| 1. |
- Björkqvist, Maria, et al.
(författare)
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Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer's disease.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need for biomarkers in plasma to identify Alzheimer's disease (AD). It has previously been shown that a signature of 18 plasma proteins can identify AD during pre-dementia and dementia stages (Ray et al, Nature Medicine, 2007). We quantified the same 18 proteins in plasma from 174 controls, 142 patients with AD, and 88 patients with other dementias. Only three of these proteins (EGF, PDG-BB and MIP-1δ) differed significantly in plasma between controls and AD. The 18 proteins could classify patients with AD from controls with low diagnostic precision (area under the ROC curve was 63%). Moreover, they could not distinguish AD from other dementias. In conclusion, independent validation of results is important in explorative biomarker studies.
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| 2. |
- 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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| 3. |
- Gao, Carol Man, et al.
(författare)
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Aβ40 oligomers identified as a potential biomarker for the diagnosis of Alzheimer's disease.
- 2010
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's Disease (AD) is the most prevalent form of dementia worldwide, yet the development of therapeutics has been hampered by the absence of suitable biomarkers to diagnose the disease in its early stages prior to the formation of amyloid plaques and the occurrence of irreversible neuronal damage. Since oligomeric Aβ species have been implicated in the pathophysiology of AD, we reasoned that they may correlate with the onset of disease. As such, we have developed a novel misfolded protein assay for the detection of soluble oligomers composed of Aβ x-40 and x-42 peptide (hereafter Aβ40 and Aβ42) from cerebrospinal fluid (CSF). Preliminary validation of this assay with 36 clinical samples demonstrated the presence of aggregated Aβ40 in the CSF of AD patients. Together with measurements of total Aβ42, diagnostic sensitivity and specificity greater than 95% and 90%, respectively, were achieved. Although larger sample populations will be needed to confirm this diagnostic sensitivity, our studies demonstrate a sensitive method of detecting circulating Aβ40 oligomers from AD CSF and suggest that these oligomers could be a powerful new biomarker for the early detection of AD.
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| 4. |
- 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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| 5. |
- Palmqvist, Sebastian, et al.
(författare)
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Comparison of Brief Cognitive Tests and CSF Biomarkers in Predicting Alzheimer's Disease in Mild Cognitive Impairment: Six-Year Follow-Up Study
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Early identification of Alzheimer's disease (AD) is needed both for clinical trials and in clinical practice. In this study, we compared brief cognitive tests and cerebrospinal fluid (CSF) biomarkers in predicting conversion from mild cognitive impairment (MCI) to AD. Methods: At a memory clinic, 133 patients with MCI were followed until development of dementia or until they had been stable over a mean period of 5.9 years (range 3.2-8.8 years). The Mini-Mental State Examination (MMSE), the clock drawing test, total tau, tau phosphorylated at Thr(181) (P-tau) and amyloid-beta(1-42) (A beta(42)) were assessed at baseline. Results: During clinical follow-up, 47% remained cognitively stable and 53% developed dementia, with an incidence of 13.8%/year. In the group that developed dementia the prevalence of AD was 73.2%, vascular dementia 14.1%, dementia with Lewy bodies (DLB) 5.6%, progressive supranuclear palsy (PSP) 4.2%, semantic dementia 1.4% and dementia due to brain tumour 1.4%. When predicting subsequent development of AD among patients with MCI, the cognitive tests classified 81% of the cases correctly (AUC, 0.85; 95% CI, 0.77-0.90) and CSF biomarkers 83% (AUC, 0.89; 95% CI, 0.82-0.94). The combination of cognitive tests and CSF (AUC, 0.93; 95% CI 0.87 to 0.96) was significantly better than the cognitive tests (p = 0.01) and the CSF biomarkers (p = 0.04) alone when predicting AD. Conclusions: The MMSE and the clock drawing test were as accurate as CSF biomarkers in predicting future development of AD in patients with MCI. Combining both instruments provided significantly greater accuracy than cognitive tests or CSF biomarkers alone in predicting AD.
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| 6. |
- Schultz, Nina, et al.
(författare)
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Levels of islet amyloid polypeptide in cerebrospinal fluid and plasma from patients with Alzheimers disease
- 2019
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- The biologically active pancreatic hormone peptide islet amyloid polypeptide (IAPP) regulates brain functions such as appetite and cognition. It also plays a role in clearance of amyloid beta (A beta), a peptide implicated in the dementia disorder Alzheimers disease (AD). If IAPP becomes modified, it loses its biological activity and starts to aggregate. Such aggregations have been found in the AD brain and decreased plasma levels of the unmodified IAPP (uIAPP) have been shown in the same patients. In the current study, we analyze levels of uIAPP and total IAPP (unmodified and modified) in cerebrospinal fluid (CSF) to investigate its potential as a biomarker for AD. We found no differences in neither CSF nor plasma levels of uIAPP or total IAPP in AD patients compared to cognitive healthy individuals (NC). The levels of uIAPP in CSF of NC were positively correlated with uIAPP in plasma, Q-albumin and albumin levels in CSF, but negatively correlated with CSF levels of t-tau and p-tau. These findings were not seen in AD patients. Levels of total CSF IAPP correlated positively with total Q-albumin and albumin levels in CSF in both AD and NC. In addition, total plasma IAPP correlated positively with CSF t-tau and p-tau in NC and negatively with CSF A beta(42) in AD patients. To conclude, our studies did not find evidence supporting the use of CSF IAPP as an AD biomarker. However, our findings, indicating a compromised translocation of uIAPP in and out of the brain in AD patients as well as the correlations between total plasma IAPP and AD biomarkers, encourage further research on the role for IAPP in AD.
