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K Blennow

Publications and source records attributed to K Blennow.

At least 55 records · Page 3Linked to original sources
PubMed2002

The transcobalamin codon 259 polymorphism influences the risk of human spontaneous abortion.

BACKGROUND: The remethylation cycle of methionine is folate and vitamin B(12) (cobalamin) dependent and appears to be crucial for embryonic development, probably through effects on synthesis of DNA, proteins and polyamines. Transcobalamin (TC) transports vitamin B(12) to the tissues. The objective of the present investigation was to explore the putative association between the major TC genetic polymorphism (Pro259Arg) and human spontaneous abortion. METHODS: The prevalence of the TC Pro259Arg polymorphism was determined in DNA samples from embryos that had been spontaneously aborted between the 6th and 20th week after conception, and adult controls using solid-phase minisequencing technique. RESULTS: The 259-Pro allele was significantly less frequent in the spontaneous abortion group than in the control group (42.2 and 57.0% respectively; P = 0.005), while the frequency of 259-Arg was significantly increased. There was a lower prevalence of 259-Pro homozygotes in the spontaneous abortion group compared with the control group (9.1 and 32.2% respectively; P < 0.001). CONCLUSIONS: The 259-Pro allele seems to have beneficial influences during embryogenesis, conceivably through its positive effect on vitamin B(12) intracellular bioavailability. Our results warrant additional investigations addressing the question if vitamin B(12) supplementation in addition to folic acid supplementation may prevent spontaneous abortion in women planning a pregnancy.

Abortion, Spontaneous↗
PubMed2001

Low cerebrospinal fluid beta-amyloid 42 in patients with acute bacterial meningitis and normalization after treatment.

CSF-A beta 42 may be a marker of Alzheimer's disease (AD). A decreased level of CSF-A beta 42 is consistently found in AD and has been suggested to be related to the deposition of amyloid plaques in the brain. However, low CSF-A beta 42 levels have also been found in disorders devoid of plaques, for instance Creutzfeldt-Jakob disease. To examine if the level of A beta 42 in CSF is related to inflammatory processes, we studied CSF-A beta 42 levels in eight patients with acute purulent bacterial meningitis, 10 patients with acute viral meningitis and 18 age-matched controls. In acute purulent bacterial meningitis, the CSF-A beta 42 level was markedly reduced (28% of that in controls, P<0.0001), whereas no change was found in viral meningitis. After successful treatment of bacterial meningitis, the CSF-A beta 42 level increased (P<0.05 compared to baseline) and did no longer differ from that in controls (ns). The decrease could not be explained by interference with high protein levels, since addition of increasing volumes of serum did not influence the CSF-A beta 42 levels. Our findings suggest that the reduction in CSF-A beta 42 found in bacterial meningitis is not a direct consequence of the inflammatory process. The cause may be disturbance of the clearance of A beta 42 from the brain.

Acute Disease↗
PubMed2001

Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia.

Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate-receptor. Mounting evidence indicate that the compound is significantly involved in basal neurophysiological processes in the brain. In the present investigation, cerebrospinal fluid (CSF) level of kynurenic acid was analyzed in 28 male schizophrenic patients and 17 male healthy controls by means of high pressure liquid chromatography and fluorescence detection. Schizophrenic patients showed elevated CSF levels of kynurenic acid (1.67+/-0.27 nM) compared to the control group (0.97+/-0.07 nM). Furthermore, CSF levels of kynurenic acid in schizophrenic patients were also found to correlate with age. The present finding is indicative of a contribution of kynurenic acid in the pathogenesis of schizophrenia.

Adolescent↗
PubMed2001

Neurofilament protein in cerebrospinal fluid: a marker of white matter changes.

