| 1. |
- Andreasen, Niels, et al.
(author)
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Cerebrospinal fluid levels of total-tau, phospho-tau and A beta 42 predicts development of Alzheimer's disease in patients with mild cognitive impairment.
- 2003
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In: Acta neurologica Scandinavica. Supplementum. - : Hindawi Limited. - 0065-1427 .- 0001-6314. ; 179, s. 47-51
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) biochemical diagnostic markers may be valuable to help in the diagnosis early in the course of Alzheimer's disease (AD), especially in the phase before clinically overt dementia, i.e. in patients with mild cognitive impairment (MCI). We studied 44 patients with MCI who, at 1-year follow-up investigation, had progressed to AD with dementia, and 32 controls. Three CSF biomarkers related to the central pathogenic processes in AD were analysed, including CSF total-tau (T-tau) (as a marker for neuronal degeneration), CSF phospho-tau (P-tau) (as a marker for hyperphosphorylation of tau and possibly for the formation of neurofibrillary tangles), and CSF A beta 42 (as a marker for A beta metabolism, and possibly for the formation of senile plaques). At baseline, 35/44 (79.5%) of the MCI patients had high CSF T-tau, 31/44 (70.4%) high CSF P-tau, while 34/44 (77.3%) had low CSF-A beta 42 levels. The positive likelihood ratio was 8.45 for CSF T-tau, 7.49 for CSF P-tau and 8.20 for CSF A beta 42. These findings suggest that these CSF-markers are abnormal before the onset of clinical dementia, and that they may help to identify MCI patients that will progress to AD. CSF diagnostic markers will be especially important when drugs with potential effects on the progression of AD (e.g. gamma-secretase inhibitors) will reach the clinical phase.
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| 2. |
- Andreasen, Niels
(author)
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Search for reliable diagnostic markers for Alzheimer’s disease
- 2000
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Doctoral thesis (other academic/artistic)abstract
- The diagnosis of Alzheimer’s disease (AD) is rather difficult not at least in the earlier stages of the disease. The diagnostic accuracy has been reported to be around 65-90%. These figures however, come from academic centers with a special interest in the disease and are based on patients followed for several years. One can speculate that the accuracy is lower at the non-specialist level. This thesis deals with the problem of finding reliable biomarkers in the cerebrospinal fluid (CSF) with acceptable sensitivity and specificity which can be utilized as diagnostic tools not only for the specialist. The defining lesions of AD are the neurofibrillary tangles (NFT) and senile plaques (SP), composed of hyperphosphorylated tau and ß-amyloid (Aß) respectively. Therefore, we focused on total CSF-tau and Aß42 as markers for AD, both individually and in combination with each other. Paper I demonstrates a high sensitivity of CSF-tau for the diagnosis of AD but a lower specificity against other dementias. Specificity for more limited cerebral lesions such as ALS and Parkinsons disease, depression and normal aging is good. Moreover, we demonstrate that the stability between baseline CSF-tau and follow-up is good. Paper II demonstrates high sensitivity for CSF-Aß42 as a diagnostic marker for AD and a low intra-individual variation. Low CSF- Aß42 levels are found even early in the course of the disease. In paper III we again focus on CSF-tau but this time in a large prospective sample of consecutive AD patients from a community based sample. CSF-tau was analyzed in routine clinical neurochemistry. We confirm the high sensitivity and specificity for depression and normal aging demonstrated in paper I. An increase in CSF-tau is seen very early in the course of the disease. In paper IV we combine CSF-tau and CSF-Aß42, looking at all patients referred to the clinic during one year. Both assays were analyzed in routine clinical neurochemistry. Again we can demonstrate high sensitivity and specificity. We suggest the use of the combination of the two biomarkers in common clinical practice as an inexpensive and reliable tool in the diagnosis of AD. In paper V we proceed with the early diagnosis. As we previously found high CSF-tau and low CSF- Aß42 very early in the clinical course of AD we wanted to examine the potential of the two markers in MCI and indeed we found the usefulness even here. Since the sample was relatively small, more studies are required to confirm our findings. Our conclusion is that the combination of the biomarkers tau and Aß42 in the CSF have high sensitivity in the diagnosis of AD even in the very early course of the disease. The specificity for psychiatric disorders (e.g. depression) and some neurological disorders (e.g. Parkinson and ALS) is also good, but lower specificity is found for other dementias. Thus, we also stress that these biomarkers cannot be used alone, but should be part of the full clinical work-up.
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| 3. |
- Blennow, Kaj, 1958, et al.
(author)
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No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression.
- 2000
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In: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 107:8-9, s. 1065-79
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Journal article (peer-reviewed)abstract
- 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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| 4. |
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| 5. |
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| 6. |
- Davidsson, Pia, 1962, et al.
