| 1. |
- Cicognola, Claudia, et al.
(författare)
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Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment
- 2021
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Plasma glial fibrillary acidic protein (GFAP) is a marker of astroglial activation and astrocytosis. We assessed the ability of plasma GFAP to detect Alzheimer’s disease (AD) pathology in the form of AD-related amyloid-β (Aβ) pathology and conversion to AD dementia in a mild cognitive impairment (MCI) cohort. Method: One hundred sixty MCI patients were followed for 4.7 years (average). AD pathology was defined using cerebrospinal fluid (CSF) Aβ42/40 and Aβ42/total tau (T-tau). Plasma GFAP was measured at baseline and follow-up using Simoa technology. Results: Baseline plasma GFAP could detect abnormal CSF Aβ42/40 and CSF Aβ42/T-tau with an AUC of 0.79 (95% CI 0.72–0.86) and 0.80 (95% CI 0.72–0.86), respectively. When also including APOE ε4 status as a predictor, the accuracy of the model to detect abnormal CSF Aβ42/40 status improved (AUC = 0.86, p = 0.02). Plasma GFAP predicted subsequent conversion to AD dementia with an AUC of 0.84 (95% CI 0.77–0.91), which was not significantly improved when adding APOE ε4 or age as predictors to the model. Longitudinal GFAP slopes for Aβ-positive and MCI who progressed to dementia (AD or other) were significantly steeper than those for Aβ-negative (p = 0.007) and stable MCI (p < 0.0001), respectively. Conclusion: Plasma GFAP can detect AD pathology in patients with MCI and predict conversion to AD dementia.
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| 2. |
- Hertze, Joakim, et al.
(författare)
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Changes in cerebrospinal fluid and blood plasma levels of IGF-II and its binding proteins in Alzheimer's disease : an observational study
- 2014
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Ingår i: BMC Neurology. - : BioMed Central. - 1471-2377. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Insulin-like Growth Factor (IGF)-related system is implicated in neuroregeneration and cell repair, as well as regulating lifespan. IGF-II, one component of this system, has also been found to affect memory functions in a rat model. In this study we explored changes in the IGF-related system in patients with Alzheimer's disease (AD), including changes in IGF-II levels.METHODS: We measured blood plasma and cerebrospinal fluid (CSF) levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in 72 healthy controls and 92 patients with AD.RESULTS: We found significantly lower blood plasma levels of IGF-II and IGFBP-3 in patients with AD, compared with controls. The levels of IGF-II and IGFBP-2 were significantly elevated in the CSF from patients with AD. We also found correlations between established CSF biomarkers for AD (tau and P-tau) and components of the IGF system.CONCLUSIONS: CSF and blood plasma levels of IGF-II and some of its binding proteins are changed in patients with AD. Further investigation into this area may unravel important clues to the nature of this disease.
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| 3. |
- Hertze, Joakim, et al.
(författare)
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Evaluation of CSF Biomarkers as Predictors of Alzheimer's Disease: A Clinical Follow-Up Study of 4.7 Years.
- 2010
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 21, s. 1119-1128
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Abeta42, Abeta40, Abeta38, sAbetaPPalpha, and sAbetaPPbeta were analyzed in 327 CSF samples obtained at baseline from patients with AD (n= 94), MCI (n= 166), depressive disorder (n= 29), and cognitively healthy controls (n= 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable after a follow-up of 4.7 years (range 3.0-7.4). Optimal cut-offs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cut-offs, a combination of Abeta42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Abeta42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6-58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria.
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| 4. |
- Hertze, Joakim
(författare)
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Pathophysiological Mechanisms and Diagnostic Markers in Alzheimer’s Disease
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD), the most common cause of dementia, is a growing concern. As the life expectancy increases across the globe, the number of affected people is estimated to reach 100 million by 2050. Efforts to develop effective treatments for humans have mostly been based on the assumption that a faulty homeostasis of beta amyloid (Aβ) is the triggering or the driving factor behind this condition. So far these efforts have failed, making a better understanding of other pathophysiological mechanisms behind this disease necessary in order to find new therapeutic approaches. The aim for this thesis was to explore such mechanisms. Besides changes typical of AD, these patients often show signs of vascular disease. In order to explore how white matter changes (WMLs) affects the course of disease, we analyzed CSF levels of phosphorylated tau (P-tau) and assessed WMLs on brain scans in healthy controls and patients with mild cognitive impairment. We found that a pathological level of P-tau and WMLs in the parietal lobes independently increased the risk of developing AD dementia, but that the risk was considerably higher for patients that had both. Next, we analyzed the CSF/plasma ratio of albumin, as a proxy for blood-brain barrier integrity, and found it to be increased in AD and other common dementias. This ratio was not associated with the APOE genotype, as had previously been suggested, or markers of Aβ load. Instead, we found it to be associated with diabetes mellitus and markers of microvascular damage in the brain. We then moved on from vascular factors to other mechanisms suggested in AD.The insulin-like growth factor (IGF) related system is implicated in regulating life-span and in growth-promotion and neuroprotection in the human nervous system. There are reports of changes to the IGF-related system in cognitive disorders. When we analyzed components of this system in healthy controls and patients with AD we found differences in CSF and blood plasma levels of IGF-II and some of its associated binding proteins, possibly reflecting an activated general response to neuronal damage. Lastly, we analyzed CSF biomarkers of synaptic degeneration (neurogranin) and microglial activation (YKL-40) in healthy controls, patients with mild cognitive impairment and patients with common dementias. We found the former to be selectively increased in AD dementia, whereas the latter was increased in both AD and frontotemporal dementia. However, these biomarkers did not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to established CSF biomarkers of AD. Nevertheless, we think they are useful, since they reflect other processes in AD than Aβ deposition and axonal damage. We hope that the results from this thesis has provided new insights into the pathophysiological mechanisms in AD and that they might suggest novel routes for exploring this complex condition.