The objective of this study was to compare cerebrospinal fluid (CSF) levels of the light subtype of the neurofilament proteins (NFL), tau, and beta-amyloid42 (Abeta42) in individuals with moderate or severe white matter changes (WMC) and in those with mild or no WMC. Twenty-two patients with Alzheimer's disease (AD), nine patients with subcortical vascular dementia (SVD), and 20 normal controls were included in the study. The occurrence of WMC was evaluated by a neuroradiologist using the Blennow-Wallin scale. Thirty-seven subjects had no or only punctate WMC; 14 had moderate to severe WMC. Both diagnostic group and WMC, but not gender or apolipoproteinE E4 inheritance, contributed to the variance in the CSF levels of tau, NFL, and Abeta42. In patients with moderate to severe WMC, CSF NFL (P < 0.01), but not CSF tau or CSF Abeta42, was increased also after correction for age, gender, and degree of cognitive impairment. A comparison between patients and controls with any signs of WMC and those without such signs yielded a similar result: CSF NFL (P < 0.001) was increased in the group with signs of WMC. As in numerous previous studies, we found that CSF tau was increased in AD (P < 0.001) compared with controls. Furthermore, CSF NFL was increased in both AD and SVD compared with controls (P < 0.001 for both). Although diagnostic group seems to be a stronger predictor of the variance found in CSF NFL, a clear association between the presence of WMC and increased CSF NFL was found. Because NFL is located mainly in large myelinated axons, increased CSF NFL in individuals with WMC probably reflects axonal degeneration.

Aged↗
PubMed2001

[CSF-analyses in clinical diagnosis of Creutzfeldt-Jakob disease. A literature review and three cases from routine clinical practice].

The clinical diagnosis of Creutzfeldt-Jakob disease (CJD) is often difficult, since the clinical presentation varies between patients and is often uncharacteristic. Therefore, CJD is often not suspected until late in the disease process, due to the rapid progress of the disease. Suspected CJD is, however, frequent in routine clinical practice, in the investigation of patients with rapidly progressing dementia and/or uncharacteristic neurological symptoms. We present results from cerebrospinal fluid (CSF) analyses in CJD, focusing on the two neuron-specific proteins 14-3-3 and tau. Analysis of 14-3-3 protein is performed by Western blotting, in which 14-3-3 is either detectable in CSF or not, while CSF-tau is analyzed using quantitative ELISA methodology, in which a markedly increased CSF level of tau (< 1500 pg/mL) is indicative of CJD. Tau and 14-3-3 findings show comparable sensitivity and specificity, higher than the presence of spike and wave complexes on an EEG. The increase in CSF-tau in CJD is substantially higher than in Alzheimer's disease, with low overlap between the disorders. Instead, false positive results are found in disorders with massive acute neuronal damage (encephalitis, stroke and CNS tumors). In cases in which these disorders cannot be differentiated from CJD on clinical grounds, they can often be identified by MRT or by the finding of blood-brain barrier damage or signs of inflammation upon CSF analysis. CSF-tau is increasingly used in the routine diagnosis of Alzheimer's disease, and the analysis also seems to be of use in the clinical diagnosis of CJD. We also present three cases from routine clinical practice, all with a marked increase in CSF-tau, which was the only positive objective sign in two of the cases.

Aged↗
PubMed2001

Differential increase in cerebrospinal fluid-acetylcholinesterase after treatment with acetylcholinesterase inhibitors in patients with Alzheimer's disease.

The clinical significance and the effects of pharmacological treatment of patients with Alzheimer's disease (AD) were evaluated by measurement of acetylcholinesterase (AChE) in the cerebrospinal fluid (CSF). CSF-AChE of AD patients was lower, not significantly, compared with controls. However, CSF-AChE was significantly increased after treatment of AD patients with AChE inhibitors (donepezil and galantamine). The increase was higher in patients treated with donezepil than in those treated with galantamine, which might be related to different mechanisms for the substances. The increase was also dose-dependent, and was especially marked in patients showing a clinical response. These data suggest that CSF biomarkers are capable not only of identifying a biochemical effect of drugs, but also of differentiating between different compounds in a dose-dependent manner.

Acetylcholinesterase↗
PubMed2001

Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke.

An increase in cerebrospinal fluid (CSF)-total-tau, and recently also in CSF-phospho-tau, has been found in Alzheimer's disease (AD). However, the mechanisms for these changes are not known. We examined longitudinal CSF samples from nine patients with acute stroke. As compared with baseline levels (day 0-1), CSF-total-tau showed an increase at day 2-3 (179%; P=0.018), day 7-9 (257%; P=0.003), and after 3 weeks (425%; P=0.002) and returned to normal levels after 3-5 months (140%; NS). In contrast, there was no significant change in CSF-phospho-tau. These findings suggest that total tau and phospho-tau in CSF reflect different pathogenic processes in the brain; total-tau the degree of neuronal damage and phospho-tau the phosphorylation state of tau and thus possibly the formation of neurofibrillary tangles.

Aged↗
PubMed2001

Haptoglobins as markers of blood-CSF barrier dysfunction: the findings in normal CSF.

