PubMed Health⌕ Search

Biomedical subjects

Christoph Hock

Publications and source records attributed to Christoph Hock.

36 records · Page 2Linked to original sources
PubMed2003

Glucocorticoid-related genetic susceptibility for Alzheimer's disease.

Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for Alzheimer's disease (AD). We analyzed single-nucleotide polymorphisms in 10 glucocorticoid-related genes in a population of 814 AD patients and unrelated control subjects. Set-association analysis revealed that a rare haplotype in the 5' regulatory region of the gene encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) was associated with a 6-fold increased risk for sporadic AD. Results of a reporter-gene assay indicated that the rare risk-associated haplotype altered HSD11B1 transcription. HSD11B1 controls tissue levels of biologically active glucocorticoids and thereby influences neuronal vulnerability. Our results indicate that a functional variation in the glucocorticoid system increases the risk for AD, which may have important implications for the diagnosis and treatment of this disease.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2003

A functional genetic variation of the 5-HT2a receptor affects human memory.

Human memory capacity is highly variable across individuals and is influenced by both genetic and environmental factors. A roughly 50% heritability estimate indicates that naturally occurring genetic variations have an important impact on this cognitive ability. Therefore, we investigated a functional variation of a memory-related serotonin receptor in 349 healthy young volunteers, and found 21% poorer memory performance in subjects with the rare variant.

Case-Control Studies↗
PubMed2003

Safety of injectable opioid maintenance treatment for heroin dependence.

BACKGROUND: There is a growing debate about injectable opioid treatment programs in many Western countries. This is the first placebo-controlled study of the safety of injectable opioids in a controlled treatment setting. METHODS: Twenty-five opioid-dependent patients on intravenous (IV) heroin or IV methadone maintenance treatment were randomly assigned to either their individual prescribed IV maintenance dose or placebo. Acute drug effects were recorded, focusing on electrocardiography, respiratory movements, arterial blood oxygen saturation, and electroencephalography (EEG). RESULTS: After heroin injection, marked respiratory depression progressing to a Cheyne-Stokes pattern occurred. Peripheral arterial blood oxygenation decreased to 78.9 +/- 8.7% (mean +/- SD) ranging from 52%-90%. During hypoxia, 7 of the 16 subjects experienced intermittent and somewhat severe bradycardia. Five subjects exhibited paroxysmal EEG patterns. After methadone injection, respiratory depression was less pronounced than after heroin injection. No relevant bradycardia was noted. CONCLUSIONS: Opioid doses commonly prescribed in IV opioid treatment induce marked respiratory and circulatory depression, as well as occasionally irregular paroxysmal EEG activity. Further studies are needed to optimize the clinical practice of IV opioid treatment to prevent serious complications. Moreover, the extent of the observed effects raises questions about the appropriateness of IV opioid treatment in the present form.

Adult↗
PubMed2003

Functional neuroimaging predicts individual memory outcome after amygdalohippocampectomy.

We examined memory-related activity within to-be-resected medial temporal lobe (MTL) structures in 12 epilepsy patients with PET before amygdalohippocampectomy and studied the reallocation of memory functions to the contralateral MTL before and after surgery. Learning tasks were designed to activate predominantly the right or left MTL. Those patients who significantly activated to-be-resected ipsilateral MTL structures during the ipsilateral learning task (i.e. the left MTL during verbal learning or the right MTL during nonverbal learning) experienced a postoperative memory decline. Preoperative activation in the contralateral MTL during the ipsilateral learning task positively correlated with the postoperative outcome for ipsilateral memory. There was no significant postoperative reallocation of ipsilateral memory functions to the contralateral MTL.

Adolescent↗
PubMed2003

Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease.

To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimer's disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease.

Activities of Daily Living↗
PubMed2003

Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism.

