| 1. |
- Deming, Yuetiva, et al.
(author)
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Sex-specific genetic predictors of Alzheimer’s disease biomarkers
- 2018
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 857-872
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.
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| 2. |
- Johansson, Annica, 1969, et al.
(author)
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Increased frequency of a new polymorphism in the cell division cycle 2 (cdc2) gene in patients with Alzheimer's disease and frontotemporal dementia.
- 2003
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In: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 340:1, s. 69-73
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Journal article (peer-reviewed)abstract
- Recent studies show linkage between Alzheimer's disease (AD) and two loci on chromosome 10. The cell division cycle 2 (cdc2) gene is located close to one of the chromosome 10 markers, and is a candidate gene for AD since it is involved in the pathogenesis of AD. We sequenced coding exons and flanking intronic sequences and the promoter region on the cdc2 gene and found three new single nucleotide polymorphisms (SNPs). We analyzed 272 Caucasian AD cases, 160 controls and 70 cases with frontotemporal dementia (FTD) for these SNPs. Homozygosity for one of the SNPs (Ex6+7I/D) was more frequent in both AD and FTD cases than in controls. In the combined tauopathy (AD and FTD) group the odds ratio (OR) was 1.77 (95% CI 1.19-2.63) for the Ex6+7II genotype. Our findings suggest that the Ex6+7I allele is associated with tauopathies, both AD and FTD.
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| 3. |
- Norberg, Joakim, et al.
(author)
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Regional Differences in Effects of APOE epsilon 4 on Cognitive Impairment in Non-Demented Subjects
- 2011
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In: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 32:2, s. 135-142
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Journal article (peer-reviewed)abstract
- Background: The APOE epsilon 4 allele is a risk factor for Alzheimer's disease (AD). APOE epsilon 4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE epsilon 4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. Methods: Data from 16 centers across Europe were analyzed. Results: A north-south gradient in APOE epsilon 4 prevalence existed in the total sample (62.7% for APOE epsilon 4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE epsilon 4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. Conclusion: The APOE epsilon 4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE epsilon 4 allele and cognition is region dependent.
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| 4. |
- van de Pol, L. A., et al.
(author)
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White matter hyperintensities and medial temporal lobe atrophy in clinical subtypes of mild cognitive impairment: the DESCRIPA study
- 2009
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 80:10, s. 1069-1074
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Journal article (peer-reviewed)abstract
- Background: Clinical subtypes of mild cognitive impairment (MCI) may represent different underlying aetiologies. Methods: This European, multicentre, memory clinic based study (DESCRIPA) of non-demented subjects investigated whether MCI subtypes have different brain correlates on MRI and whether the relation between subtypes and brain pathology is modified by age. Using visual rating scales, medial temporal lobe atrophy (MTA) (0-4) and white matter hyperintensities (WMH) (0-30) were assessed. Results: Severity of MTA differed between MCI subtypes (p < 0.001), increasing from a mean of 0.8 (SD 0.7) in subjective complaints (n = 77) to 1.3 (0.8) in non-amnestic MCI (n = 93), and from 1.4 (0.9) in single domain amnestic MCI (n = 70) to 1.7 (0.9) in multiple domain amnestic MCI (n = 89). The association between MCI subtype and MTA was modified by age and mainly present in subjects >70 years of age. Severity of WMH did not differ between MCI subtypes (p = 0.21). However, the combination of MTA and WMH differed between MCI subtypes (p = 0.02) Conclusion: We conclude that MCI subtypes may have different brain substrates, especially in older subjects. Isolated MTA was mainly associated with amnestic MCI subtypes, suggesting AD as the underlying cause. In non-amnestic MCI, the relatively higher prevalence of MTA in combination with WMH may suggest a different pathophysiological origin.
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| 5. |
- Deming, Yuetiva, et al.
(author)
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Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
- 2017
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:5, s. 839-856
-
Journal article (peer-reviewed)abstract
- More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
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| 6. |
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| 7. |
- Johansson, A, et al.
