Further investigation of citalopram on alcohol consumption in heavy drinkers: responsiveness possibly linked to the DRD2 A2/A2 genotype.
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Adult↗
Biomedical subjects
K Blennow
Publications and source records attributed to K Blennow.
Local and systemic GM-CSF increase in Alzheimer's disease and vascular dementia.
A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of brain damage in dementia. The aim of the present study was to investigate patterns of local and systemic cytokine release in patients with Alzheimer's disease (AD) and vascular dementia (VAD). The intrathecal levels of cytokines were related to neuronal damage and cerebral apoptosis. Twenty patients with early AD and 26 patients with VAD were analyzed with respect to cerebrospinal fluid (CSF) and serum levels of pro- and anti-inflammatory cytokines. In addition, CSF levels of Fas/APO-1 and bcl-2, a measure for apoptosis, and Tau protein, a marker for neuronal degradation, were studied. Significantly increased CSF levels of GM-CSF but not of other cytokines were observed in both dementia groups. These patients displayed a significant correlation between the GM-CSF levels and the levels of Fas/APO-1 and Tau protein in CSF. Our study demonstrates an intrathecal production of GM-CSF, a cytokine stimulating microglial cell growth and exerting inflammatogenic properties. It is suggested that GM-CSF once secreted induces programmed cell death in the brain tissue of patients with dementia.
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Lack of replication of association findings in complex disease: an analysis of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's disease.
There is considerable enthusiasm for the prospect of using common polymorphisms (primarily single nucleotide polymorphisms; SNPs) in candidate genes to unravel the genetics of complex disease. This approach has generated a number of findings of loci which are significantly associated with sporadic Alzheimer's disease (AD). In the present study, a total of 15 genes of interest were chosen from among the previously published reports of significant association in AD. Genotyping was performed on polymorphisms within those genes (14 SNPs and one deletion) using Dynamic Allele Specific Hybridization (DASH) in 204 Swedish patients with sporadic late-onset AD and 186 Swedish control subjects. The genes chosen for analysis were; low-density lipoprotein receptor-related protein (LRP1), angiotensin converting enzyme (DCP1), alpha-2-macroglobulin (A2M), bleomycin hydrolase (BLMH), dihydrolipoyl S-succinyltransferase (DLST), tumour necrosis factor receptor superfamily member 6 (TNFRSF6), nitric oxide synthase (NOS3), presenilin 1 (PSEN1), presenilin 2 (PSEN2), butyrylcholinesterase (BCHE), Fe65 (APBB1), oestrogen receptor alpha (ESR1), cathepsin D (CTSD), methylenetetrahydrofolate reductase (MTHFR), and interleukin 1A (IL1A). We found no strong evidence of association for any of these loci with AD in this population. While the possibility exists that the genes analysed are involved in AD (ie they have weak effects and/or are population specific), results reinforce the need for extensive replication studies if we are to be successful in defining true risk factors in complex diseases.
Alleles↗
Hyperactivity in the hypothalamic-pituitary-adrenal axis in demented patients with delirium.
Occurrence of delirium is known to be related to, among other things, organic brain disorder, somatic disease and old age. It has been hypothesized that delirium is also associated with stress. Disturbances of the hypothalamic-pituitary-adrenal (HPA) system have been found in delirious patients in various studies. The aim of the present study was to determine the activity in the HPA axis in demented patients to ascertain whether the stress regulating system was more disturbed in patients with delirium than in those without delirium. Demented inpatients with no acute medical illness were included in the study. Basal cortisol levels in serum were measured and dexamethasone suppression test (DST) was performed. The most important finding of the study was a strong relationship between delirium and DST pathology irrespective of age and severity of dementia. It is suggested that certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.
Aged↗
Robust and accurate single nucleotide polymorphism genotyping by dynamic allele-specific hybridization (DASH): design criteria and assay validation.
We recently introduced a generic single nucleotide polymorphism (SNP) genotyping method, termed DASH (dynamic allele-specific hybridization), which entails dynamic tracking of probe (oligonucleotide) to target (PCR product) hybridization as reaction temperature is steadily increased. The reliability of DASH and optimal design rules have not been previously reported. We have now evaluated crudely designed DASH assays (sequences unmodified from genomic DNA) for 89 randomly selected and confirmed SNPs. Accurate genotype assignment was achieved for 89% of these worst-case-scenario assays. Failures were determined to be caused by secondary structures in the target molecule, which could be reliably predicted from thermodynamic theory. Improved design rules were thereby established, and these were tested by redesigning six of the failed DASH assays. This involved reengineering PCR primers to eliminate amplified target sequence secondary structures. This sophisticated design strategy led to complete functional recovery of all six assays, implying that SNPs in most if not all sequence contexts can be effectively scored by DASH. Subsequent empirical support for this inference has been evidenced by approximately 30 failure-free DASH assay designs implemented across a range of ongoing genotyping programs. Structured follow-on studies employed standardized assay conditions, and revealed that assay reproducibility (733 duplicated genotypes, six different assays) was as high as 100%, with an assay accuracy (1200 genotypes, three different assays) that exceeded 99.9%. No post-PCR assay failures were encountered. These findings, along with intrinsic low cost and high flexibility, validate DASH as an effective procedure for SNP genotyping.
