Gene-gene interaction between interleukin-6 and alpha2-macroglobulin influences the risk for Alzheimer's disease.
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Alleles↗
Biomedical subjects
R Heun
Publications and source records attributed to R Heun.
Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.
Alzheimer's disease (AD) is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss associated with membrane cholesterol release. 24S-hydroxycholesterol (24S-OH-Chol) is an enzymatically oxidized product of cholesterol mainly synthesized in the brain. We tested the hypothesis that plasma levels of this oxysterol could be used as a putative biochemical marker for an altered cholesterol homeostasis in the brain of AD patients. Thirty patients with clinical criteria for AD, 30 healthy volunteers, 18 depressed patients, and 12 patients with vascular dementia (non-Alzheimer demented) were studied. Plasma concentrations of 24S-OH-Chol were assayed by isotope dilution;-mass spectrometry, cholesterol was measured enzymatically, and apolipoprotein E (apoE) was genotyped by polymerase chain reaction and restricted fragment length polymorphism. The concentration of 24S-OH-Chol in AD and non-Alzheimer demented patients was modestly but significantly higher than in healthy controls and in depressed patients. There was no significant difference in the concentrations of 24S-OH-Chol between depressed patients and healthy controls nor between AD and non-Alzheimer demented patients. The apoE straightepsilon4 allele influences plasma 24S-OH-Chol. However, this influence could be completely accounted for by the elevated plasma cholesterol in apoE4 hetero- or homozygotes. Plasma 24S-OH-Chol levels correlated negatively with the severity of dementia. AD and vascular demented patients appear to have higher circulating levels of 24S-OH-Chol than depressed patients and healthy controls. We speculate that 24S-OH-Chol plasma levels may potentially be used as an early biochemical marker for an altered cholesterol homeostasis in the central nervous system. 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.
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A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease.
Cathepsin D (catD) is an intracellular acid protease possibly involved in Alzheimer's disease (AD)-related neurodegeneration through cleavage of amyloid precursor protein into amyloidogenic components. We studied whether an exonic polymorphism of the catD gene (C --> T [Ala --> Val] transition at position 224), which possibly influences pro-catD secretion and intracellular maturation of the enzyme, was associated with the risk for the development of AD in 127 demented patients and 184 controls. The catD*T allele was significantly overrepresented in demented patients (11.8%) compared with nondemented controls (4.9%). Carriers of the catD*T allele had a 3.1-fold increased risk for developing AD than noncarriers. Carriers of the apolipoprotein E (ApoE) epsilon4 allele (ApoE*4) had a 3.9-fold increased risk than non-carriers. The adjusted odds ratio for subjects with the ApoE*4 and the catD*T allele was 19.0 compared with subjects with neither of these two alleles. Our data confirm the results of a recently performed pilot study in an independent sample and suggest that the catD genotype is strongly associated with the risk for AD.
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No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer disease in a German population.
A polymorphism in intron 8 of the presenilin-1 (PS-1) gene has been demonstrated to increase the risk for developing late-onset Alzheimer disease (AD). Conflicting results exist for the association between this intronic polymorphism and AD probably due to variations in the PS-1 gene among different ethnic groups. We investigated the genetic association between this intronic polymorphism in the PS-1 gene and AD in a homogenous group of German Caucasians. The control group consisted of healthy subjects and depressed patients. There were no significant differences in the distribution of the PS-1 genotypes and allele frequencies between AD patients and controls. Our data do not support an association between the intronic polymorphism of the PS-1 gene and AD and there was no interaction between the PS-1 genotype and apolipoprotein E epsilon4 allele.
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Activation of human language processing brain regions after the presentation of random letter strings demonstrated with event-related functional magnetic resonance imaging.
This study addresses the question, to what extent the processing of meaningless random letter strings involves classical language related brain regions. Using event-related functional magnetic resonance imaging (fMRI), which allows random stimulus presentation, we could demonstrate activation in the left inferior frontal gyrus, the left superior temporal gyrus, left parietal and occipital regions after the presentation of random letter strings compared to real words. The activation in these classical language related brain areas reflects an intense lexical evaluation process of the meaningless stimuli. Real words contrasted with random letter strings activated the left angular gyrus, bilateral precuneus and the left posterior cingulate gyrus, which may reflect the access of higher semantic associations.
