| 1. |
- Andersson, Carl-Henrik, et al.
(author)
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A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease
- 2016
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 53:4, s. 1353-1363
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Journal article (peer-reviewed)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. |
- Henjum, Kristi, et al.
(author)
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Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease
- 2016
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 8:1
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Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease (AD) neuropathology is associated with neuroinflammation, but there are few useful biomarkers. Mutant variants of triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to late-onset AD and other neurodegenerative disorders. TREM2, a microglial receptor, is involved in innate immunity. A cleaved fragment, soluble TREM2 (sTREM2), is present in the cerebrospinal fluid (CSF). Methods: We developed and used a novel enzyme-linked immunosorbent assay to investigate the potential value of CSF sTREM2 as an AD biomarker in two independent cohorts: an AD/mild cognitive impairment (MCI)/control cohort (n = 100) and an AD/control cohort (n = 50). Results: We found no significant difference in sTREM2 levels between groups of controls and patients with AD or MCI. However, among all controls there was a positive correlation between sTREM2 and age (Spearman rho = 0.50; p <0.001; n = 75). In the AD/MCI/control cohort, CSF sTREM2 correlated positively with total Tau (T-tau) (Spearman rho 0.57; p <0.001; n = 50), phosphorylated Tau (P-tau) (Spearman rho 0.63; p <0.001; n = 50) and amyloid-β1-42 (Aβ42) (Spearman rho 0.35; p = 0.01; n = 50) in control subjects. Among controls with a CSF Aβ42 above a cut-off value (700 pg/ml) in this cohort, the positive correlation between sTREM2 and Aβ42 was stronger (Spearman rho = 0.44; p = 0.002; n = 46). Conclusions: sTREM2 in CSF correlates with aging in controls, and with the neurodegenerative markers CSF T-tau/P-tau among controls who are negative for AD CSF core biomarkers Aβ42, T-tau or P-tau.
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| 4. |
- Janelidze, Shorena, et al.
(author)
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CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios : better diagnostic markers of Alzheimer disease
- 2016
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In: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 3:3, s. 65-154
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF Aβ42 alone.METHODS: The study comprised three different cohorts (n = 1182) in whom CSF levels of Aβ42, Aβ40, and Aβ38 were assessed. CSF Aβs were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ((18)F-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients.RESULTS: When using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios were significantly better predictors of abnormal amyloid PET than CSF Aβ42. Lower Aβ42, Aβ42/Aβ40, and Aβ42/Aβ38 ratios, but not Aβ40 and Aβ38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower Aβ38, Aβ40, and Aβ42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the Aβ42/Aβ40 and Aβ42/Aβ38 ratios showed increased accuracy compared to Aβ42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all Aβs (including Aβ42) were decreased.INTERPRETATION: The CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are significantly better than CSF Aβ42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF Aβ42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF Aβ42 should be used in the clinical work-up of AD.
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| 5. |
- Mattsson, Niklas, 1979, et al.
(author)
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Increased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis.
- 2016
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Increased APP (amyloid precursor protein) processing causes β-amyloid (Aβ) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic Aβ accumulation. We tested healthy controls and patients with mild cognitive symptoms (N=331) in the BioFINDER study, using cerebrospinal fluid (CSF) Aβ40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Aβ fibrils (measured by 18F-flutemetamol PET) are independently associated with high CSF Aβ40 (P<0.001) and APOE ɛ4 (P<0.001). The association between CSF Aβ40 and brain Aβ is stronger in APOE ɛ4-negative than in positive people (P=0.0080). The results are similar for CSF Aβ38 and for a combination of CSF Aβ38 and CSF Aβ40. In conclusion, sporadic Aβ accumulation may be partly associated with increased amyloidogenic APP production, especially in APOE ɛ4-negative subjects. The risk for sporadic AD may consequently depend on increased Aβ production, in addition to decreased Aβ clearance.
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| 6. |
- Nilsson, Erik, et al.
(author)
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Associations of central and brachial blood pressure with cognitive function : a population-based study
- 2016
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In: Journal of Human Hypertension. - : Nature Publishing Group. - 0950-9240 .- 1476-5527. ; 30:2, s. 95-99
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Journal article (peer-reviewed)abstract
- Previous observational studies on the association between brachial blood pressure (BP) and cognition have reported conflicting results. Central BP has been hypothesized to be more strongly related to cognition than brachial BP. The aim of this study was to assess the association between brachial as well as central BP and cognitive function, both cross-sectionally and with brachial BP measured 17 years before cognitive testing. The study population comprised 2548 individuals aged 61-85 years at follow-up (61.4% women). The cognitive tests administered were A Quick Test of cognitive speed and the Mini Mental State Examination. In fully adjusted linear regressions, small but significant cross-sectional associations were found between higher BP (systolic, diastolic and pulse pressure) and worse results on both of the cognitive tests (P-values <0.05). No significant prospective associations were found. Central BP did not show a stronger association than brachial BP did. After stratification, significant results were mainly found in the group taking BP-lowering drugs at follow-up. In summary, these findings add to existing evidence on the relationship between BP and cognition, but they do not support a superior role of central compared with brachial BP in the elderly.
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| 7. |
- Nilsson, Erik D., et al.
