| 1. |
- Boström, Gustaf, et al.
(författare)
-
Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid
- 2021
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 81:2, s. 629-640
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.
|
|
| 2. |
- Emami Khoonsari, Payam, et al.
(författare)
-
Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers
- 2019
-
Ingår i: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 67:2, s. 639-651
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: A beta(42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCl/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.
|
|
| 3. |
- Libard, Sylwia, et al.
(författare)
-
Mixed Pathologies in a Subject with a Novel PSEN1 G206R Mutation
- 2022
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:4, s. 1601-1614
-
Tidskriftsartikel (refereegranskat)abstract
- Background: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed.Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer's disease (sAD).Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations.Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations.Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.
|
|
| 4. |
- Olsson, Erika, et al.
(författare)
-
Dietary Patterns and Cognitive Dysfunction in a 12-Year Follow-up Study of 70 Year Old Men
- 2015
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 43:1, s. 109-119
-
Tidskriftsartikel (refereegranskat)abstract
- Background:Adherence to dietary patterns has been associated with cognitive decline and dementia, but studies are inconsistent.Objective:Dietary patterns, i.e., WHO recommendations (Healthy Diet Indicator), a Mediterranean-like diet (modified Mediterranean Diet Score, mMDS), and a low carbohydrate high protein diet (LCHP), were related to incident cognitive dysfunction, as indicated by Alzheimer's disease (AD), all-type dementia, and all-type cognitive impairment, in a cohort of 1,138 elderly Swedish men.Methods:Dietary patterns were derived from 7-day records. Risk relations were calculated by Cox and logistic regression analyses, adjusted for potential confounders. Sensitivity analysis was performed in a subpopulation (n = 564) with energy intake according to the Goldberg cut-off. Results:During a mean follow-up of 12 years, 84, 143, and 198 men developed AD, all-type dementia, and all-type cognitive impairment, respectively. There was no association between Healthy Diet Indicator and any of the outcomes. Hazard ratios associated with 1 standard deviation (SD) increment in the LCHP score were 1.16 (95% confidence interval [CI]: 0.95, 1.43) for AD and 1.16 (95% CI: 0.99, 1.37) for all-type dementia. mMDS was not associated with dementia diagnosis. Odds ratio (OR)/1 SD increase for mMDS and all-type cognitive impairment was 0.82 (95% CI: 0.65, 1.05). In the subpopulation OR for mMDS and all-type cognitive impairment was 0.32 (95% CI: 0.11, 0.89).Conclusion:We found no strong associations with development of cognitive dysfunction for any of the dietary patterns investigated. However, there was a potentially beneficial association for a Mediterranean-like diet on the development of cognitive dysfunction in the subpopulation.
|
|
| 5. |
- Sundelöf, Johan, et al.
(författare)
-
Cystatin C Levels are Positively Correlated with both Aβ42 and Tau Levels in Cerebrospinal Fluid in Persons with Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Controls
- 2010
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 21:2, s. 471-478
-
Tidskriftsartikel (refereegranskat)abstract
- Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-beta (Abeta) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Abeta42, and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Abeta42, and tau levels in CSF in AD, MCI, and controls. As a secondary aim, the relationships between cystatin C, Abeta42, and tau levels across disease groups were investigated. Cystatin C, Abeta42, total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Abeta and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Mean cystatin C levels were similar in cases of AD (5.6 mumol/L +/- 1.7), MCI (5.4 mumol/L +/- 1.48), and controls (5.6 mumol/L +/- 1.6). However, CSF cystatin C levels were strongly and positively correlated with total tau and phosphorylated tau levels (r=0.61-0.81, p< 0.0001) and Abeta42 (r=0.35-0.65, p< 0.001) independent of age, gender, and APOE genotype. Mean CSF cystatin C levels did not differ between patients with AD and MCI and healthy controls. Interestingly, cystatin C levels were positively correlated with both tau and Abeta42 levels in CSF independent of age, gender, and APOE genotype.
|
|
| 6. |
- Sundelöf, Johan, et al.
(författare)
-
Higher Cathepsin B Levels in Plasma in Alzheimer's Disease Compared to Healthy Controls
- 2010
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 22:4, s. 1223-1230
-
Tidskriftsartikel (refereegranskat)abstract
- Cathepsin B is suggested to be involved in amyloid-β (Aβ) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aβ1-40 and Aβ1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aβ1-40 and Aβ1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted.
|
|
| 7. |
- Sundelöf, Johan, et al.