Adult↗
Genetic polymorphism of cathepsin D is strongly associated with the risk for developing sporadic Alzheimer's disease.
The beta amyloid peptide derives from its precursor protein via proteolytic cleavage of yet unidentified proteases (beta- and gamma-secretases). Cathepsin D is an intracellular protease with in-vitro beta-secretase-like features. An exonic polymorphism of the cathepsin D gene (alanine to valine transition at position 224, exon 2) has been associated with altered enzyme function. We tested the hypothesis that this polymorphism is associated with an increased risk for Alzheimer's disease in 102 demented patients, 191 healthy subjects, and 160 depressed patients. There was a highly significant overrepresentation of the cathepsin D*T allele in demented patients (14.2%) compared to non-demented controls (6.7%, P = 0.0012). Carriers of the cathepsin D*T allele had a 2.4-fold increased risk for developing AD than non-carriers. Carriers of the apolipoprotein E epsilon 4 allele had a 4.1 -fold increased risk than non-carriers. The odds ratio for subjects with the apolipoprotein E epsilon 4 and the cathepsin D*T allele was 5.9. Our data suggest that the cathepsin D genotype is strongly associated with the risk for Alzheimer's disease.
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Functional MRI of cerebral activation during encoding and retrieval of words.
The aims of the present study were to identify the cerebral structures associated with encoding and retrieval of verbal material. To circumvent the inherent disadvantages of the conventional block designs used in functional magnetic resonance imaging (MRI), an event-related design compared activation related to randomly intermixed old and new words during recognition. To support the validity of results, both nonparametric analyses in regions of interest (ROI) and statistical parametric mapping (SPM 96) were used. Twelve healthy volunteers, ages 22-35 years, performed three tasks: intentional encoding of words, recognition of old (previously learned) words, and discrimination between words and nonwords, a task to control for visual input and motor output during recognition. Echo-planar magnetic resonance imaging of blood-level, oxygen-dependent, task-related changes was used to compare cerebral activity under active and resting conditions as well as to detect event-related activity within blocks of trials. Comparable results were obtained following nonparametric statistical analysis of selected ROI and SPM. Encoding of words was associated with increased activity in the left inferior frontal gyrus, including Broca's area and in the left parietal association cortex. Event-related data analysis revealed activation of the right medial frontal gyrus, the right anterior cingulate gyrus, and parietal association cortices during recognition of previously presented words. In the lexical decision task, words in comparison with nonwords were associated with activation of the left parietal association cortex. The right medial frontal gyrus, the right anterior cingulate gyrus, and the right parietal association cortex are likely to be involved in episodic memory functions during recognition of previously presented verbal material. The comparison of event-related activation occurring within one trial block instead of among several trial blocks may significantly improve the performance of memory studies.
Adult↗
Validity of family history diagnosis for dementia.
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Age of Onset↗
A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease.
Local inflammatory processes surrounding the amyloid plaques contribute to the progression and acceleration of the Alzheimer's disease (AD)-related neurodegeneration. Interleukin-6 (IL-6) is an inflammatory cytokine with possible involvement in the local immune response occurring in the central nervous system of AD patients. We tested the hypothesis as to whether a genetic polymorphism of the IL-6 gene (IL-6) modifies the age at onset and risk for sporadic AD. Our results support an association of the C allele of the IL-6 genotype with a delayed initial onset and reduced disease risk and indicate that genetically determined alterations of the immune response may modify the course of AD.
Age of Onset↗
Reference deconvolution in the frequency domain.
Reference deconvolution, i.e., using the lineshape distortions of a reference signal with known ideal shape to deduce a correction function for the whole spectrum, is normally performed in the time domain. As a disadvantage, reference signals of higher multiplicity cannot be employed because of mathematical instabilities. In this work we show that these difficulties can be circumvented by carrying out reference deconvolution in the frequency domain. The computational demands of this approach are higher, but not prohibitive, because the width of the correction function is only a fraction of that of the whole spectrum. An iterative algorithm was implemented that yields the optimum widths of the correction function and of the ideal reference signal. Singular value decomposition was found to produce better results than LU decomposition of the design matrix. The feasibility of the deconvolution method and of the algorithm are demonstrated using both synthetic and experimental data.
Algorithms↗
Screening for depression in the elderly: a study on misclassification by screening instruments and improvement of scale performance.