Cerebrospinal fluid from 39 healthy individuals showed evidence for increasing blood-CSF barrier permeability with age, and confirmed that haptoglobins are more sensitive but less predictive markers of barrier permeability than total protein. Haptoglobin (Hp) species were identified by polyacrylamide gel electrophoresis followed by immunoblotting. Hp 1-1 (35 A, 85 kDa) was detected in all (9/9) subjects who exhibited this phenotype. Hp 2-1 (42 A, 120 kDa) was detected in 53% (8/15) of subjects in whom Hp 2-1 was the phenotype. Hp 2-2 (54 A, 160 kDa) was detected in only 20% (3/15) of subjects who exhibited this phenotype. The likelihood of detecting any haptoglobin species corresponded to the molecular size and the consequent resistance offered by the barrier. Among younger subjects aged < or =45 years, a significant difference in incidence occurred between the two smaller species Hp 1-1 and Hp 2-1. However, among those aged >45, the significant difference in incidence was between the two larger species Hp 2-1 and Hp 2-2. The incidence of detection among those with Hp 2-1 phenotypes was higher in the older age group. The increased likelihood of detecting haptoglobins with age is in keeping with the notion that barrier function is compromised by age, and also indicates that Hp 2-1 and Hp 2-2 are sensitive markers of barrier function. The appreciable incidence of haptoglobins in normal CSF, even of the larger species, suggests reservation in assuming that their presence signifies barrier damage.

Adolescent↗
PubMed2001

Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice.

OBJECTIVE: To evaluate the diagnostic potential of cerebrospinal fluid (CSF) levels of tau and beta-amyloid protein ending at amino acid 42 (Abeta42) as biomarkers for Alzheimer disease (AD) in clinical practice. DESIGN: A 1-year prospective study. SETTING: Community population-based sample of all consecutive patients admitted for investigation of cognitive symptoms to the Piteå River Valley Hospital, Piteå, Sweden. PATIENTS: A total of 241 patients with probable AD (n = 105), possible AD (n = 58), vascular dementia (n = 23), mild cognitive impairment (n = 20), Lewy body dementia (n = 9), other neurological disorders (n = 3), and psychiatric disorders (n = 5) and nondemented individuals (n = 18). MAIN OUTCOME MEASURES: Cerebrospinal fluid tau and CSF-Abeta42 were assayed each week as routine clinical neurochemical analyses. Sensitivity and specificity were defined using the regression line from 100 control subjects from a multicenter study. Positive and negative predictive values were calculated for different prevalence rates of AD. RESULTS: We found increased CSF-tau and decreased CSF-Abeta42 levels in probable and possible AD. Sensitivity was 94% for probable AD, 88% for possible AD, and 75% for mild cognitive impairment, whereas specificity was 100% for psychiatric disorders and 89% for nondemented. Specificity was lower in Lewy body dementia (67%) mainly because of low CSF-Abeta42 levels and in vascular dementia (48%) mainly because of high CSF-tau levels. Sensitivity for CSF-tau and CSF-Abeta42 increased in patients with AD possessing the ApoE epsilon4 allele, approaching 100%. At a prevalence of AD of 45%, the positive predictive value was 90% and the negative predictive value was 95%. CONCLUSIONS: Cerebrospinal fluid tau and CSF-Abeta42 have so far been studied in research settings, under conditions providing data on the optimal performance. We examined a prospective patient sample, with assays run in clinical routine, giving figures closer to the true performance of CSF-tau and CSF-Abeta42. The predictive value for AD was greater than 90%. Therefore, these biomarkers may have a role in the clinical workup of patients with cognitive impairment, especially to differentiate early AD from normal aging and psychiatric disorders.

Aged↗
PubMed2001

Identification of the apolipoprotein E4 isoform in cerebrospinal fluid with preparative two-dimensional electrophoresis and matrix assisted laser desorption/ionization-time of flight-mass spectrometry.

Apolipoprotein E (apoE) was isolated from human cerebrospinal fluid (CSF) from control individuals and patients with Alzheimer's disease (AD). The purification was performed with preparative two-dimensional electrophoresis (2-DE), involving liquid-phase isoelectric focusing (IEF) in the Rotofor cell in combination with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and electroelution in the Mini Whole Gel Eluter. ApoE was characterized by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) analysis of tryptic digests. The known change of Cys to Arg in position 112 of the apoE4 isoform was identified. This was detected in CSF from AD patients, reflecting the increased frequency of the apoE4 allele in this population. This peptide was not detected in CSF samples from healty control individuals. The use of this rapid electrophoretic separation in proteomic studies of CSF proteins provides single proteins, such as apoE, of high purity in yields sufficient for characterization by MALDI-TOF-MS. Characterization of proteins and their modifications (amino acid substitutions, glycosylation or phosphorylation) in CSF will be a useful tool in the investigation of the pathophysiology of brain disorders such as AD.

