| 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. |
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| 3. |
- Faucherre, Samuel, et al.
(författare)
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Short and Long-Term Controls on Active Layer and Permafrost Carbon Turnover Across the Arctic
- 2018
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Ingår i: Journal of Geophysical Research - Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 123:2, s. 372-390
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Tidskriftsartikel (refereegranskat)abstract
- Decomposition of soil organic matter (SOM) in permafrost terrain and the production of greenhouse gases is a key factor for understanding climate change-carbon feedbacks. Previous studies have shown that SOM decomposition is mostly controlled by soil temperature, soil moisture, and carbon-nitrogen ratio (C:N). However, focus has generally been on site-specific processes and little is known about variations in the controls on SOM decomposition across Arctic sites. For assessing SOM decomposition, we retrieved 241 samples from 101 soil profiles across three contrasting Arctic regions and incubated them in the laboratory under aerobic conditions. We assessed soil carbon losses (Closs) five times during a 1 year incubation. The incubated material consisted of near-surface active layer (ALNS), subsurface active layer (ALSS), peat, and permafrost samples. Samples were analyzed for carbon, nitrogen, water content, δ13C, δ15N, and dry bulk density (DBD). While no significant differences were observed between total ALSS and permafrost Closs over 1 year incubation (2.3 ± 2.4% and 2.5 ± 1.5% Closs, respectively), ALNS samples showed higher Closs (7.9 ± 4.2%). DBD was the best explanatory parameter for active layer Closs across sites. Additionally, results of permafrost samples show that C:N ratio can be used to characterize initial Closs between sites. This data set on the influence of abiotic parameter on microbial SOM decomposition can improve model simulations of Arctic soil CO2 production by providing representative mean values of CO2 production rates and identifying standard parameters or proxies for upscaling potential CO2 production from site to regional scales.
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| 4. |
- García-Ayllón, María-Salud, et al.
(författare)
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HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer's Disease Brain.
- 2017
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Ingår i: Molecular neurobiology. - : Springer Science and Business Media LLC. - 1559-1182 .- 0893-7648. ; 54:1, s. 188-199
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Tidskriftsartikel (refereegranskat)abstract
- The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell-extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer's disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, β-1,4-galactosyltransferase (β4GalT), glucuronyltransferases GlcAT-P and GlcAT-S, or sulfotransferase HNK-1ST. Over-expression of amyloid precursor protein in Tg2576 transgenic mice and in vitro treatment of SH-SY5Y neuroblastoma cells with the amyloidogenic Aβ42 peptide resulted in a decrease in HNK-1 immunoreactivity levels in brain and cellular extracts, whereas the levels of soluble HNK-1 glycoproteins detected in culture media were not affected by Aβ treatment. HNK-1 levels remain unaffected in the brain extracts of Tg-VLW mice, a model of mutant hyperphosphorylated tau, and in SH-SY5Y cells over-expressing hyperphosphorylated wild-type tau. These results provide evidence that cellular levels of HNK-1 carrier glycoforms are decreased in the brain of AD subjects, probably influenced by the β-amyloid protein.
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| 5. |
- Herukka, Sanna-Kaisa, et al.
(författare)
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Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment.
- 2017
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 13:3, s. 285-295
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Tidskriftsartikel (refereegranskat)abstract
- This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.
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| 6. |
- Karami, Azadeh, et al.
(författare)
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Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:11, s. 1316-1328
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. Method: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. Results: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-beta, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. Discussion: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
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| 7. |
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| 8. |
- Landen, Jaren W., et al.
(författare)
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Ponezumab in mild-to-moderate Alzheimer's disease : Randomized phase II PET-PIB study
- 2017
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Ingår i: Alzheimer's and Dementia: Translational Research and Clinical Interventions. - : Wiley. - 2352-8737. ; 3:3, s. 393-401
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The safety, pharmacokinetics, and effect on peripheral and central amyloid β (Aβ) of multiple doses of ponezumab, an anti-Aβ monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year. Methods Subjects were aged ≥50 years with Mini–Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg (n = 12) or placebo (n = 6) quarterly. Cohort M was randomized to a loading dose of ponezumab 10 mg/kg or placebo, followed by monthly ponezumab 7.5 mg/kg (n = 12) or placebo (n = 6), respectively. Results Ponezumab was generally well tolerated. Plasma concentrations increased dose dependently, but cerebrospinal fluid (CSF) penetration was low. Plasma Aβ increased dose dependently with ponezumab, but CSF biomarkers, brain amyloid burden, cognition, and function were not affected. Conclusions Both ponezumab dosing schedules were generally safe and well tolerated but did not alter CSF biomarkers, brain amyloid burden, or clinical outcomes.
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| 9. |
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| 10. |
- Lleó, Alberto, et al.
(författare)
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Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases.
- 2015
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Ingår i: Nature reviews. Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 11, s. 41-55
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Forskningsöversikt (refereegranskat)abstract
- Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.
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