1. The study compares the psychometric performance of the CES-D and the GHQ-12 in a sample of elderly community residents. Misclassification rates of the questionnaires were analyzed and suggestions for improvement of scale performance are made. 2. 287 subjects out of the general population aged 60-99 years were personally interviewed with standardized diagnostic tools and completed both the GHQ-12 and the CES-D. Best-estimate diagnoses served as standards for receiver operating characteristics (ROC) analysis. 3. Both the GHQ-12 and the CES-D discriminated well between depressive and nondepressive subjects (AUROC = 0.794 and AUROC = 0.782, respectively). The amount of false positive results was high for both questionnaires (GHQ-12: 80.6%, CES-D: 90.1%). Increasing age led to more false positive results on the GHQ-12, whereas the CES-D yielded more false positive results in subjects living in an old age residence or together with family members when compared to those living together with their spouse. 4. The GHQ-12 and the CES-D were valid screening instruments for depression in a community sample of elderly subjects. However, both questionnaires yielded a considerable proportion of false positive results. Elevation of the cut-off score may reduce the misclassification rate of the GHQ-12 but not that of the CES-D.
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The impact of dementia on the detection of depression in elderly subjects from the general population.
BACKGROUND: The performance of the CES-D in a sample of elderly community residents was assessed. The influence of dementia on test performance and the necessity for the use of four factor scores instead of a single summary score of the CES-D were studied. METHOD: Two hundred and eighty-seven subjects out of the general population aged 60-99 years were personally interviewed with standardized diagnostic tools and completed the CES-D. Best-estimate diagnoses served as 'gold standards' for receiver operating characteristics (ROC) analysis. RESULTS: The CES-D discriminated well between depressive and non-depressive subjects. Exclusion of demented subjects from the sample did not markedly increase test performance. Current depressive illness and dementia led to high scores on the CES-D. Unlike the factors 'depressive affect', 'somatic/vegetative complaints', and 'interpersonal relations', the factor' positive affect' of the CES-D discriminated well between demented and non-demented participants. CONCLUSIONS: The CES-D is a valid instrument for screening for depression in a community sample of elderly subjects. Its use can be recommended even if the presence of dementia is likely. The use of factor scores of the CES-D does not substantially contribute to an improvement of overall test performance, but, nevertheless, allows a more detailed insight and better interpretation of test results.
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Schizophrenia and complications of pregnancy and labor: an individual patient data meta-analysis.
Several epidemiological studies have reported an association between complications of pregnancy and delivery and schizophrenia, but none have had sufficient power to examine specific complications that, individually, are of low prevalence. We, therefore, performed an individual patient meta-analysis using the raw data from case control studies that used the Lewis-Murray scale. Data were obtained from 12 studies on 700 schizophrenia subjects and 835 controls. There were significant associations between schizophrenia and premature rupture of membranes, gestational age shorter than 37 weeks, and use of resuscitation or incubator. There were associations of borderline significance between schizophrenia and birthweight lower than 2,500 g and forceps delivery. There was no significant interaction between these complications and sex. We conclude that some abnormalities of pregnancy and delivery may be associated with development of schizophrenia. The pathophysiology may involve hypoxia and so future studies should focus on the accurate measurement of this exposure.
Case-Control Studies↗
Internal and external validity of the WHO Well-Being Scale in the elderly general population.
The objectives of this study were (i) to evaluate the validity of the WHO Well-Being Scale in elderly subjects and (ii) to assess the influence of demographic variables on subjective quality of life. A sample of 254 elderly subjects completed the 22-item WHO Well-Being Scale. The scale had an adequate internal and external validity. However, the short 10-item and 5-item versions were equally valid. Low scores indicating decreased well-being were related to the presence of a psychiatric disorder or, independently, to poor living conditions. The Well-Being Scale and their short versions would appear to be useful instruments for identifying subjects with reduced subjective quality of life.
Adult↗
Detection of subthreshold depression and subthreshold anxiety in the elderly.
