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Kaj Blennow

Publications and source records attributed to Kaj Blennow.

At least 37 records · Page 2Linked to original sources
PubMed2006

Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry.

Early pathogenic events in Alzheimer's disease (AD) involve increased production and/or reduced clearance of beta-amyloid (Abeta), especially the 42 amino acid fragment Abeta1-42. The Abeta1-42 peptide is generated through cleavage of the amyloid precursor protein by beta- and gamma-secretase and is catabolised by a variety of proteolytic enzymes such as insulin-degrading enzyme and neprilysin. Here, we describe a method that employs immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to determine the pattern of C-terminally truncated Abeta peptides in cerebrospinal fluid (CSF). Using antibodies coupled to magnetic beads, we have detected 18 C-terminally and 2 N-terminally truncated Abeta peptides in CSF. By determining the identity and profile of the truncated Abeta peptides, more insight may be gained about differences in the metabolism and structural properties of Abeta in AD. Finally, the Abeta fragment signatures may prove useful as a diagnostic test for AD.

Amino Acid Sequence↗
PubMed2006

Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND: Total tau (T-tau) and beta-amyloid((1-42)) (Abeta(1-42)) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. METHODS: The analytical performance of the INNOTEST PHOSPHO-TAU(181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Abeta(1-42), for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. RESULTS: CSF concentrations of tau phosphorylated at threonine 181 (P-tau(181P)) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau(181P) was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. CONCLUSIONS: P-tau(181P) quantification is a robust and reliable assay that may be useful in discriminating AD from DLB.

Aged↗
PubMed2006

Vagus nerve stimulation in patients with Alzheimer's disease: Additional follow-up results of a pilot study through 1 year.

BACKGROUND: Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported. METHOD: All patients (N = 17) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Responder rates for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) were measured as improvement or absence of decline from baseline. Global change, depressive symptoms, and quality of life were also assessed. Cerebrospinal fluid (CSF) levels for total tau, tau phosphorylated at Thr181 (phosphotau), and Abeta42 were measured by standardized enzyme-linked immunosorbent assay (ELISA). RESULTS: VNS was well tolerated. After 1 year, 7 (41.2%) of 17 patients and 12 (70.6%) of 17 patients improved or did not decline from baseline on the ADAS-cog and MMSE, respectively. Twelve of 17 patients were rated as having no change or some improvement from baseline on the Clinician Interview-Based Impression of Change (CIBIC+). No significant decline in mood, behavior, or quality of life occurred during 1 year of treatment. The median change in CSF tau at 1 year was a reduction of 4.8% (p = .057), with a 5.0% increase in phosphotau (p = .040; N = 14). CONCLUSION: The results of this study support long-term tolerability of VNS among patients with AD and warrant further investigation.

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PubMed2005

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-beta 1-42 and plasma apolipoprotein levels.

The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of beta-amyloid (Abeta) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Abeta 1-42 levels, reinforcing emerging evidence of a connection between lipid and Abeta metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Abeta 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDL-cholesterol (LDL-C) among smokers (P = 0.000055 and P = 0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus non-smokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Abeta and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.

ATP Binding Cassette Transporter 1↗
PubMed2005

Towards compendia of negative genetic association studies: an example for Alzheimer disease.

Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.

Aged↗
PubMed2005

Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease.

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid(1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F(2, 626) = 7.0, p = 0.001) and the homozygous CDC2 Ex6 + 7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD.

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PubMed2005

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment.

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.

Aged↗
PubMed2005

Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF.

This investigation describes the discovery of novel possible cerebrospinal fluid (CSF) biomarkers for frontotemporal dementia (FTD) using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS). Sixteen clinically diagnosed FTD patients and 12 non-demented controls were included in the study. CSF was collected and analyzed for protein expression by SELDI-TOF MS. The samples were analyzed on four different array surfaces using two different energy-absorbing molecules as matrices. In total each sample was subjected to eight different surface/matrix conditions. About 2000 protein peaks (mass/charge ratios) were detected. Forty-two peaks were differentially expressed in FTD (P < 0.01). After exclusion of peaks with low signal-to-noise ratio and/or poor resolution and peaks representing differentially charged proteins, 10 peaks remained, five of which were increased and five decreased in FTD cases compared to controls. Using partial least square discriminant analysis (PLS-DA), the combination of these biomarkers discriminated FTD from non-demented controls with a sensitivity of 94%, a specificity of 83% and an accuracy of 89%. Five of the peaks were purified further and identified by tandem MS as a fragment of neurosecretory protein VGF, transthyretin, S-cysteinylated transthyretin, truncated cystatin C and a fragment of chromogranin B. With use of these potential biomarkers, FTD can be distinguished from control subjects with high accuracy in this pilot study.

Adult↗
PubMed2005

Amino-truncated beta-amyloid42 peptides in cerebrospinal fluid and prediction of progression of mild cognitive impairment.