Alleles↗
Both total and phosphorylated tau are increased in Alzheimer's disease.
BACKGROUND: [corrected] Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES: To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS: Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS: Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p<0.001), SAE (p<0.001), PD (p<0.001), and controls (p<0.001). CSF phosphotau was increased in possible AD compared with FTD (p<0.001) and SAE (p<0.001). CSF tau and CSF phosphotau were positively correlated in all the groups. Molecular weight forms of tau ranging from 25 kDa to 80 kDa were found in the CSF CONCLUSION: Both phosphorylated and unphosphorylated tau isoforms were present in the CSF, and tau protein appeared in both truncated and full length forms. The results suggest that the CSF concentrations of tau and phosphotau are increased in about two thirds of patients with probable AD and in half of those with possible AD but are normal in FTD, SAE, and PD compared with normal aging. Values in the normal range do not exclude AD.
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Evaluation of CSF biomarkers for axonal and neuronal degeneration, gliosis, and beta-amyloid metabolism in Alzheimer's disease.
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Aged↗
One-carbon metabolism and other biochemical correlates of cognitive impairment as visualized by principal component analysis.
In the present report, 101 ambulatory elderly patients complaining about cognitive disturbances were investigated using the Mini-Mental State Examination (MMSE). Laboratory investigations, brain imaging, and electroencephalography were performed. Twelve patients were diagnosed with subjective memory complaints (SMC), 32 with mild cognitive impairment (MCI), 43 with dementia of the Alzheimer type (DAT), and 14 with vascular dementia (VAD). Thirty-three percent of the SMC group, 31% of the MCI group, 45% of the DAT group, and 62% of the VAD group had increased serum homocysteine (s-HCY). Principal component analysis of 19 variables showed 3 significant principal components by cross-validation. The cognitive impairment in the patients (MMSE) was explained to 50%. According to the principal component analysis, the population followed two different routes to cognitive impairment: one correlated with disturbance of one-carbon metabolism (cerebrospinal fluid vitamin B12, plasma B12, plasma folate, and s-HCY) and the other correlated with more classic dementia, as marked by cerebrospinal fluid tau, vascular risk factors, atrophy on brain imaging, possession of the apolipoprotein E4 allele, and age. There was poor discrimination between DAT and VAD.
Aged↗
Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values.
BACKGROUND: Tau protein and the 42-amino acid form of beta-amyloid (Abeta42) measured in cerebrospinal fluid (CSF) have been proposed as potential biochemical diagnostic markers for Alzheimer disease. For the introduction of these assays in clinical practice, adequate reference values are of importance. METHODS: CSF samples were obtained from 231 neurologically and psychiatrically healthy individuals, 21-93 years of age, all with a MiniMental State examination score of 28 or above. Standardized ELISAs were used to measure tau and Abeta42 in CSF. Following IFCC recommendations, we used a rank-based method; the 0.90 and 0.10 fractiles were estimated to establish reference values for CSF-tau and CSF-Abeta42, respectively. Putative confounding factors, such as the influence of the passage of proteins from peripheral blood to CSF, influence of dysfunction of the blood-brain barrier, and freezing and thawing of CSF, were investigated. RESULTS: A correlation with age was found for CSF-tau (r = 0.60; P <0.001). Therefore, separate reference values for different age groups were established for CSF-tau: <300 ng/L in the group 21-50 years of age, <450 ng/L in the group 51-70 years of age, and <500 ng/L in the group 71-93 years of age. CSF-Abeta42 did not correlate with age (r = -0.045), and the reference value was set to >500 ng/L. No correlation was found between blood-brain barrier function and CSF-tau or CSF-Abeta42. CONCLUSIONS: These reference values can be applied when using CSF-tau and CSF-Abeta42 in clinical practice.
Adult↗
No evident neuronal damage after electroconvulsive therapy.