(author)
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Increased frequency of a new polymorphism in the cycle 2 (cdc2) gene in patients with Alzheimer's disease frontotemporal dementia
- 2003
-
In: Neuroscience Letters. - 0304-3940. ; 340:1, s. 69-73
-
Journal article (peer-reviewed)abstract
- Recent studies show linkage between Alzheimer's disease (AD) and two loci on chromosome 10. The cell division cycle 2 (cdc2) gene is located close to one of the chromosome 10 markers, and is a candidate gene for AD since it is involved in the pathogenesis of AD. We sequenced coding exons and flanking intronic sequences and the promoter region on the cdc2 gene and found three new single nucleotide polymorphisms (SNPs). We analyzed 272 Caucasian AD cases, 160 controls and 70 cases with frontotemporal dementia (FTD) for these SNPs. Homozygosity for one of the SNPs (Ex6 + 7I/D) was more frequent in both AD and FTD cases than in controls. In the combined tauopathy (AD and FTD) group the odds ratio (OR) was 1.77 (95% CI 1.19-2.63) for the Ex6 + 7II genotype. Our findings suggest that the Ex6 + 7I allele is associated with tauopathies, both AD and FrD. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.
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| 8. |
- Norberg, J, et al.
(author)
-
Regional differences in effects of APOE ε4 on cognitive impairment in non-demented subjects
- 2011
-
In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 32:2, s. 135-142
-
Journal article (peer-reviewed)abstract
- <i>Background:</i> The <i>APOE</i> ε4 allele is a risk factor for Alzheimer’s disease (AD). <i>APOE</i> ε4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the <i>APOE</i> ε4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. <i>Methods:</i> Data from 16 centers across Europe were analyzed. <i>Results:</i> A north-south gradient in <i>APOE</i> ε4 prevalence existed in the total sample (62.7% for <i>APOE</i> ε4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the <i>APOE</i> ε4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. <i>Conclusion:</i> The <i>APOE</i> ε4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the <i>APOE</i> ε4 allele and cognition is region dependent.
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| 9. |
- Visser, P. J., et al.
(author)
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Development of screening guidelines and clinical criteria for predementia Alzheimer's disease
- 2008
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In: Neuroepidemiology. - : S. Karger AG. - 1423-0208 .- 0251-5350. ; 30:4, s. 254-265
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Journal article (peer-reviewed)abstract
- Background: There is an urgent need to identify subjects with Alzheimer's disease (AD) in the predementia phase, but validated diagnostic approaches are currently lacking. In this paper, we present the background, design and methods of a study, which aims to develop clinical criteria for predementia AD. We also present baseline characteristics of the subjects included. The study was part of the multicentre DESCRIPA project, which is being conducted within the network of the European Alzheimer's Disease Consortium. Methods: Clinical criteria will be based on a prospective cohort study of non-demented subjects older than 55 years and referred to a memory clinic. At baseline, a number of markers and risk factors for AD were collected, including demographic variables, measures of performance in activities of daily living, cognitive, neuroimaging and genetic markers, and serum and cerebrospinal fluid markers. Subjects will be reassessed annually for 2 - 3 years, and we will evaluate which combination of variables best predicts AD-type dementia at follow-up. Results: Between 2003 and 2005, 881 subjects were included from 20 memory clinics. Subjects were on average 70.3 years old, and had 10.4 years of education. The average score on the Mini-Mental State Examination was 27.4.
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| 10. |
- Vos, S. J. B., et al.
(author)
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Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI
- 2013
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In: Neurology. - 0028-3878 .- 1526-632X. ; 80:12, s. 1124-1132
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Journal article (peer-reviewed)abstract
- Objective: To compare the predictive accuracy of beta-amyloid (A beta)1-42 and total tau in CSF, Methods: We selected 399 subjects with aMCI and 226 subjects with naMCI from a multicenter Results: At least 1 follow-up was available for 538 subjects (86%). One hundred thirty-two subjects with Conclusions: AD biomarkers are useful to predict AD-type dementia in subjects with aMCI and naMCI.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Bretillon, L, et al.