BACKGROUND: Early identification of patients with mild cognitive impairment (MCI) progressing to Alzheimer disease (MCI-AD) by use of biomarkers in cerebrospinal fluid (CSF) is an essential step toward improving clinical diagnosis and drug development. We evaluated whether different beta-amyloid(42) (Abeta42) peptides can add further information to the combined use of tau and Abeta1-42 for predicting risk of progression of MCI to AD. METHODS: We used xMAP technology to simultaneously quantify different Abeta42 peptides modified at the amino terminus, tau, and phosphorylated tau (P-tau181P) in CSF. Abeta42 peptide concentrations were measured by use of immunoreactivity toward Abeta monoclonal antibodies [3D6 (Abeta42-3D6), WO2 (Abeta42-WO2), 6E10 (Abeta42-6E10), and 4G8 (Abeta42-4G8)]. The discriminant ability of the markers was evaluated by ROC curve analysis. RESULTS: The areas under the curves for the separation of MCI-AD from nonprogressing MCI (MCI-N) were significantly higher when we used Abeta42-3D6/Abeta42-WO2, Abeta42-3D6/Abeta42-6E10, or Abeta42-3D6/Abeta42-4G8 compared with Abeta42-3D6. In addition, differentiation of MCI-N from MCI-AD was improved by quantification of full-length Abeta1-42 (Abeta42-3D6) compared with Abeta42-WO2, Abeta42-6E10, or Abeta42-4G8. Several Abeta42 peptides truncated at the amino terminus (Abeta11-42 and Abeta8-42) were identified in CSF by surface-enhanced laser desorption/ionization time-of-flight technology. CONCLUSION: The CSF markers tau, Abeta42 forms, and P-tau181P, when used as adjuncts to clinical diagnosis, have the potential to help identify AD pathology and could be a valuable asset for early AD diagnosis.

Aged↗
PubMed2005

Statin treatment and a disease-specific pattern of beta-amyloid peptides in Alzheimer's disease.

According to the amyloid cascade hypothesis, sporadic Alzheimer's disease (AD) is caused by the production and aggregation of beta-amyloid (Abeta), and the production of Abeta has recently been linked to the metabolism of cholesterol. We have previously published clinical studies where the effect of statin treatment on Abeta production has been investigated. No effect on Abeta was found, which is in disagreement with cell and animal studies. In the present study we investigated the effect of statin treatment on a disease-specific pattern consisting of a C-terminally-truncated quintet of Abeta peptides. Nineteen patients with AD were treated with simvastatin for 12 months and the quintet of Abeta peptides were analysed in cerebrospinal fluid before and after treatment. Also included was a group of 15 untreated patients with AD. We found that the Abeta peptide pattern at baseline was in agreement with earlier findings; however, we did not find any change in the Abeta peptide pattern after statin treatment. We suggest that clinical studies with extended treatment periods are performed where higher dosages of statins are used. We also believe that the pleiotropic effects of statins should be investigated further in order to elucidate the connection between Alzheimer's disease and statin treatment.

Aged↗
PubMed2005

Evaluation of factors of importance for clinical dementia diagnosis.

Diagnosing clinical dementia is based on an assessment of different variables, such as the patient's medical history, known risk factors, and biochemical features. Partial least squares discriminant analysis was used to evaluate variables of importance for diagnosing dementia in a clinical dementia population. Polymorphism for genotypes of glutathione S-transferase (GST) and sulfotransferase 1A1, hypothetically of importance in dementia disorders, was also included in the analysis. The study population consisted of 73 patients with Alzheimer's disease (AD), 14 with mixed dementia, 75 patients with vascular dementia, and 28 control cases. We found that several of the variables, such as the presence of ApoE4 allele, high cerebrospinal fluid levels of total tau protein, low levels of beta-amyloid((1-42)), and a low score on the Mini-Mental State Examination, facilitated a discrimination between the diagnoses compared with the controls. The different diagnoses overlapped. There were indications that genotypes of GSTs contributed to a subgrouping within AD.

Aged↗
PubMed2005

Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers.

Alzheimer's disease, the most common cause of dementia, is multifactorial and heterogeneous; its diagnosis remains probable. We postulated that more than one disease mechanism yielded Alzheimer's histopathology, and that subgroups of the disease might be identified by the cerebrospinal fluid (CSF) levels of proteins associated with senile (neuritic) plaques and neurofibrillary tangles. We immunoassayed levels of tau, ubiquitin, and Abeta(1-42) in retrospectively collected CSF samples of 468 clinically diagnosed Alzheimer's disease patients (N = 353) or non-Alzheimer's subjects (N = 115). Latent profile analysis assigned each subject to a cluster based on the levels of these molecular markers. Alzheimer's disease was subdivided into at least five subgroups based on CSF levels of Abeta(1-42), tau, and ubiquitin; each subgroup presented a different clinical profile. These subgroups, which can be identified by CSF analysis, might benefit differently from different therapeutic drugs.

Aged↗
PubMed2005

Analysis of proteins from a glioma cell line by using micro-scale solution isoelectric focusing in combination with liquid chromatography/tandem mass spectrometry.