(författare)
-
Systemic inflammation and the risk of Alzheimer's disease and dementia : a prospective population-based study
- 2009
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 18:1, s. 79-87
-
Tidskriftsartikel (refereegranskat)abstract
- Inflammation is suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Serum interleukin-6 (IL-6) and high sensitivity serum reactive protein C (hsCRP) as markers of systemic inflammation were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 1062 and age 77, n = 749). In addition, serum amyloid protein A (SAA) and urinary prostaglandin F2alpha (PGF2alpha) metabolite levels were analyzed at age 77 in this cohort. Two serial samples (at ages 70 and 77) were available from 704 individuals. Using Cox regression analyses, associations between serum IL-6, hsCRP, SAA and PGF2alpha metabolite levels and risk of AD, any type of dementia (all-cause dementia) and non-AD dementia were analyzed. On follow-up (median, 11.3 years) in the age 70 cohort, 81 subjects developed AD and 165 subjects developed all-cause dementia. Serum IL-6, hsCRP, SAA, or PGF2alpha levels were not associated with risk of AD. At age 70, high IL-6 levels were associated with an increased risk of non-AD dementia (Hazard ratio 2.21 for above vs. below/at median, 95%confidence interval 1.23-3.95, p-value = 0.008). A longitudinal change in CRP or IL-6 levels was not associated with AD ordementia. In conclusion, Serum IL-6, hsCRP, SAA, and PGF2alpha levels are not associated with the risk of AD. High serum IL-6 levels may be associated with increased risk of non-AD dementia.
|
|
| 8. |
- Sundelöf, Johan, et al.
(författare)
-
Systemic tocopherols and F2-isoprostanes and the risk of Alzheimer's disease and dementia : a prospective population-based study
- 2009
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 18:1, s. 71-78
-
Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress in the brain is suggested to be involved in the pathophysiology of Alzheimer's disease (AD). In this study, serum alpha- and gamma-tocopherol, the two major systemic antioxidants, were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 616 and age 77, n = 761). In addition, urinary F2-isoprostane levels, as markers of systemic oxidative stress, were analyzed at the age of 77 in this cohort (n = 679). Cox regression analyses were used to examine associations between serum alpha-, gamma-tocopherol and urinary F2-isoprostane levels and AD, any type of dementia (all-cause dementia) and non-AD dementia. On follow-up (median, 12.3 years), 40 subjects developed AD and 86 subjects developed all-cause dementia. Serum alpha- and gamma-tocopherol or urinary F2-isoprostane levels were not associated with the future risk of AD or dementia. In conclusion, systemic serum alpha- and gamma-tocopherol and urinary F2-isoprostane levels are not associated with the future risk of AD or dementia and do not seem to be useful predictors of clinical AD or dementia.
|
|
| 9. |
- Söllvander, Sofia, et al.
(författare)
-
Increased Number of Plasma B Cells Producing Autoantibodies Against A beta(42) Protofibrils in Alzheimer's Disease
- 2015
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 48:1, s. 63-72
-
Tidskriftsartikel (refereegranskat)abstract
- The Alzheimer's disease (AD)-related peptide amyloid-beta (A beta) has a propensity to aggregate into various assemblies including toxic soluble A beta protofibrils. Several studies have reported the existence of anti-A beta antibodies in humans. However, it is still debated whether levels of anti-A beta antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma A beta makes it difficult to reliably measure the concentration of circulating anti-A beta antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-A beta antibody production on a cellular level by measuring the amount of anti-A beta antibody producing cells instead of the plasma level of anti-A beta antibodies. To our knowledge, this is the first time the anti-A beta antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding A beta(40) monomers, whereas the number of cells producing antibodies toward A beta(42) protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic A beta protofibrils, which is significantly increased in AD patients.
|
|
| 10. |
- Vestin, Erika, et al.
(författare)
-
Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults : A Prospective Study
- 2024
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 97:4, s. 1841-1850
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer's disease (AD). Objective: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to antiherpesvirus treatment and potential APOE epsilon 4 carriership interaction. Methods: This studywas conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001-2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied. Results: CumulativeADand all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE epsilon 4 or anti-CMV IgG. Similar results were obtained for HSV-1. Conclusions: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD.
|
|