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| 5. |
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| 6. |
- Hölttä, Mikko, et al.
(författare)
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Evaluating amyloid-β oligomers in cerebrospinal fluid as a biomarker for Alzheimer's disease.
- 2013
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Ingår i: PloS one. - San Francisco, CA, United States : Public Library of Science (PLoS). - 1932-6203. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- The current study evaluated amyloid-β oligomers (Aβo) in cerebrospinal fluid as a clinical biomarker for Alzheimer's disease (AD). We developed a highly sensitive Aβo ELISA using the same N-terminal monoclonal antibody (82E1) for capture and detection. CSF samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were examined. The assay was specific for oligomerized Aβ with a lower limit of quantification of 200 fg/ml, and the assay signal showed a tight correlation with synthetic Aβo levels. Three clinical materials of well characterized AD patients (n=199) and cognitively healthy controls (n=148) from different clinical centers were included, together with a clinical material of patients with MCI (n=165). Aβo levels were elevated in the all three AD-control comparisons although with a large overlap and a separation from controls that was far from complete. Patients with MCI who later converted to AD had increased Aβo levels on a group level but several samples had undetectable levels. These results indicate that presence of high or measurable Aβo levels in CSF is clearly associated with AD, but the overlap is too large for the test to have any diagnostic potential on its own.
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| 7. |
- Janelidze, Shorena, et al.
(författare)
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Cerebrospinal fluid neurogranin and YKL-40 as biomarkers of Alzheimer's disease.
- 2016
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Ingår i: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 3:1, s. 12-20
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Tidskriftsartikel (refereegranskat)abstract
- Widespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non-AD dementias. Novel and promising CSF biomarkers include neurogranin, a marker of synaptic degeneration, and YKL-40, a marker of neuroinflammation.
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| 8. |
- Janelidze, Shorena, et al.
(författare)
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Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 51, s. 104-112
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Tidskriftsartikel (refereegranskat)abstract
- Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF bio-markers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage. (C) 2016 The Authors. Published by Elsevier Inc.
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| 9. |
- Olsson, Bob, 1969, et al.
(författare)
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Cerebrospinal Fluid Levels of Heart Fatty Acid Binding Protein are Elevated Prodromally in Alzheimer's Disease and Vascular Dementia
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 34:3, s. 673-679
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Tidskriftsartikel (refereegranskat)abstract
- Heart fatty acid binding protein (HFABP) is expressed in the brain and is elevated in cerebrospinal fluid (CSF) from patients with several forms of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease with dementia, Lewy body dementia, vascular dementia (VaD), and Creutzfeldt-Jakob disease. However, whether HFABP in CSF is a stable biomarker or if it can help predict conversion from mild cognitive impairment (MCI) to AD or VaD has not been well studied. To address the role of HFABP in neurodegeneration, we analyzed CSF levels of HFABP in 96 AD patients and 65 controls and also in 170 patients with MCI with an average follow up time of 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six month interval in between. HFABP levels in CSF were very stable over the six month period (r = 0.93, p < 0.001). Furthermore, the CSF levels of HFABP were significantly elevated in AD compared with controls after adjustments for age and gender (p < 0.001). They were also elevated in the patients with MCI that subsequently converted to AD or VaD compared with those that remained stable (p < 0.001 and p < 0.05, respectively). However, ROC curve analysis showed that HFABP had lesser predictive value in determining conversion from MCI to AD and VaD than A beta(42), t-tau, and p-tau. In conclusion, HFABP seems to be a stable CSF biomarker that reflects neuronal cell death in several neurodegenerative disorders, including early stages of AD and VaD.
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| 10. |
- Olsson, Bob, 1969, et al.
(författare)
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Microglial markers are elevated in the prodromal phase of Alzheimer's disease and vascular dementia.
- 2013
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908 .- 1387-2877. ; 33:1, s. 45-53
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Tidskriftsartikel (refereegranskat)abstract
- Microglia manage immunosurveillance and mediate inflammation, both suggested to be important in Alzheimer's disease (AD). The aim of this study was to investigate if microglial markers could differentiate, firstly between AD and controls, and secondly between stable mild cognitive impairment (MCI) and those progressing to AD and vascular dementia (VaD). Furthermore, we investigated if these markers were sufficiently stable to be used in clinical trials. We quantified YKL-40 and sCD14 in cerebrospinal fluid (CSF) from 96 AD patients, 65 healthy controls, and 170 patients with MCI from baseline and over 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six-month interval in between. YKL-40, but not sCD14, was significantly elevated in AD compared with healthy controls (p = 0.003). Furthermore, YKL-40 and sCD14 were increased in MCI patients who converted to VaD (p = 0.029 and p = 0.008), but not to AD according to NINCDS-ADRDA. However, when stratified according to CSF levels of tau and Aβ42, YKL-40 was elevated in those with an AD-indicative profile compared with stable MCI with a normal profile (p = 0.037). In addition, YKL-40 and sCD14 were very stable in AD patients with good correlation between time-points (r = 0.94, p = 3.4 × 10-25; r = 0.77, p = 2.0 × 10-11) and the cortical damage marker T-tau. Thus, microglial markers are stable and may be used as safety markers for monitoring CNS inflammation and microglia activation in clinical trials. Moreover, YKL-40 differentiates between AD and controls and between stable MCI to AD and those that convert to AD and VaD.
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