In this study we have investigated whether micro-solution isoelectric focusing (microsol-IEF) can be used as a pre-fractionation step prior to liquid chromatography/tandem mass spectrometry (LC/MS/MS) and if extensive sample purification of the different fractions is required. We found that, in spite of the high concentrations of buffer and detergents, no clean up of the digested microsol-IEF fractions was necessary before analysis by LC/MS/MS. We also concluded that it is possible to identify at least twice as many proteins in a glioma cell lysate with the combination of microsol-IEF and LC/MS/MS than with LC/MS/MS alone. Furthermore, most of the proteins that were identified from one microsol-IEF fraction by using analytical narrow-range two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and peptide mass fingerprinting with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) were also identified by LC/MS/MS. Finally, we used the combination of microsol-IEF and LC/MS/MS to compare two sample preparation methods for glioma cells and found that several nuclear, mitochondria, and endoplasmic reticulum proteins were only present in the sample that had been subjected to lipid extraction by incubating the homogenized cells in chloroform/methanol/water.

Cell Line, Tumor↗
PubMed2005

Methylenetetrahydrofolate reductase genetic polymorphisms in patients with cataract.

PURPOSE: Hyperhomocysteinemia is commonly associated with polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. The level of homocysteine can be lowered by dietary intake of folate. A protective effect of folate supplementation has been reported against cataract. Here we investigate MTHFR polymorphisms in human cataract. DESIGN: Retrospective case-control association study. METHODS: Patients with nuclear (n = 77), cortical (n = 155), posterior subcapsular (n = 119), and mixed (n = 151) cataract, and 187 controls were analyzed for the MTHFR 677C-->T and 1298A-->C polymorphisms using minisequencing technique. RESULTS: The wild-type MTHFR 677CC/1298AA genotype was strongly overrepresented among cataract cases (P = .003). This effect was most pronounced in the mixed cataract group (P < .001). Hyperhomocysteinemia-associated genotypes had similar frequencies in cataract and control groups. CONCLUSIONS: The previously reported protective effect of folate against cataract is not due to overrepresentation of hyperhomocysteinemia-associated MTHFR genotypes. Instead, the strong predominance of wild-type MTHFR in cataract may suggest impaired DNA synthesis as a cataractogenic factor.

Adult↗
PubMed2005

CSF biomarkers for mild cognitive impairment and early Alzheimer's disease.

A correct clinical diagnosis, early in the course of Alzheimer's disease (AD), is of importance given the currently available symptomatic treatment with acetylcholine esterase inhibitors. The development of disease-modifying drugs like beta-sheet breakers or gamma- and beta-secretase inhibitors, emphasizes the need of improved diagnostic accuracy, especially in patients with mild cognitive impairment (MCI) that have incipient AD. Therefore, diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field. Three cerebrospinal fluid biomarkers (the 42 amino acid form of beta-amyloid (A beta), total tau, and phospho tau) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal aging, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. If these biomarkers are used in combination with a careful medical history, clinical examination, standard laboratory tests and imaging techniques of the brain, the diagnostic accuracy may be appropriate for the clinical evaluation of MCI cases.

Alzheimer Disease↗
PubMed2005

Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer's disease brain.

Insulin degrading enzyme, encoded by IDE, plays a primary role in the degradation of amyloid beta-protein (A beta), the deposition of which in senile plaques is one of the defining hallmarks of Alzheimer's disease (AD). We recently identified haplotypes in a broad linkage disequilibrium (LD) block encompassing IDE that associate with several AD-related quantitative traits. Here, by examining 32 polymorphic markers extending across IDE and testing quantitative measures of plaque density and cognitive function in three independent Swedish AD samples, we have refined the probable position of pathogenic sequences to a 3' region of IDE, with local maximum effects in the proximity of marker rs1887922. To replicate these findings, a subset of variants were examined against measures of brain A beta load in an independent English AD sample, whereby maximum effects were again observed for rs1887922. For both Swedish and English autopsy materials, variation at rs1887922 explained approximately 10% of the total variance in the respective histopathology traits. However, across all clinical materials studied to date, this variant site does not appear to associate directly with disease, suggesting that IDE may affect AD severity rather than risk. Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients.

Alzheimer Disease↗
PubMed2005

The link between cholesterol and Alzheimer's disease.

A leading hypothesis on the pathophysiology of Alzheimer's disease (AD) is the mis-metabolism of amyloid precursor protein. This mis-metabolism causes the 42-amino acid form of A beta(Abeta42) to form oligomers that in turn start a chain of events leading to the accumulation of amyloid plaques. Vascular factors such as hypertension, hypercholesterolemia and diabetes as well as the inheritance of the epsilon4 allele of the ApoE gene are risk factors for AD. These risks are thought to promote the production of beta-amyloid (Abeta). An association between cholesterol and the development of AD was suggested in 1994 and since then, research has confirmed a link between cholesterol and the development of AD. A high cholesterol level in mid-life is a risk for AD and statins i.e. cholesterol-lowering drugs, reduce this risk. Statins inhibit enzymes involved in the endogenous synthesis of cholesterol and evidence is mounting that they also affect enzymes in Abeta metabolism i.e. beta-secretase. This normalises the breakdown of the precursor of Abeta, amyloid precursor protein, thereby promoting the nonamyloidogenic pathway. This review focusses on the link between cholesterol and Alzheimer's disease.

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