| 1. |
- Andersson, Carl-Henrik, et al.
(författare)
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A Genetic Variant of the Sortilin 1 Gene isAssociated with Reduced Risk ofAlzheimer's Disease
- 2016
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 53:4, s. 1353-1363
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc=0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
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| 2. |
- Höglund, Kina, 1976, et al.
(författare)
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Longitudinal Stability Evaluation of Biomarkers and Their Correlation in Cerebrospinal Fluid and Plasma from Patients with Alzheimer's Disease
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 32:4, s. 939-947
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Tidskriftsartikel (refereegranskat)abstract
- There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of alpha- and beta-cleaved soluble amyloid-beta protein precursor (sA beta PP alpha and sA beta PP beta), A beta(1-40) together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer's disease. In addition, the stability of A beta(1-40), beta(1-42), and sA beta PP beta in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sA beta PP beta (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84-17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1-42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs.
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| 3. |
- 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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| 4. |
- Olsson, Bob, et al.
(författare)
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Extreme Stability of Chitotriosidase in Cerebrospinal Fluid makes it a Suitable Marker for Microglial Activation in Clinical Trials
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 32:2, s. 273-276
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Tidskriftsartikel (refereegranskat)abstract
- Microglia is thought to be important in Alzheimer's disease. Therefore, our aim was to investigate the usefulness of the microglial marker chitotriosidase in clinical trials. Chitotriosidase was analyzed in cerebrospinal fluid from Alzheimer's disease patients on acetylcholine esterase inhibitors (AChEI) and in cerebrospinal fluid from multiple sclerosis patients before and after natalizumab treatment. Chitotriosidase activity was extremely stable during treatment with the non-inflammatory drug AChEI. However, the immunomodulatory treatment with natalizumab led to lower chitotriosidase activity. Thus, chitotriosidase may be useful in clinical trials where microglia is targeted or as a safety biomarker in other trials where the brain is a bystander organ.
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| 5. |
- 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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| 6. |
- Chalbot, Sonia, et al.
(författare)
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Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease.
- 2011
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 25:3, s. 505-15
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Tidskriftsartikel (refereegranskat)abstract
- The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer's disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb) and CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42, and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD. These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients.
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| 7. |
- Hansson, Sarah, 1976, et al.
(författare)
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Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer's disease patients.
- 2009
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Ingår i: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 16:2, s. 389-97
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta(Abeta) aggregation is a major hallmark of Alzheimer's disease (AD). Previous studies have suggested that only unbound Abeta can take part in the aggregation process. Therefore, endogenous Abeta-binding proteins may have an important role in preventing AD. Here, we analyzed cerebrospinal fluid (CSF) samples from 35 subjects with AD, 18 subjects with frontotemporal dementia (FTD) and 29 non-demented controls to test if reduced Abeta-binding capacity in CSF is a specific feature of AD. A panel of known Abeta-binding CSF proteins, including beta-trace/prostaglandin D2 synthase (beta-trace), transthyretin (TTR), cystatin C (CysC) and alpha(1)-antitrypsin (AAT), were quantified and related to diagnosis and CSF levels of Abeta(1-38), Abeta(1-40) and Abeta(1-42). AD patients displayed a mild reduction in the CSF levels of beta-trace (p=0.020), CysC (p=0.017), AAT (p=0.019) and TTR (p=0.012) compared with controls. While the reductions in AAT and TTR were AD-specific, the levels of beta-trace and CysC were also reduced in FTD. As expected, CSF Abeta(1-42) was reduced in AD compared with controls (p=0.00005) and with FTD patients (p=0.015). Positive correlations between Abeta(1-42) and beta-trace, CysC and TTR, respectively, were seen only in the AD group, suggesting that deficient Abeta-binding capacity in CSF may contribute to the amyloidogenic process in AD.
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| 8. |
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