(author)
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Copeptin, a Marker of Vasopressin, Predicts Vascular Dementia but not Alzheimer's Disease
- 2016
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 52:3, s. 1047-1053
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Journal article (peer-reviewed)abstract
- BACKGROUND: Copeptin is a reliable surrogate marker for the neurohypophyseal hormone vasopressin. Elevated plasma level of copeptin has been associated with cardiovascular and metabolic disease risk.OBJECTIVE: To investigate the association between copeptin and risk of dementia.METHODS: In all, 18,240 individuals from Malmö, Sweden, were examined between 2002 and 2006 (mean age 69.3 years, 69.8% men). Incident cases of dementia until 31 December 2009 were identified by linkage with the Swedish National Patient Register. To validate the dementia diagnoses, medical records as well as laboratory and neuroimaging data were carefully reviewed. Baseline level of copeptin was measured in frozen plasma in: (1) all participants who were diagnosed with dementia during follow-up, (2) a random sample of 5100 individuals of the cohort.RESULTS: During a median follow-up of 4.2 years, there were 374 incident dementia cases (age range 60-83 years at baseline): 120 were classified as Alzheimer's disease (AD), 84 as vascular dementia (VaD), and 102 as mixed dementia. In logistic regressions adjusted for cardiovascular risk factors, baseline level of copeptin predicted incident VaD (Odds ratio (OR) 1.30 per 1 SD increase in log copeptin, 95% CI 1.03-1.64). Copeptin did not predict incidence of all-cause dementia (OR 1.05, 95% CI 0.94-1.18), AD (OR 0.97, 95% CI 0.79-1.18), or mixed dementia (OR 0.85, 95% CI 0.68-1.05).CONCLUSION: Elevated plasma level of copeptin is a risk marker for incident VaD, but not for incident AD. This suggests that the vasopressin hormonal system might be involved in the development of VaD.
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| 8. |
- Pannee, Josef, 1979, et al.
(author)
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Reference measurement procedure for CSF amyloid beta (Aβ)1–42 and the CSF Aβ1–42/Aβ1–40 ratio – a cross-validation study against amyloid PET
- 2016
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 139:4, s. 651-658
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Journal article (peer-reviewed)abstract
- A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry (MS) reference measurement procedures for absolute quantification of Aβ1–42 in CSF. The CSF Aβ1–42/Aβ1–40 ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aβ production. Our aim was to cross-validate the reference measurement procedure as well as the Aβ1–42/Aβ1–40 and Aβ1–42/Aβ1–38 ratios in CSF, measured by high-resolution MS, with the cortical level of Aβ fibrils as measured by amyloid (18F-flutemetamol) positron emission tomography (PET). We included 100 non-demented patients with cognitive symptoms from the Swedish BioFINDER study, all of whom had undergone both lumbar puncture and 18F-flutemetamol PET. Comparing CSF Aβ1–42 concentrations with 18F-flutemetamol PET showed high concordance with an area under the receiver operating characteristic curve of 0.85 and a sensitivity and specificity of 82% and 81%, respectively. The ratio of Aβ1–42/Aβ1–40 or Aβ1–42/Aβ1–38 significantly improved concordance with an area under the receiver operating characteristic curve of 0.95 and a sensitivity and specificity of 96% and 91%, respectively. These results show that the CSF Aβ1–42/Aβ1–40 and Aβ1–42/Aβ1–38 ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by 18F-flutemetamol PET. (Figure presented.).
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| 9. |
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| 10. |
- Torisson, Gustav, et al.
(author)
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Reliability, validity and clinical correlates of the Quality of Life in Alzheimer's disease (QoL-AD) scale in medical inpatients
- 2016
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In: Health and Quality of Life Outcomes. - : Springer Science and Business Media LLC. - 1477-7525. ; 14:1
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Journal article (peer-reviewed)abstract
- Background: There is a lack of standardisation in quality of life (QoL) measurements to be used in older multimorbid patients. An ideal QoL measurement should be reliable, valid, subjective, multidimensional, feasible and generic. We hypothesised that the QoL-AD (Quality of Life in Alzheimer's Disease) scale could have these properties. Our aim was to determine the psychometric properties and clinical correlations of QoL-AD in a population of elderly, multimorbid medical inpatients. Methods: QoL-AD was performed in 200 medical inpatients, and available caregivers. Reliability was determined using cronbach's alpha and corrected item-total correlations. The agreement between patient and proxy ratings were examined using intra-class correlations (ICC). Correlations between QoL-AD and demographic data, comorbidity, cognitive tests, ADL (activities of daily living) and depression were examined. To characterise the underlying constructs of QoL-AD, an exploratory factor analysis was performed. Results: In total, 199 patients fulfilled the QoL-AD rating, with 139 proxy ratings. Cronbach's alpha (95% CI) was 0.74 (0.68-0.79) for patients and 0.86 (0.83-0.90) for proxies. Patient-proxy ICC (95% CI) was 0.31 (0.16-0.46). Lower QoL was correlated to depression, cognitive impairment, ADL impairment and solitary living, but not with comorbidity. The factor analysis gave a three-factor solution, with factors representing phsyical, social and psychological well-being. Conclusion: The QoL-AD scale showed some promising properties but more research is needed before it can be recommended in this setting. If replicated, the finding that cognitive impairment, depression and ADL impairment were more associated with lower QoL than somatic comorbidity could have clinical implications for further studies aiming to improve QoL in this population.
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