BACKGROUND: CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain. OBJECTIVE: To study the association of polymorphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD. DESIGN: Alzheimer disease traits (beta-amyloid load, beta-amyloid peptides, hyperphosphorylated tau protein) were assessed in brain tissues and in the cerebrospinal fluid of patients with AD and control subjects. Genetic associations were studied in 2 independent populations. SETTING: Specialized centers for memory disorders in Switzerland, Greece, and Italy. PARTICIPANTS: Fifty-five brain tissues from nondemented elderly patients for the histopathological studies; 38 patients with AD and 25 control subjects for the cerebrospinal fluid studies; 201 patients with AD and 248 control subjects for the genetic association studies. RESULTS: A polymorphism of CYP46 was associated with increased beta-amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau protein. Moreover, this CYP46 polymorphism was associated with higher risk of late-onset sporadic AD in 2 independent populations (odds ratio, 2.16; 95% confidence interval [CI], 1.41-3.32; P<.001). The additional presence of 1 or 2 apolipoprotein E epsilon4 alleles synergistically increased the risk of AD to an odds ratio of 9.6 (95% CI, 4.9-18.9; P<.001) as compared with 4.4 for apolipoprotein E epsilon4 alone (95% CI, 2.8-6.8; P<.001). CONCLUSION: CYP46 influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.

Age of Onset↗
PubMed2003

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.

Adult↗
PubMed2003

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.

Adult↗
PubMed2003

Glucocorticoid-induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe.

Previous work indicates that stress levels of circulating glucocorticoids can impair retrieval of declarative memory in human subjects. Several studies have reported that declarative memory retrieval relies on the medial temporal lobe. The present study used H(2)(15)O-positron emission tomography to investigate whether acutely elevated glucocorticoid levels affect regional cerebral blood flow in the medial temporal lobe, as well as in other brain regions, during declarative memory retrieval in healthy male human subjects. When measured over four different declarative memory retrieval tasks, a single, stress-level dose of cortisone (25 mg) administered orally 1 h before retention testing, induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, the left visual cortex and the cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval. Cortisone administration also significantly impaired cued recall of word pairs learned 24 h earlier, while drug effects on performance in the other tasks (verbal recognition, semantic generation and categorization) were not significant. The present results provide further evidence that acutely elevated glucocorticoid levels can impair declarative memory retrieval processes and suggest that such impairments may be related to a disturbance of medial temporal lobe function.

Adult↗
PubMed2003

Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease.

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

Aged↗
PubMed2002

Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease.

To characterize antibodies produced in humans in response to Abeta42 vaccination, we carried out immunohistochemical examinations of the brains of both transgenic mice and human patients with beta-amyloid pathology. We collected sera from patients with Alzheimer disease who received a primary injection of pre-aggregated Abeta42 followed by one booster injection in a placebo-controlled study. Antibodies in immune sera recognized beta-amyloid plaques, diffuse Abeta deposits and vascular beta-amyloid in brain blood vessels. The antibodies did not cross-react with native full-length beta-amyloid precursor protein or its physiological derivatives, including soluble Abeta42. These findings indicate that vaccination of AD patients with Abeta42 induces antibodies that have a high degree of selectivity for the pathogenic target structures. Whether vaccination to produce antibodies against beta-amyloid will halt the cognitive decline in AD will depend upon clinical assessments over time.

Aged↗
PubMed2002

Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer's disease-causing mutation.

To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyloid precursor protein (SwAPP) on the vulnerability of central nervous system neurons, we induced epileptic seizures in transgenic mice expressing SwAPP. The transgene expression did not change the seizure threshold, but consistently more neurons degenerated in brains of SwAPP mice as compared with wild-type littermates. The degenerating neurons were stained both by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and by Gallyas silver impregnation. A susceptible population of neurons accumulated intracellular Abeta and immunoreacted with antibodies against activated caspase-3. To demonstrate that increased Abeta levels mediated the increased vulnerability, we infused antibodies against Abeta and found a significant reduction in neuronal loss that was paralleled by decreased brain levels of Abeta. Because the SwAPP mice exhibited no amyloid plaques at the age of these experiments, transgenic overproduction of Abeta in brain rendered neurons susceptible to damage much earlier than the onset of amyloid plaque formation. Our data underscore the possibility that Abeta is toxic, that it increases the vulnerability of neurons to excitotoxic events produced by seizures, and that lowering Abeta by passive immunization can protect neurons from Abeta-related toxicity.