(author)
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Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases
- 2000
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In: Neuroscience Letters. - 0304-3940. ; 293:2, s. 87-90
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Journal article (peer-reviewed)abstract
- The brain is the exclusive or almost exclusive site of formation of 24S-hydroxycholesterol and we have shown that the circulating level of 24S-hydroxycholesterol is dependent upon the relation between cerebral production and hepatic clearance. In the present work we determined plasma levels of 24S-hydroxycholesterol in patients with various neurological diseases. Eleven subjects with brain death occurring 6-10 h before collection of the plasma samples had markedly reduced circulating levels of 24S-hydroxycholesterol (-43%, P<0.001). Patients with advanced Alzheimer's disease and cerebral inflammatory diseases had slightly lower levels of 24S-hydroxycholesterol in plasma when compared to matched controls. Patients with acute ischemic stroke, multiple sclerosis and primary brain tumors had levels not significantly different from those of controls. The conditions leading to reduced plasma levels of 24S-hydroxycholesterol had no significant effect on plasma levels of another side-chain oxidized oxysterol, 27-hydroxycholesterol. Except for conditions characterized by very marked destruction of the central nervous system, different severe neurological diseases seem to have relatively small effects on the flux of 24S-hydroxycholesterol from the brain.
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| 15. |
- Elfgren, C., et al.
(author)
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Neuropsychological tests as discriminators between dementia of Alzheimer type and frontotemporal dementia
- 1994
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In: International Journal of Geriatric Psychiatry. - : Wiley. - 1099-1166 .- 0885-6230. ; 9:8, s. 635-642
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Journal article (peer-reviewed)abstract
- The aim of this study was to examine whether cognitive test performance alone could distinguish patients with dementia of Alzheimer type (DAT) from those with frontotemporal dementia (FTD). Scores from three neuropsychological tests were used as discriminating variables in 28 cases with postmortem verified diagnoses. The selected tests measured verbal ability, visuospatial ability and verbal memory. Eighty-nine per cent of the sample was correctly classified by discriminant analysis. Evaluating the ability of the obtained discriminant function to differentiate between groups of DAT and FTD in a new, clinically diagnosed sample of 38 cases yielded an overall success rate of 84%. The results suggest that cognitive tests may be helpful for differential diagnosis in the context of a neuropsychiatric examination.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Sjölander, Annica, 1969, et al.
(author)
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Functional Mannose-Binding Lectin Haplotype Variants are Associated with Alzheimer's Disease
- 2013
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 35:1, s. 121-127
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Journal article (peer-reviewed)abstract
- Mannan-Binding lectin (MBL) is a serum lectin and an important constituent of the innate immune system. Processes linked to the innate immune response have previously been implicated in Alzheimer's disease (AD). MBL is associated with blood vessels in the brain and AD patients demonstrate lower MBL levels in the cerebrospinal fluid compared to controls. We investigated six single nucleotide polymorphisms, linked to MBL deficiency, in the corresponding MBL2 gene in AD patients and controls. Two MBL2 haplotypes, LXP and LYQ, were significantly associated with AD risk (OR = 1.6, p = 0.01 and OR = 1.5, p = 0.02, respectively). The present study is the first investigating MBL2 genotypes and haplotypes in relation to AD. Our findings support that the MBL2 gene impact the disease risk.
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| 20. |
- Spangberg, K, et al.
(author)
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SveDem, how do you do, Sweden?
- 2005
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In: INTERNATIONAL PSYCHOGERIATRICS. - 1041-6102. ; 17, s. 337-338
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Conference paper (other academic/artistic)
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| 21. |
- van Rossum, Ineke A, et al.
(author)
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Injury markers predict time to dementia in subjects with MCI and amyloid pathology.
- 2012
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In: Neurology. - 1526-632X. ; 79:17, s. 1809-16
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Journal article (peer-reviewed)abstract
- Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology.
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| 22. |
- Vos, S., et al.
(author)
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Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI
- 2012
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:10, s. 2272-2281
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Journal article (peer-reviewed)abstract
- Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (A beta)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF A beta 1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF A beta 1-42/tau increased predictive accuracy in subjects with normal HCV (p < 0.001) and abnormal HCV (p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF A beta 1-42/tau (p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD. (c) 2012 Elsevier Inc. All rights reserved.
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| 23. |
- Zhang, Y, et al.
(author)
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Medial temporal lobe atrophy increases the specificity of cerebrospinal fluid biomarkers in Alzheimer disease with minor cerebrovascular changes.
