the same assay and all

Neurochemical diagnosis of Alzheimer’s dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau

Cerebrospinal fluid (CSF) concentrations of amyloid β peptides ending at positions 42 and 40 (Aβ42 and Aβ40, respectively), and total tau (tTau) protein were measured by ELISA in order to compare their accuracy in discriminating patients with Alzheimer’s disease (AD, n=22), non-Alzheimer dementia (nAD, n=11) and control subjects (CON, n=35). As compared to the other groups, the concentrations of Aβ42 and tTau were decreased (P<0.001) and increased (P<0.001) in AD, respectively, while Aβ40 did not differ significantly among the groups. Receiver operating characteristic (ROC) analysis was performed to define cut-off values for maximized sensitivity and specificity. For all groups compared the Aβ peptide ratio 42/40 classified more patients correctly, as compared to the concentration of Aβ42 alone: AD versus controls, 94 and 86.7%; AD versus nAD, 90 and 85% and AD versus nAD plus controls, 90.8 and 87%, respectively. The percentage of correctly classified patients was further improved when the Aβ ratio was combined with the analysis of the tTau concentration. Presence of the apolipoprotein E e4 allele, age or degree of mental disability did not significantly influence the parameters studied.

SPECT imaging of dopamine and serotonin transporters with [123I]β-CIT. Binding kinetics in the human brain

Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [123I]-2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane ([123I]β-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamusmidbrain area. Here, we report on the regional kinetic uptake of [123I]β-CIT in the brain of 4 normal volunteers and 2 patients with Parkinsons disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinsons disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only mildly diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinsons disease. Consequently, in Parkinsons disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [123I]β-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.