| 1. |
- Blennow, Kaj, 1958, et al.
(författare)
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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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Ingår i: 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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Tidskriftsartikel (refereegranskat)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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| 2. |
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| 3. |
- Nägga, Katarina, 1962-
(författare)
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Aspects on clinical diagnosis of dementia, with focus on biological markers
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The clinical dementia diagnosis has become more complex with increasing knowledge of the heterogeneity of the disorder and its different aetiological aspects. A clinical dementia population and a control group were investigated with the following aims: I. To study the CSF levels of tau phosphorylated at threonine 181 (P-tau), total tau (T-tau) and ß-amyloid1-42 (Aß42) in the different diagnoses. II. To study associations between dementia disorder, cobalamin and/or folate deficiency, and gastritis. III. To study the presence and severity of CT brain changes in different dementia diagnoses. IV. To investigate to what extent different biomarkers and disease history contribute to the diagnostics of clinical dementia.I. CSF Levels of P-tau, T-tau and Aß42 were analysed with ELISA methods. Elevated CSF levels of P-tau were found in probable Alzheimer's disease (AD) patients compared with cognitively non-disturbed controls. Increased CSF T-tau, and decreased levels of Aß42 were found in both AD, mixed type of dementia, and vascular dementia (VaD) patients compared with the controls. Increased P-tau levels were more specific for AD pathology, but there was still an overlap with the controls, mixed dementia and VaD patients.II. Serological markers for cobalamin and folate deficiencies, and for gastritis were assessed in patients with different dementia diagnoses. Hyperhomocysteinaemia were commonly found in dementia without predominance in any of the investigated categories. Low levels of serum cobalamin or blood folate rarely reflected the elevated Hey levels. A lack of association between serological markers for cobalamin and folate deficiencies and for gastritis was demonstrated.III. A protocol for evaluation of the CT scans was used. Atrophy on the CT scans, although common in dementia, is an unspecific fmding in dementia of different backgrounds. White-matter changes and lacunes, indicating small-vessel disease, were common in dementia of different aetiologies. Dementia of mixed-type pathology was underestimated. More distinct criteria for this diagnostic category are warranted.IV. Partial Least Squares Discriminant Analysis (PLS-DA) was used on a large number of variables covering cognitive and biological markers and disease history. There were good discriminations of subgroups of dementia from the controls. However, the included variables were not able to distinguish between the investigated groups, indicating that several clinical parameters used in diagnosing dementia are in fact observed across different subtypes of dementia.It is concluded that there are no known biomarkers available that can provide a precise differential diagnosis of dementia. The clinical dementia diagnosis must still be based on a combination of a careful disease history, evaluation of risk factors, symptomatology, clinical findings, neurocognitive tests, blood analysis and other available methods such as CT and CSF markers.
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| 4. |
- Nägga, Katarina, et al.
(författare)
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Cerebrospinal fluid phospho-tau, total tau and β-amyloid1-42 in the differentiation between Alzheimer's disease and vascular dementia
- 2002
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 14:3-4, s. 183-190
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Tidskriftsartikel (refereegranskat)abstract
- The two most frequently examined biomarkers in the diagnosis of dementia are cerebrospinal fluid (CSF) tau and β-amyloid1-42 (Aβ1-42). An assay for tau phosphorylated at threonine 181 (phospho-tau) has recently been developed. We studied these three markers in patients with possible Alzheimer's disease (AD; n = 23), probable AD (n = 50), AD with relevant cerebrovascular disease (AD with CVD; n = 14), possible vascular dementia (VaD; n = 39), probable VaD (n = 36), cognitively impaired (n = 13) and 27 neurologically healthy controls. Compared with the controls, tau levels were significantly increased in possible AD, probable AD, AD with CVD and probable VaD. Aβ1-42 was decreased in all dementia groups compared with the controls. In contrast, phospho-tau levels were increased only in probable AD compared with the controls. From the results of the present study, it is concluded that neither measurement of phospho-tau, tau nor Aβ1-42 in CSF can discriminate entirely between dementia and cognitively non-disturbed controls or between dementia of different aetiologies in the clinical diagnostic procedure.
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| 5. |
- Nägga, Katarina, 1962-, et al.
(författare)
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Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia
- 2003
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 16:4, s. 269-275
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of dementia disorders, cobalamin and/or folate deficiency as well as gastritis increases with age. To investigate whether there is an association between these conditions, plasma homocysteine (Hcy), serum methylmalonic acid, serum cobalamin and blood folate concentrations were measured. Gastritis was indirectly diagnosed by measuring serum antibodies against H,K-ATPase, Helicobacter pylori and intrinsic factor, using enzyme-linked immunosorbent assays. The studied groups consisted of 47 patients with Alzheimer’s disease (AD), 9 with AD pathology in combination with additive vascular lesions, 59 with vascular dementia, 8 who were cognitively impaired, and 101 control cases. Plasma Hcy concentrations were significantly elevated in the dementia groups, with the highest levels in patients with vascular pathology. We conclude that hyperhomocysteinemia is a common finding in patients with dementia disorders of different etiologies. The markers for gastritis did not contribute to an elucidation of a possible connection between this condition, dementia disorders, or cobalamin/folate deficiency.
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| 6. |
- Nägga, Katarina, 1962-, et al.
(författare)
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CT brain findings in clinical dementia investigation : underestimation of mixed dementia
- 2004
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 18:1, s. 59-66
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Tidskriftsartikel (refereegranskat)abstract
- Dementia has been found to display a more heterogeneous clinical picture than previously recognized. We investigated brain changes on computed tomography (CT) in a clinical dementia population consisting of 67 cases with Alzheimer's disease (AD), 13 with mixed dementia (AD and vascular dementia, VaD), 71 with VaD, and 12 cases that were not demented. Temporal cortical atrophy and atrophy around the temporal horns were more common in patients with mixed dementia compared to patients with VaD and the non-demented, respectively. Frontal white matter changes were present in 64% of AD, in 85% of mixed dementia and in 79% of VaD cases, but there were no differences between the dementia groups. Lacunes were present in almost 40% of AD cases and in 80 and 85% of VaD and mixed dementia cases, respectively. Only 14% of the VaD cases had large infarcts on the CT. We conclude that large infarcts were rare, even in VaD cases. The increased incidence of white matter changes and lacunes in AD patients strongly indicates an underestimation of the mixed dementia diagnosis. More distinct criteria for this diagnostic category are warranted.
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| 8. |
- Prince, J.A., et al.
(författare)
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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
- 2001
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 9:6, s. 437-444
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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