Electroconvulsive therapy (ECT) is regarded as one of the most effective treatments for major depressive disorder but has also been associated with cognitive deficits possibly reflecting brain damage. The aim of this study was therefore to evaluate whether ECT induces cerebral damage as reflected by different biochemical measures. The concentrations in the cerebrospinal fluid (CSF) of three established markers of neuronal/glial degeneration, tau protein (tau), neurofilament (NFL) and S-100 beta protein, were determined in nine patients who fulfilled DSM-IV criteria for major depression. CSF samples were collected before and after a course of six ECT sessions. The CSF/serum (S) albumin ratio reflecting potential blood-brain barrier (BBB) dysfunction was also determined at these time points. The treatment was clinically successful with a significant decline of depressive symptoms in all patients as assessed by the Montgomery-Asberg Rating Scale for Depression. Several patients had signs of BBB dysfunction and/or neuronal damage before the start of treatment. Levels of CSF-tau, CSF-NFL and CSF-S-100 beta levels were not significantly changed by ECT. Also the CSF/S albumin ratio was found to be unchanged after the course of ECT. In conclusion, no biochemical evidence of neuronal/glial damage or BBB dysfunction could be demonstrated following a therapeutic course of ECT.
Adult↗
TNF gene polymorphism and its relation to intracerebral production of TNFalpha and TNFbeta in AD.
OBJECTIVE: To analyze the extent of tumor necrosis factor-alpha (TNFalpha) and TNFbeta gene polymorphism in patients with AD and to relate it to intrathecal levels of these cytokines. METHODS: Analyses of TNFalpha and TNFbeta gene polymorphism were performed using PCR in 52 patients with AD and in 25 control subjects, and the levels of corresponding cytokines were analyzed using ELISA. RESULTS: Patients with AD displayed significantly higher intrathecal levels of TNFalpha, but not TNFbeta, compared with the control subjects. The levels of these cytokines did not differ significantly in patients displaying different alleles of the TNF gene. CONCLUSIONS: Results indicate that increased intrathecal production of TNFalpha in AD is preferentially controlled by environmental stimuli rather than genetic makeup.
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GDNF but not BDNF is increased in cerebrospinal fluid in amyotrophic lateral sclerosis.
Cerebrospinal fluid from 15 patients with ALS and 11 controls without neurological disease were analysed for levels of the neurotrophic factors BDNF and GDNF. Analyses were performed using a sensitive sandwich immunoassay (ELISA). There was no significant difference in BDNF levels between the ALS patients and the control subjects studied. Measurable levels of GDNF were found in 12 out of 15 ALS samples. GDNF was not detected in CSF from any of the control subjects. The finding of increased CSF levels of GDNF in ALS compared to controls, together with earlier findings of increased expression of GDNF mRNA in muscle in ALS, indicates that the capacity to synthesize GDNF is enhanced in this disorder.
Adult↗
Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD.
OBJECTIVE AND BACKGROUND: To investigate the CSF levels of tau and the light neurofilament protein (NFL) in patients with frontotemporal dementia (FTD) and other common dementia disorders as well as normal control subjects. Both proteins have been implicated in the pathophysiology of FTD. METHODS: CSF levels of tau and NFL were investigated in 18 patients with FTD, 21 patients with early-onset AD (EAD), 21 patients with late-onset AD (LAD), and 18 age-matched control subjects. RESULTS: Mean +/- SD CSF NFL levels were increased in patients with FTD (1442 +/- 1183 pg/mL; p < 0.05) and LAD (1006 +/- 727 pg/mL; p < 0.001) compared with control subjects (241 +/- 166 pg/mL) and in LAD compared with EAD (498 +/- 236 pg/mL; p < 0.05), and tended to be increased in FTD compared with EAD. CSF tau levels were increased in EAD (751 +/- 394 pg/mL; p < 0.01) and LAD (699 +/- 319 pg/mL; p < 0.01) compared with control subjects (375 +/- 170 pg/mL), and in EAD (p < 0.001) and LAD (p < 0. 01) compared with FTD (354 +/- 140 pg/mL). CSF NFL correlated positively with degree of cognitive impairment in FTD (r = 0.59; p < 0.05) and LAD (r = 0.61; p < 0.01). No significant differences were found in CSF NFL or CSF tau when comparing patients who did and did not possess the APOE-epsilon4 allele within each diagnostic group. CONCLUSION: The results suggest a differential involvement of these cytoskeleton proteins in FTD and EAD, with NFL primarily involved in the pathophysiology of FTD and tau in that of EAD. The increase in CSF NFL found in LAD might reflect the white-matter degeneration found in a proportion of LAD cases.
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Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization.