- 2009
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In: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 50:6, s. 674-81
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Journal article (peer-reviewed)abstract
- BACKGROUND: Although cerebrospinal fluid (CSF) biomarkers and medial temporal lobe atrophy (MTA) contribute to the diagnosis of Alzheimer disease (AD), they may not be specific. Relatively little is known about how they correlate with each other. PURPOSE: To identify the validity of the radiological linear measurements of brain atrophy in AD diagnosis by examining the correlation with CSF biomarkers and by examining if specificity could be improved in classification of AD from controls, when the linear measurements are combined with the CSF biomarkers. MATERIAL AND METHODS: 59 controls (20 male/39 female, age 73+/-8 years), 162 pure AD patients (49/113, 74+/-7 years), and 86 AD patients with minor cerebrovascular changes (CVC) (31/55, 77+/-5 years), aged between 52 and 94 years, were recruited from the Malmo Alzheimer Study. AD patients were subgrouped into "pure AD" and "AD + CVC" in order to clarify the possible influence of CVC on atrophy or CSF biomarkers in AD patients. Abeta42, T-tau, and P-tau in CSF were examined. Computed tomography (CT) linear measurements were performed, which included temporal horn ratio and suprasellar cistern ratio that reflect MTA. RESULTS: Compared with the 14 significant correlations between the CT measurements and three CSF biomarkers in the pure AD group, there was only one significant correlation in the AD + CVC group and one in the control group. In particular, P-tau correlates with temporal horn ratio only in pure AD. When the CT measurements were added with CSF biomarkers as independent variables in discriminant analysis, the percentage of correct classification of AD + CVC from controls increased from 79.5% (only CSF biomarkers) to 84.6% (combined CT measurements with CSF biomarkers). However, little was changed in the pure AD group. CONCLUSION: P-tau correlates with the linear CT measure of MTA only in pure AD without CVC. Combined with the measure of MTA, the specificity of CSF biomarkers can be increased, but only in AD + CVC. The linear measurements of MTA are of value in AD diagnosis.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Ballard, Clive, et al.
(author)
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alpha-synuclein antibodies recognize a protein present at lower levels in the CSF of patients with dementia with Lewy bodies
- 2010
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In: International Psychogeriatrics. - 1741-203X. ; 22:2, s. 321-327
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Journal article (peer-reviewed)abstract
- Background: Dementia with Lewy bodies (DLB) accounts for 15-20%, of the millions of people worldwide with dementia. Accurate diagnosis is essential to avoid harm and optimize clinical management. There is therefore an urgent need to identify reliable biomarkers. Methods: Mass spectrometry was used to determine the specificity of antibody alpha-synuclein (211) for alpha-synuclein. Using gel electrophoresis we measured protein levels detected by alpha-synuclein specific antibodies in the cerebrospinal fluid (CSF) of DLB patients and compared them to age matched controls. Results: A 24 kDa band was detected using alpha-synuclein specific antibodies which was significantly reduced in the CSF of DLB patients compared to age matched controls (p < 0.05). Further analysis confirmed that even DLB patients with mild dementia showed significant reductions in this protein in comparison to controls. Conclusions: The current study emphasizes the necessity for further studies of CSF alpha-synuclein as a biomarker of DLB and extends our previous knowledge by establishing a potential relationship between alpha-synuclein and the severity of cognitive impairment. The identification of this 24 kDa protein is the next important step in these studies.
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| 29. |
- Clerx, Lies, et al.
(author)
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Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment
- 2013
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 34:8, s. 2003-2013
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Journal article (peer-reviewed)abstract
- Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1-42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1-42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI. (c) 2013 Elsevier Inc. All rights reserved.
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| 30. |
- Darreh-Shori, T., et al.
(author)
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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
- 2006
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In: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 113:11, s. 1791-1801
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Journal article (peer-reviewed)abstract
- 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 (>= 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 (<= 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.
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| 31. |
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| 32. |
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| 33. |
- Jacobs, Heidi I. L., et al.