(author)
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Proteome analysis of cerebrospinal fluid proteins in Alzheimer patients.
- 2002
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In: Neuroreport. - : Ovid Technologies (Wolters Kluwer Health). - 0959-4965. ; 13:5, s. 611-5
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Journal article (peer-reviewed)abstract
- By comparing the CSF proteome between Alzheimer disease (AD) patients and controls it may be possible to identify proteins that play a role in the disease process and thus to study the pathogenesis of AD. We used mini-gel technology in a two-dimensional electrophoresis procedure, sensitive SYPRO Ruby staining and mass spectrometry for clinical screening of disease-influenced CSF proteins in 15 AD patients and 12 controls. The levels of six proteins and their isoforms, including proapolipoprotein, apolipoprotein E, beta-2 microglobulin, retinol-binding protein, transthyretin, and ubiquitin, were significantly altered in CSF of AD patients. The most prominently altered proteins were the apolipoproteins, especially proapolipoprotein.
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| 7. |
- Hampel, Harald, et al.
(author)
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Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study.
- 2004
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In: Archives of general psychiatry. - : American Medical Association (AMA). - 0003-990X. ; 61:1, s. 95-102
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Journal article (peer-reviewed)abstract
- BACKGROUND: Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVE: To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias. DESIGN AND SETTING: Cross-sectional, bicenter, memory clinic-based studies. PARTICIPANTS: One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206). MAIN OUTCOME MEASURES: Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays. RESULTS: The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers. CONCLUSIONS: The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.
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| 8. |
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| 9. |
- Johansson, Annica, 1969, et al.
(author)
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CYP46A1 Variants Interact with Age and APOE to Influence CSF Aβ42 and Phospho-Tau Levels in Alzheimer's Disease
- 2004
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In: The 9th International Conference on Alzheimer's Disease (ICAD), Philadelphia, Pennsylvania, USA, 20-25 July 2004.
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Conference paper (other academic/artistic)abstract
- Recent studies have suggested that variants of CYP46A1, encoding cholesterol 24-hydroxylase (CYP46), confer risk to Alzheimer's disease (AD), a prospect substantiated by evidence of genetic association with several quantitative traits related to AD pathology, including cerebrospinal fluid (CSF) levels of the 42 amino-acid cleavage product of β-amyloid (Aβ42) and the tau protein. In the present study, these claims have been explored by the genotyping of previously associated markers in CYP46A1 in three independent Northern European case-control series encompassing 1323 individuals, which include approximately 400 patients with measures of CSF Aβ42 and phospho-tau protein levels. Tests of association in case-control models revealed limited evidence that CYP46A1 variants contribute to AD risk across these samples. However, models testing for potential effects upon CSF measures suggested possible interaction of an intronic marker (rs754203) with age and APOE genotype. In stratified analyses, significant effects were evident that were restricted to elderly APOE ε4 carriers for both CSF Aβ42 (P = 0.0009) and phospho-tau (P = 0.046). Computational analyses indicate that the rs754203 marker probably does not impact the binding of regulatory factors, suggesting that other polymorphic sites underlie observed associations. Results provide an important independent replication of previous findings, supporting the existence of CYP46A1 sequence variants that contribute to variability in β-amyloid metabolism.
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| 10. |
- Johansson, Annica, 1969, et al.
(author)
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Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42 levels in Alzheimer's disease.
- 2004
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In: Human genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 114:6, s. 581-7
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Journal article (peer-reviewed)abstract
- Recent studies have suggested that variants of CYP46A1, encoding cholesterol 24-hydroxylase (CYP46), confer risk for Alzheimer's disease (AD), a prospect substantiated by evidence of genetic association from several quantitative traits related to AD pathology, including cerebrospinal fluid (CSF) levels of the 42 amino-acid cleavage product of beta-amyloid (Abeta42) and the tau protein. In the present study, these claims have been explored by the genotyping of previously associated markers in CYP46A1 in three independent northern European case-control series encompassing 1323 individuals and including approximately 400 patients with measurements of CSF Abeta42 and phospho-tau protein levels. Tests of association in case-control models revealed limited evidence that CYP46A1 variants contributed to AD risk across these samples. However, models testing for potential effects upon CSF measures suggested a possible interaction of an intronic marker (rs754203) with age and APOE genotype. In stratified analyses, significant effects were evident that were restricted to elderly APOE epsilon4 carriers for both CSF Abeta42 ( P=0.0009) and phospho-tau ( P=0.046). Computational analyses indicate that the rs754203 marker probably does not impact the binding of regulatory factors, suggesting that other polymorphic sites underlie the observed associations. Our results provide an important independent replication of previous findings, supporting the existence of CYP46A1 sequence variants that contribute to variability in beta-amyloid metabolism.
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