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| 7. |
- Silajdzic, Edina, et al.
(författare)
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No diagnostic value of plasma clusterin in Alzheimer's disease.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need for biomarkers to enable early diagnosis of Alzheimer's disease (AD). It has recently been shown that a variant within the clusterin gene is associated with increased risk of AD and plasma levels of clusterin have been found to be associated with the risk of AD. We, therefore, investigated the diagnostic value of clusterin by quantifying clusterin using an ELISA in plasma from 171 controls, 127 patients with AD, 82 patients with other dementias and 30 patients with depression. We observed similar plasma clusterin levels in controls, AD patients and patients with other dementias, suggesting that plasma clusterin levels have no diagnostic value for AD. There was a slight, but significant, increase in plasma clusterin in patients with depression compared to all other groups tested, which may warrant further investigation.
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| 8. |
- Stubendorff, Kajsa, et al.
(författare)
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The impact of autonomic dysfunction on survival in patients with dementia with lewy bodies and Parkinson's disease with dementia.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Autonomic dysfunction is a well-known feature in neurodegenerative dementias, especially common in α-synucleinopathies like dementia with Lewy bodies and Parkinson's disease with dementia. The most common symptoms are orthostatic hypotension, incontinence and constipation, but its relevance in clinical practice is poorly understood. There are no earlier studies addressing the influence of autonomic dysfunction on clinical course and survival. The aim of this study was to investigate the frequency of the three most common features of autonomic dysfunction and analyze how it affects survival.
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| 9. |
- Svärd, Daniel, et al.
(författare)
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The effect of white matter hyperintensities on statistical analysis of diffusion tensor imaging in cognitively healthy elderly and prodromal Alzheimer’s disease
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:9
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Tidskriftsartikel (refereegranskat)abstract
- Diffusion tensor imaging (DTI) has been used to study microstructural white matter alterations in a variety of conditions including normal aging and Alzheimer’s disease (AD). White matter hyperintensities (WMH) are common in cognitively healthy elderly as well as in AD and exhibit elevated mean diffusivity (MD) and reduced fractional anisotropy (FA). However, the effect of WMH on statistical analysis of DTI estimates has not been thoroughly studied. In the present study we address this in two ways. First, we investigate the effect of WMH on MD and FA in the dorsal and ventral cingulum, the superior longitudinal fasciculus, and the corticospinal tract, by comparing two matched groups of cognitively healthy elderly (n = 21 + 21) with unequal WMH load. Second, we assess the effects of adjusting for WMH load when comparing MD and FA in prodromal AD subjects (n = 83) to cognitively healthy elderly (n = 132) in the abovementioned white matter tracts. Results showed the WMH in cognitively healthy elderly to have a generally large effect on DTI estimates (Cohen’s d = 0.63 to 1.27 for significant differences in MD and −1.06 to −0.69 for FA). These effect sizes were comparable to those of various neurological and psychiatric diseases (Cohen’s d = 0.57 to 2.20 for differences in MD and −1.76 to −0.61 for FA). Adjusting for WMH when comparing DTI estimates in prodromal AD subjects to cognitively healthy elderly improved the explanatory power as well as the outcome of the analysis, indicating that some of the differences in MD and FA were largely driven by unequal WMH load between the groups rather than alterations in normal-appearing white matter (NAWM). Thus, our findings suggest that if the purpose of a study is to compare alterations in NAWM between two groups using DTI it may be necessary to adjust the statistical analysis for WMH.
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| 10. |
- Wennström, Malin, et al.
(författare)
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Low CSF Levels of Both α-Synuclein and the α-Synuclein Cleaving Enzyme Neurosin in Patients with Synucleinopathy.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Neurosin is a protease that in vitro degrades α-synuclein, the main constituent of Lewy bodies found in brains of patients with synucleinopathy including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Several studies have reported reduced cerebrospinal fluid (CSF) levels of α-synuclein in synucleinopathy patients and recent data also proposes a significant role of α-synuclein in the pathophysiology of Alzheimer's disease (AD). To investigate potential links between neurosin and its substrate α-synuclein in vivo we used a commercially available sandwich ELISA and an in-house developed direct ELISA to quantify CSF levels of α-synuclein and neurosin in patients diagnosed with DLB, PD and PD dementia (PDD) versus AD patients and non-demented controls. We found that patients with synucleinopathy displayed lower CSF levels of neurosin and α-synuclein compared to controls and AD patients. In contrast, AD patients demonstrated significantly increased CSF α-synuclein but similar neurosin levels compared to non-demented controls. Further, CSF neurosin and α-synuclein concentrations were positively associated in controls, PD and PDD patients and both proteins were highly correlated to CSF levels of phosphorylated tau in all investigated groups. We observed no effect of gender or presence of the apolipoprotein Eε4 allele on neither neurosin or α-synuclein CSF levels. In concordance with the current literature our study demonstrates decreased CSF levels of α-synuclein in synucleinopathy patients versus AD patients and controls. Importantly, decreased α-synuclein levels in patients with synucleinopathy appear linked to low levels of the α-synuclein cleaving enzyme neurosin. In contrast, elevated levels of α-synuclein in AD patients were not related to any altered CSF neurosin levels. Thus, altered CSF levels of α-synuclein and neurosin in patients with synucleinopathy versus AD may not only mirror disease-specific neuropathological mechanisms but may also serve as fit candidates for future biomarker studies aiming at identifying specific markers of synucleinopathy.
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