OBJECTIVE: To assess the ability of screening instruments to detect subthreshold depression or subthreshold anxiety and to make suggestions for the improvement of instrument performance. DESIGN: Group definition relied on the presence or absence of major psychiatric disorders or of subthreshold disorders (Composite International Diagnostic Interview). SETTING: A community-based study in Germany. PARTICIPANTS: The total sample comprised 274 subjects over 60 years of age; 57 subjects suffered from acute subthreshold depression, 26 subjects suffered from acute subthreshold anxiety, 173 subjects were defined as being healthy (i.e. no acute or lifetime major psychiatric disorder, no acute subthreshold disorder). MEASURES: The short version of the General Health Questionnaire (GHQ-12), the Center for Epidemiologic Studies--Depression Scale (CES-D), the Structured Interview for the Diagnosis of Dementia of the Alzheimer-type, Multiinfarct Dementia and Dementias of other Etiology (SIDAM) for cognitive impairment. RESULTS: Subjects with subthreshold disorders scored higher on the CES-D and the GHQ-12 than healthy individuals. The most distinct increase was observed in the CES-D score of subjects with subthreshold anxiety. The CES-D factor for the presence of somatic/vegetative symptoms performed slightly better compared to the other CES-D factors. CONCLUSIONS: The CES-D moderately detected subthreshold anxiety. Subthreshold depression could not be efficiently detected by either questionnaire. The combination of items indicating the presence of somatic symptoms and depressive affect could improve instrument performance when screening for subthreshold anxiety but not for subthreshold depression.
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The validity of psychometric instruments for detection of dementia in the elderly general population.
OBJECTIVE: To compare the validity of different instruments for screening and diagnosis of dementia and to provide threshold scores for these purposes, ie screening focusing on a high sensitivity and diagnosis focusing on a high specificity. SETTING: 287 subjects from a general population sample who had completed more than one of these psychometric tests. METHODS: The performances of the Structured Interview for the Diagnosis of Dementia of the Alzheimer Type, Multi-Infarct Dementia and Dementias of Other Aetiology according to ICD-10 and DSM-III-R, the Mini-Mental State Examination, the Blessed Dementia Rating Scale, the Global Deterioration Scale, the Verbal Fluency Test, the Word list Learning Task, the Trail Making Test and the Labyrinth Test were compared using receiver operating characteristics analysis. RESULTS: The validity of composite instruments for the discrimination of dementia and cognitive health was higher than the validity of individual tests. However, some cognitive tests, ie verbal fluency and immediate recall of words, reached a high validity, making them useful and short screening instruments for dementia. CONCLUSION: There is no perfect instrument for screening and diagnosis of dementia. Different threshold scores for different purposes were provided in the present study. Recommendations for improving the validity of the Delayed Word List Learning Task for discriminating dementia and cognitive health include the expansion of list length and shortening of delay.
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[Dementia screening in routine clinical practice. A comparative analysis of MMSE, SIDAM and ADAS].
Dementia-screening in clinical routine requires short, sensitive and specific tools. A number of standardized instruments are available for this purpose. The present study analysed the relationship between size of three exemplary dementia-screening tests and their diagnostic accuracy. The Mini-Mental-State-Examination (MMSE), the Structured Interview for the Diagnosis of Dementia of the Alzheimer-type, Multiinfarct Dementia and Dementias of other Aetiologies according to ICD-10 and DSM-III-R (SIDAM) and the Alzheimer's Disease Assessment Scale (ADAS) were applied to 71 patients with dementia of the Alzheimer-type and 73 non-demented controls. A ROC-analysis revealed that neither SIDAM nor ADAS differentiated better between demented and non-demented probands than the MMSE. This was also true for patients with mild dementia. In dementia staging the more comprehensive instruments did not surpass the MMSE, too. Due to it's brevity, the MMSE is the preferential screening-instrument for clinical routine.
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Reliability of interview information in a family study in the elderly.
The aim of the present study was to evaluate the combined test-retest and interrater reliability of different psychiatric lifetime diagnoses yielded in the course of a family study in elderly patients and controls. The following interviews and questionnaires were used in combination: the Composite International Diagnostic Interview (CIDI), the Structured Interview for the Diagnosis of Dementia of the Alzheimer Type, Multi-infarct Dementia and Dementias of Other Aetiology (SI-DAM), the General Health Questionnaire (GHQ-12) and questionnaires for neurasthenia and recurrent brief depression (RBD). Depressive and dementia disorders can be diagnosed with good reliability in a family study setting with the use of these instruments. The diagnoses of phobic disorders, neurasthenia, RBD, subthreshold RBD and psychiatric caseness as indicated by GHQ-12 scores were less reliable in this setting and are therefore less suitable for use in family studies.
Adult↗