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N Andreasen

Publications and source records attributed to N Andreasen.

At least 19 recordsLinked to original sources
PubMed2006

Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer's disease following chronic donepezil treatment.

OBJECTIVES: To evaluate long-term changes in acetylcholinesterase (AChE) activity in CSF and blood following donepezil treatment in relation to the concentration of donepezil and cognition in AD patients. METHODS: CSF or blood (or both) samples of a total of 104 patients with mild AD were used [MMSE score 23 +/- 0.4; age 75 +/- 1 years (mean +/- SEM); n=53 for CSF and n=51 for plasma/red blood cell (RBC) samples]. The patients were treated with 5 or 10 mg/day donepezil and clinically followed for 2 years. The CSF and RBC AChE activities were measured by the Ellman's direct colorimetric assay. Protein levels of two variants of AChE ("read-through" AChE-R and synaptic AChE-S) were determined by an ELISA-like method. RESULTS: The plasma donepezil concentration was dose-dependent (between 30 and 60 ng/mL in the 5-mg and 10-mg group, respectively). The CSF donepezil concentration was 10 times lower than the plasma level and showed dose- and time-dependent kinetics. The RBC AChE inhibition was moderate (19-29%). CSF AChE-S inhibition was estimated to 30-40% in the 5-mg and 45-55% in the 10-mg group. Positive correlations were observed between the CSF AChE inhibition, an increased protein level of the AChE-R variant and MMSE examination. Patients with high AChE inhibition (>or=45%) showed a stabilized MMSE test result after up to two years, while a significant decline was observed in AD patients with lower AChE inhibition (<or=30%). CONCLUSIONS: An increase in the protein level of the AChE-R variant corresponded to a high AChE inhibition in CSF and favored less cognitive deterioration.

Acetylcholinesterase↗
PubMed2006

CSF biomarkers for Alzheimer's Disease: levels of beta-amyloid, tau, phosphorylated tau relate to clinical symptoms and survival.

UNLABELLED: Cerebrospinal fluid (CSF) samples from 21 patients with a clinical diagnosis of Alzheimer's disease (AD) participating in a 5-year treatment study with the choline esterase inhibitor tacrin were retrospectively analyzed for the contents of beta-amyloid (Abeta42), total tau (T-tau) and phosphorylated tau (P-tau). A significant positive correlation between the level of P-tau and the number of symptoms according to the DSM-IV criteria (p = 0.041) and the NINCDS-ADRDA (p = 0.029) was observed (i.e. higher levels were found in cases with more symptoms). A significant positive correlation between T-tau, P-tau and ADAS-cog score was identified (i.e. higher levels were found with more severe cognitive dysfunction). Patients who died during the 5-year follow-up had significantly lower levels of Abeta42 (p = 0.011) than those who were still alive. Patients who had died in a 6-year follow-up had significantly lower levels of Abeta42 (p = 0.034) and higher levels of T-tau (p = 0.041) than patients still alive. CONCLUSION: CSF biomarkers do aid the clinical diagnosis of AD. Increased levels of P-tau and T-tau are possible markers for severity and abundance of symptoms in AD. Low levels of Abeta42 may indicate a higher risk of early death in AD.

Aged↗
PubMed2004

APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42.

The epsilon4 allele of APOE is a risk factor for Alzheimer disease (AD). By analysis of a large cohort of AD patients (n = 563) and control subjects (n = 118), it is shown that the epsilon4 allele is strongly associated with reduced CSF levels of beta-amyloid (1-42) (Abeta42) in both AD (p < 10(-9)) and control (p = 0.0012) populations. As no associations of APOE variants with other indexes of AD severity were observed, this effect may reflect a fundamental involvement of ApoE in Abeta metabolism.

Aged↗
PubMed2004

Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment.

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.

Aged↗
PubMed2003

Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer's disease.

The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.

Acetylcholinesterase↗
PubMed2003

Intrathecal inflammation precedes development of Alzheimer's disease.

OBJECTIVES: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), GM-CSF, of the anti-inflammatory cytokine TGFbeta, of tau protein, a marker for neurodegeneration, and of beta amyloid (Abeta), a protein involved in the formation of senile plaques, in prospectively followed up patients with mild cognitive impairment (MCI). METHODS: Analyses of CSF levels of TNFalpha, IL1beta, GM-CSF, TGFbeta, betaa, and tau protein were performed using ELISA in 56 patients with MCI who were followed up prospectively and in 25 age matched, healthy controls. RESULTS: Patients with MCI displayed significantly higher levels of TNFalpha and tau protein and significantly lower levels of TGFbeta and Abeta compared with the healthy controls. After nine months of follow up, 25 patients still displayed MCI while the remaining 31 patients had progressed to Alzheimer's disease (AD). Only MCI patients who progressed to AD at follow up, showed significantly higher CSF levels of TNFalpha than controls. In addition, reduced CSF-Abeta42 levels were only found in MCI patients that progressed to AD, further supporting the notion that disturbed metabolism of Abeta is an early finding in AD. CONCLUSIONS: These results demonstrate increased production of the proinflammatory cytokine, TNFalpha and decreased production of the anti-inflammatory cytokine TGFbeta in patients with MCI at risk to develop AD, suggesting a propensity towards inflammation in this patient group and indicating that CNS inflammation is a early hallmark in the pathogenesis of AD.

Aged↗
PubMed2002

CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects.

In this longitudinal study of 77 patients with mild cognitive impairment (MCI), the authors analyzed whether levels of tau protein phosphorylated at threonine 231 (p-tau(231)) in CSF correlate with progression of cognitive decline. High CSF p-tau(231) levels at baseline, but not total tau protein levels, correlated with cognitive decline and conversion from MCI to AD. Independently, old age and APOE-epsilon 4 carrier status were predictive as well. Our data indicate that an increased p-tau(231) level is a potential risk factor for cognitive decline in patients with MCI.

Adult↗
PubMed2002

Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors.

In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured the activities of AChE and butyrylcholinesterase (BuChe) and the concentrations of beta-amyloid (1-42), tau and phosphorylated tau proteins in the cerebrospinal fluid (CSF). A total of 91 patients suffering from probable AD of mild to moderate degree were treated for 6 months with donepezil (n=59), galantamine (n=15), rivastigmine (n=10), or placebo (n=7). AChE activity in CSF was significantly increased after treatment with donepezil and galantamine; the opposite was observed in the rivastigmine-treated group. Untreated patients did not show any AChE activity variation. BuChE did not show any change in any of the groups studied. Mean values of beta-amyloid(1-42), total tau and phosphorylated tau also did not vary significantly. We conclude that AChE inhibitors induce different effects on CSF AChE activity, while other CSF biomarkers are not significantly affected by treatment.

Acetylcholinesterase↗
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

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

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

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↗
PubMed2000

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↗