Adult↗
PubMed2001

Proteome studies of human cerebrospinal fluid and brain tissue using a preparative two-dimensional electrophoresis approach prior to mass spectrometry.

A preparative proteomic approach, involving liquid phase isoelectric focusing (IEF) in combination with one-dimensional electrophoresis and electroelution followed by mass spectrometry and database searches, was found to be an important tool for identifying low-abundant proteins (microgram/L) in human cerebrospinal fluid (CSF) and membrane proteins in human frontal cortex. Several neuron-related proteins, such as amyloid precursor-like protein, chromogranins A and B, glial fibrillary acid protein, beta-trace, transthyretin, ubiquitin, and cystatin C, were identified in CSF. Several types of proteins were also characterized from a detergent-solubilized human frontal cortex homogenate including membrane proteins such as synaptophysin, syntaxin and Na+/K+ ATPase. One-third of the identified proteins have not previously been identified in human CSF or human frontal cortex using proteomic techniques. The absence of these proteins in two-dimensional electrophoresis maps might be due to insufficient amounts or low solubility. The advantages of using preparative liquid phase electrophoretic separations for identifying proteins from complex biological mixtures are speed of analysis, high loadability in the IEF separation, nondiscrimination of membrane proteins or low abundance proteins, yielding sufficient amounts for characterization by mass spectrometry. The use of this strategy in proteome studies of CSF/brain tissue is expected to offer new perspectives in studies of the pathology of neurodegenerative diseases, and reveal new potential markers for brain disorders.

Brain Chemistry↗
PubMed2001

Clinic-based cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E epsilon4 frequency, but no tau gene mutations.

Frontotemporal dementia (FTD) belongs to a group of neurodegenerative disorders known as tauopathies, characterized by intracellular aggregation of hyperphosphorylated tau protein in the brain. Some tauopathies, like Alzheimer's disease (AD), consistently show increased levels of tau protein in cerebrospinal fluid (CSF). However, similar studies in FTD populations have shown variable results, although mutations in the tau gene are identified as causes of disease in certain FTD families. In the present study, a Swedish clinic-based FTD population was investigated with respect to CSF tau levels, apolipoprotein E (APOE) genotype distribution and occurrence of mutations in the tau gene. CSF tau levels were significantly increased among FTD patients (534 +/- 235 pg tau/ml, P < 0.001) (n = 47) compared to controls (316 +/- 137 pg tau/ml) (n = 51). Furthermore, a strong increase in the APOE epsilon4 allele frequency was found in the FTD population, as 52% were epsilon4 carriers, compared to 21% of the controls. However, no mutations in the tau gene were identified. These findings support the present notion of a common pathogenic pathway in the disease processes for several tauopathies, with both APOE epsilon4 and CSF tau being a pathological link between the different disorders. Furthermore, we conclude that mutations in the tau gene are a rare cause of FTD. .

Aged↗
PubMed2001

CSF studies in violent offenders. I. 5-HIAA as a negative and HVA as a positive predictor of psychopathy.

Low serotonin activity in man has been related to impulsive, self-destructive violence but not to instrumental aggression aimed at dominance. A relationship has also been suggested between aggression and high catecholaminergic activity. Several studies have reported signs of aberrant dopaminergic function in attention deficit hyperactivity disorder, autism, and schizophrenia. In 22 violent offenders undergoing pretrial forensic psychiatric investigation, interpersonal and behavioral features of psychopathy, measured by the Psychopathy Checklist Revised (PCL-R), were significantly predicted by low cerebrospinal fluid (CSF) concentrations of 5-HIAA and high CSF concentrations of HVA in multivariate regression models. CSF concentrations of MHPG did not contribute to the model. This seems to link the outward-directed aggression of psychopathy to serotonergic hypofunctioning and high dopamine turnover, which might account for disinhibition of destructive impulses.

Adolescent↗
PubMed2001

CSF studies in violent offenders. II. Blood-brain barrier dysfunction without concurrent inflammation or structure degeneration.

