| 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. |
- Andersson, Malin E, 1978, et al.
(författare)
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Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease.
- 2007
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 20:2, s. 233-9
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Tidskriftsartikel (refereegranskat)abstract
- Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.
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| 3. |
- Buchhave, Peder, et al.
(författare)
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Longitudinal study of CSF biomarkers in patients with Alzheimer's disease.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:Suppl 3, s. 337-337
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The CSF biomarkers tau and Abeta42 can identify patients with AD, even during the preclinical stages. However, previous studies on longitudinal changes of tau and Abeta42 in individual patients with AD and elderly controls report somewhat inconsistent results. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the levels of tau and Abeta42 at baseline and after 1 year in 100 patients with AD. In a second cohort of 45 AD patients we measured the CSF biomarkers at baseline and after 2 years. Moreover, in 34 healthy elderly controls the CSF biomarkers were followed for 4 years. The baseline levels of tau were increased with >60% in AD patients compared to controls (p<0.001), while baseline Abeta42 levels were decreased with >50% (p<0.001). In the AD group followed for 2 years, tau increased with 16% compared to the baseline levels (p<0.05). However, the levels of tau were stable over 4 years in the controls. The levels of Abeta42 did not change significantly over time in any of the groups. In the patients with AD, tau was moderately associated with worse cognitive performance already at baseline (p<0.05). CONCLUSIONS/SIGNIFICANCE: Tau and Abeta42 in CSF seem to reflect the underlying disease state in both early and late stages of AD. The slight increase in tau over time observed in the patients with AD is modest when compared to the relatively large difference in absolute tau levels between AD patients and controls. Therefore, these markers maintain their usefulness as state markers over time and might serve as surrogate markers for treatment efficacy in clinical trials.
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| 4. |
- Duits, Flora H., et al.
(författare)
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
- 2014
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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| 5. |
- 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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| 6. |
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| 7. |
- Mattsson, Niklas, 1979, et al.
(författare)
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CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.
- 2009
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Ingår i: JAMA : the journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 302:4, s. 385-93
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Thorsell, Annika, 1973, et al.
(författare)
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Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease
- 2010
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1362, s. 13-22
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic pathology occurs early in Alzheimer's disease (AD) development, and cerebrospinal fluid biomarkers for synaptic damage may be altered early in the disease process. In the present study we examined cerebrospinal fluid levels of the postsynaptic protein neurogranin in patients with mild cognitive impairment (MCI) or AD and controls. The low neurogranin level in cerebrospinal fluid required enrichment by immunoprecipitation prior to mass spectrometric identification and semi-quantitative immunoblot analysis. Relative quantification revealed a significant increase of neurogranin in the AD group compared with controls, while the MCI group was not statistically different from either controls or the AD group. The concentrations of the AD biomarkers T-tau, P-tau(181) and A beta(42) were significantly changed in the control and MCI groups compared with the AD group, but no significant differences were found between the MCI group and controls for the three biomarkers. Nevertheless, a trend towards increasing levels of neurogranin, T-tau and P-tau(181) was found in cerebrospinal fluid from MCI patients compared with controls. The elevated neurogranin levels in the MCI and AD groups might reflect synaptic degeneration. These results together suggest that cerebrospinal fluid neurogranin might be valuable together with the established AD biomarkers in the early diagnosis of AD and warrants further studies to determine the diagnostic value of neuroganin. (C) 2010 Elsevier B.V. All rights reserved.
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