(author)
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The association between white matter hyperintensities and executive decline in mild cognitive impairment is network dependent
- 2012
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 33:1, s. 1-201
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Journal article (peer-reviewed)abstract
- White matter hyperintensities (WMH) in Mild Cognitive Impairment (MCI) have been associated with impaired executive functioning, although contradictory findings have been reported. The aim of this study was to examine whether WMH location influenced the relation between WMH and executive functioning in MCI participants (55-90 years) in the European multicenter memory-clinic-based DESCRIPA study, who underwent MRI scanning at baseline (N = 337). Linear mixed model analysis was performed to test the association between WMH damage in three networks (frontal-parietal, frontal-subcortical and frontal-parietal-subcortical network) and change in executive functioning over a 3-year period. WMH in the frontal-parietal and in the frontal-parietal-subcortical network were associated with decline in executive functioning. However, the frontal-subcortical network was not associated with change in executive functioning. Our results suggest that parietal WMH are a significant contributor to executive decline in MCI and that investigation of WMH in the cerebral networks supporting cognitive functions provide a new way to differentiate stable from cognitive declining MCI individuals. (C) 2012 Elsevier Inc. All rights reserved.
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| 34. |
- Lautner, Ronald, et al.
(author)
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Preclinical effects of APOE epsilon 4 on cerebrospinal fluid A beta 42 concentrations
- 2017
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In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 9
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Journal article (peer-reviewed)abstract
- Background: From earlier studies it is known that the APOE epsilon 2/epsilon 3/epsilon 4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid(1-42) (A beta 42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF A beta 42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF A beta 42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of A beta 42 were lower in APOE epsilon 4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE epsilon 4 on CSF A beta 42 was age dependent. The age at which CSF A beta 42 concentrations started to decrease was estimated at 50 years in APOE epsilon 4-negative individuals and 43 years in heterozygous APOE epsilon 4 carriers. Homozygous APOE epsilon 4 carriers showed a steady decline in CSF A beta 42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE epsilon 4 allele start to show a decrease in CSF A beta 42 concentration almost a decade before APOE epsilon 4 noncarriers already in early middle age. Homozygous APOE epsilon 4 carriers might deposit A beta 42 throughout the examined age span. These results suggest that there is an APOE epsilon 4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
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| 35. |
- Mattsson, Niklas, 1979, et al.
(author)
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Age and diagnostic performance of Alzheimer disease CSF biomarkers.
- 2012
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In: Neurology. - : American Academy of Neurology (AAN). - 1526-632X .- 0028-3878. ; 78:7, s. 468-76
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Journal article (peer-reviewed)abstract
- Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.
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| 36. |
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| 37. |
- Olsson, A, et al.
(author)
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Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients
- 2003
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In: Experimental Neurology. - 0014-4886. ; 183, s. 74-
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Journal article (peer-reviewed)abstract
- One of the major histopathological hallmarks of Alzheimer's disease (AD) is redundant senile plaques mainly composed of beta-amyloid (Abeta) aggregates. Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP (sAPP) and Abeta. We examined the cerebrospinal fluid (CSF) for alpha- and beta-secretase cleaved sAPP (alpha-sAPP and beta-sAPP) in 81 sporadic AD patients, 19 patients with mild cognitive impairment, and 42 healthy controls by using newly developed sandwich enzyme-linked immunosorbent assay methods. We found that neither the level of CSF-alpha-sAPP nor CSF-beta-sAPP differed between sporadic AD patients and healthy controls. These findings further support the conclusion that there is no change in APP expression in sporadic AD. However, the level of CSF-beta-sAPP was significantly increased in patients with mild cognitive impairment compared to controls. We also investigated the relationship between the CSF level of alphabeta-sAPP and Abeta(42) and the apoE epsilon4 (apoFA.) allele. Significantly lower levels of CSF-alpha-sAPP were found in AD patients possessing one or two apoE4 alleles than in those not possessing the apoE4 allele. Neither the levels of CSF-beta-sAPP nor CSF-Abeta(42) differed when comparing ApoE4 allele-positive with allele-negative individuals. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 38. |
- Parnetti, L, et al.
(author)
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Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors
- 2002
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In: Neurological Sciences. - : Springer Science and Business Media LLC. - 1590-1874 .- 1590-3478. ; 23, s. 95-96
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Journal article (peer-reviewed)abstract
- 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 butyry1cholinesterase (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.