Hyperphosphorylation of the microtubule-associated protein tau is specifically found in those brain cells affected in several tauopathies. Tau has also been consistently found to be present in the cerebrospinal fluid (CSF). Here we report the quantification in CSF of tau phosphorylated at Thr 181 using an immunoassay with a synthetic peptide for standardization. The choice of the peptide was based on fine mapping of a phospho-dependent antibody, AT270 (P(176)PAPKT(p)P(132))and a human specific tau antibody, HT7 (P(159)PGQK(163)). CSF-phospho-tau levels were increased in Alzheimer patients (23.5+/-10.1 pM, P<0.01) compared with age-matched controls (15.9+/-5.7 pM), while decreased in patients with frontotemporal dementia (8.6+/-3.9 pM; P<0.01). In every diagnostic group, a highly significant correlation was found between total tau and phospho-tau (Alzheimer's disease, r(2)=0.73; frontotemporal dementia, r(2)=0.43; Control, r(2)=0.42), suggesting that the degree of phosphorylation of CSF-tau changes in different clinical conditions.
Amino Acid Sequence↗
[New discoveries on Alzheimer disease: new biochemical markers can hopefully improve diagnosis].
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Alzheimer Disease↗
No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression.
A polymorphism consisting of a deletion near the 5' splice site of exon 18 on the alpha2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE epsilon4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE epsilon4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.
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Reduction of the synaptic protein rab3a in the thalamus and connecting brain regions in post-mortem schizophrenic brains.
Although the psychotic symptoms in schizophrenia can be alleviated by treatment with dopaminergic receptor antagonists, the etiology and underlying neurochemical pathology remains obscure. Both neuropathological and magnetic resonance imaging studies have found evidence for neuronal loss and atrophy in the thalamus in schizophrenia, implicating this key structure for gating information to cortical areas in the pathophysiology. Recent studies have also found evidence of synaptic loss in the thalamus in schizophrenia. To further examine possible synaptic disturbances, we studied the synaptic related protein rab3a as a marker for synaptic density, using both quantitative Western blotting and immunohistochemistry. The material consisted of brains from 22 schizophrenic patients (mean age 79.3 years), and 24 control subjects (74.8 years). Reduced rab3a protein levels were found in the left thalamus in schizophrenia (0.47 +/- 0.17 vs. 1.00 +/- 0.18; p < 0.0001), while a less marked decrease was found also in the right thalamus (0.75 +/- 0.13 vs. 1.00 +/- 0.09; p < 0.0001). Immunohistochemistry, performed on two schizophrenic and two control brains, revealed that rab3a immunoreactivity was most reduced in the left anterior and mediodorsal thalamic nuclei. Therefore, we extended the study to brain regions connected these thalamic nuclei. Reduced rab3a protein levels were found schizophrenia also in the frontal cortex, hippocampus, gyrus cinguli, and parietal cortex, while no significant differences were found in the temporal cortex, or in cerebellum. The reduction in rab3a was not found to be secondary to confounding factors such as age-differences, post-mortem delay time, generalized brain atrophy, or antipsychotic medication. Therefore, the reduction of rab3a probably reflects synaptic disturbances, possibly synaptic loss, in the limbic system and neocortical areas, in schizophrenia. This part of the brain is known to be involved in behavioral and emotional control, and thus to be crucial for higher mental functions, suggesting that synaptic disturbances in the limbic system may be of importance in the development of psychotic symptoms in schizophrenia.
Adult↗
CSF levels of tau, beta-amyloid(1-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging.
Cerebrospinal fluid (CSF) levels of tau, beta-amyloid(1-42) and growth-associated protein 43 (GAP-43) were studied in patients with frontotemporal dementia (FTD; n = 17), Alzheimer's disease (AD; n = 60), subcortical white-matter dementia (SWD; n = 24), Parkinson's disease (PD; n = 23) and dysthymia (n = 19) and in age-matched controls (n = 32). CSF-tau was significantly increased only in AD, and CSF-beta-amyloid(1-42) was significantly decreased in AD and SWD as compared to controls, and in AD compared to FTD. CSF-GAP-43 was significantly decreased only in PD. The GAP-43/tau ratio was decreased in all the patient groups except the dysthymia group compared to controls. A positive correlation was found between CSF-GAP-43 and CSF-tau in all groups. The results suggest normal levels of CSF-tau and CSF-beta-amyloid(1-42) in FTD, which will aid in the clinical separation of FTD from AD. In SWD, decreased levels of CSF-beta-amyloid(1-42) suggest concomitant involvement of vascular and amyloid protein mechanisms.
Adult↗