Cerebral dysfunction without corresponding structural pathology has been reported in brain imaging studies of violent offenders. Biochemical markers in the CSF reflect various types of CNS pathology, such as blood-brain barrier dysfunction (CSF/S albumin ratio), infectious or inflammatory processes (IgG and IgM indices), neuronal or axonal degeneration (CSF-tau protein) and synaptic de- or regeneration (CSF-growth associated protein-43 (GAP-43)). We compared these CSF markers in 19 non-psychotic perpetrators of severe violent crimes undergoing pretrial forensic psychiatric investigation and 19 age- and sex-matched controls. Index subjects had significantly higher albumin ratios (p = 0.002), indicating abnormal vascular permeability as part of the complex CNS dysfunction previously reported in violent offenders. Axis I disorders, including substance abuse or current medication, did not explain this finding. Since Ig-indices, CSF-tau protein or CSF-GAP-43 were not increased, there was no support for inflammation or neuronal/synaptic degeneration as etiological factors to CNS dysfunction in this category of subjects.

Adolescent↗
PubMed2001

Tacrine and rate of progression in Alzheimer's disease--relation to ApoE allele genotype.

Today, cognitive impairment can be successfully treated with acetylcholine esterase inhibitors (AChE-I) in many, but not all, patients with Alzheimer's disease (AD). To investigate the relation between tacrine treatment, inheritance of ApoE epsilon4 alleles, and rate of progression, the differences in MMSE and CIBIC scores (efficacy parameters) after 6 and 12 months of tacrine (an AChE-I) treatment were investigated in 145 AD patients. Of these, 84 were ApoE epsilon4-positive (ApoE4) and 61 were ApoE epsilon4-negative (ApoE2-3). No differences were found after 6 months of treatment, but after 12 months the CIBIC scores revealed that the ApoE4 patients had declined more than the ApoE2-3 patients (p < 0.05). No differences were found for the last 6 months of treatment. The results primarily suggest a faster rate of decline in the ApoE4 AD compared to the ApoE2-3, but may also reflect that ApoE epsilon4 genotype inheritance is a negative predictor of treatment effect of tacrine in AD patients.

Aged↗
PubMed2001

Cerebrospinal fluid tau and beta-amyloid(1-42) in dementia disorders.

The reliability of cerebrospinal fluid (CSF)-tau and CSF-beta-amyloid assays for diagnosis of Alzheimer's disease and other dementing disorders such as frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and Creutzfeldt-Jakob disease (CJD) is reviewed. CSF assessment of the two proteins is useful in early diagnosis of AD and to differentiate it from FTD and DLB. Extremely high CSF-tau levels can discriminate CJD from AD.

Amyloid beta-Peptides↗
PubMed2001

Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two prevalent neurodegenerative disorders for which the causes are unknown, except in rare familial cases. Several changes in neuropeptide levels as measured by radioimmunoassay (RIA) have been observed in these illnesses. Somatostatin (SOM) levels in cerebrospinal fluid (CSF) are consistently decreased in AD and FTD. Neuropeptide Y (NPY) levels are decreased in AD, but normal in FTD. Galanin (GAL) levels increase with the duration of illness in AD patients. The majority of studies of neuropeptides in CSF have not been verified by HPLC. The observed decrease in a neuropeptide level as measured by RIA may therefore reflect an altered synthesis or extracellular processing, resulting in neuropeptide fragments that may or may not be detected by RIA. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-MS) has been shown to be a powerful technique in the analysis of biological materials without any pre-treatment, by detecting peptides and proteins at a specific mass-to-charge (m/z) ratio. We studied the processing of the neuropeptides NPY, NPY, SOM and GAL in the cerebrospinal fluid of patients with AD (n = 3), FTD (n = 3) and controls (n = 2) using MALDI-MS. We found that considerable inter-individual variability exists in the rate of neuropeptide metabolism in CSF, as well as the number of peptide fragments formed. Certain patients showed differences in the processing of specific neuropeptides, relative to other patients and controls. This analysis of the metabolic processing of neuropeptides in CSF yielded a large amount of data for each individual studied. Further studies are required to determine the changes in neuropeptide processing that can be associated with AD and FTD. With further investigations using MALDI-MS analysis, it may be possible to identify a neuropeptide fragment or processing enzyme that can be correlated to these disease states.

Alzheimer Disease↗