Alzheimer Disease↗
PubMed2002

New aspects in the treatment of heroin dependence with special reference to neurobiological aspects.

The Swiss trials on medical prescription of injectable diacetylmorphine (pharmaceutical heroin) for "severe" heroin dependence provoked very controversial commentaries. Despite methodological shortcomings, the evaluation of the Swiss heroin trials yielded some interesting findings. Study participants showed substantial improvements in health and well-being and noticeable declines in illicit drug use and criminal activities. Heroin prescription may thus be helpful for some of those who continue to regularly use illicit heroin while maintained on methadone or who refuse other available treatment options. However, research-based evidence suggests that the intravenous (IV) application of heroin under medical supervision may have untoward side effects. Recent studies have shown that heroin injections produce transient, but significant decreases in systemic and cortical oxygenation most likely secondary to respiratory depression. Among others, these effects are the subject of ongoing studies.

Adult↗
PubMed2002

Genetic polymorphisms and cerebrospinal fluid levels of tissue inhibitor of metalloproteinases 1 in sporadic Alzheimer's disease.

Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.

5' Untranslated Regions↗
PubMed2002

Decline in long-term circadian rest-activity cycle organization in a patient with dementia.

Continuous measurement of the circadian rest-activity cycle for 598 days in a demented patient with probable Alzheimer's disease revealed slow progressive changes in temporal organization until death. Circadian and sleep analysis of the actigraphic data provided objective documentation of the gradual insertion of wakefulness into rest and rest into wake periods. Pacing, a nonphotic zeitgeber strengthening, led to improved synchronization of the rest-activity cycle.

Aged↗
PubMedDate not supplied

Interactive computer-training as a therapeutic tool in Alzheimer's disease.

The current study sought to evaluate a novel kind of interactive computer-based cognitive training (ICT) in Alzheimer's disease (AD). AD patients (N = 9), age- and gender-matched patients with a major depressive episode (N = 9), and healthy control subjects (N = 10) were trained to use an ICT program that relates to activities of daily living (ADL). Digital photographs of a shopping route were implemented in a close-to-reality simulation on a computer touch-screen. The task was to find a predefined shopping route, to buy three items, and to answer correctly 10 multiple-choice questions addressing knowledge related to the virtual tasks. Training performance was rated using the number of mistakes (wrong way), time needed for the tasks, number of correct multiple-choice answers, and of repeat of instruction. Compared to normal controls and depressed patients, AD patients performed significantly worse with regard to all variables. Within a 4-week training period including 12 sessions, however, substantial training gains were observed, including a significant reduction of mistakes. Training effects were sustained until follow-up 3 weeks later. The performance of the depressed patients and the normal controls improved as well, with no difference between the two groups. Self-reported effects revealed that the training was well perceived. Thus, the task performance of AD patients improved substantially and subjects appeared to have liked this approach to ICT. New interactive media, therefore, may yield interesting opportunities for rehabilitation and (psycho)therapeutic interventions.

Activities of Daily Living↗
PubMedDate not supplied

ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease.

Increased formation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). High cellular cholesterol load promotes Abeta formation. The ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1 may influence cholesterol metabolism in the central nervous system (CNS) and, thus, interfere with the development of AD. Healthy elderly carriers of the A allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset, sporadic AD, this allele was associated with delayed age at onset of the disease by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in ABCA1 (rs2234886) failed to show significant association with the risk for AD. We conclude that genetic variability of ABCA1 influences the development of AD, possibly by interfering with CNS cholesterol homeostasis.

ATP Binding Cassette Transporter 1↗