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| 39. |
- Parnetti, L, et al.
(author)
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Changes in CSF acetyl- and butyrylcholinesterase activity after long-term treatment with AChE inhibitors in Alzheimer's disease.
- 2011
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In: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 124:2, s. 122-129
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Journal article (peer-reviewed)abstract
- Objectives - To measure cerebrospinal fluid (CSF) activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in patients with Alzheimer's disease (AD) participating in randomized clinical trials from three European centers, before and after long-term treatment with different AChE inhibitors (AChEIs). Materials and methods - Of the 144 patients included in the study, 104 were treated with donepezil, 15 with galantamine, 16 with rivastigmine, and nine with placebo. CSF AChE and BChE activities were measured at baseline and after 1-year treatment. Results - Donepezil and galantamine groups showed a significant increase in CSF AChE activity at follow-up, while no changes for BChE activity were observed; in donepezil group, a positive correlation between plasma concentration and AChE activity was documented. Conversely, in rivastigmine group, a decrease in CSF activity of both enzymes was observed. CSF AChE and BChE activities were not correlated with the clinical outcome in any group considered. CSF biomarkers did not show any change after treatment. Conclusions - AChEIs differently influence the activity of target enzymes in CSF independent of their pharmacodynamic effects.
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| 40. |
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| 41. |
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| 42. |
- Sjogren, M, et al.
(author)
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Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD
- 2000
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In: Neurology. - 1526-632X. ; 54:10, s. 1960-1964
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Journal article (peer-reviewed)abstract
- 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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| 43. |
- Sjögren, M, et al.
(author)
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CSF levels of tau, beta-amyloid and GAP-43 in frontotemporal 1-42 dementia, other types of dementia and normal aging
- 2000
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In: Journal of neural transmission. - 0300-9564 .- 1435-1463. ; 107:5, s. 563-579
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) levels of tau, ▀-amyloid1-42 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-▀-amyloid1-42 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-▀-amyloid1-42 in FTD, which will aid in the clinical separation of FTD from AD. In SWD, decreased levels of CSF-▀-amyloid1-42 suggest concomitant involvement of vascular and amyloid protein mechanisms.
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| 44. |
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| 45. |
- Visser, Pieter Jelle, et al.
(author)
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Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study.
- 2009
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In: Lancet neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 8:7, s. 619-27
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Journal article (peer-reviewed)abstract
- BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.
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| 46. |
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| 47. |
- Wallin, Anders, 1950, et al.
(author)
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Donepezil in Alzheimer's disease : What to expect after 3 years of treatment in a routine clinical setting
- 2007
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In: Dementia and Geriatric Cognitive Disorders. - Basel : S. Karger AG. - 1420-8008 .- 1421-9824. ; 23:3, s. 150-160
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Journal article (peer-reviewed)abstract
- Background/Aims: Clinical short-term trails have shown positive effects of donepezil treatment in patients with Alzheimer's disease. The outcome of continuous long-term treatment in the routine clinical settings remains to be investigated. Methods: The Swedish Alzheimer Treatment Study (SATS) is a descriptive, prospective, longitudinal, multicentre study. Four hundred and thirty-five outpatients with the clinical diagnosis of Alzheimer's disease, received treatment with donepezil. Patients were assessed with Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), global rating (CIBIC) and Instrumental Activities of Daily Living (IADL) at baseline and every 6 months for a total period of 3 years. Results: The mean MMSE change from baseline was positive for more than 6 months and in subgroups of patients for 12 months. After 3 years of treatment the mean change from baseline in MMSE-score was 3.8 points (95% CI, 3.0-4.7) and the ADAS-cog rise was 8.2 points (95% CI, 6.4-10.1). This is better than expected in untreated historical cohorts, and better than the ADAS-cog rise calculated by the Stern equation (15.6 points, 95% CI, 14.5-16.6). After 3 years with 38% of the patients remaining, 30% of the them were unchanged or improved in the global assessment. Conclusion: Three-year donepezil treatment showed a positive global and cognitive outcome in the routine clinical setting. Copyright © 2007 S. Karger AG.
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| 48. |
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