| 1. |
- Baldacci, Filippo, et al.
(författare)
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Age and sex impact plasma NFL and t-Tau trajectories in individuals with subjective memory complaints: a 3-year follow-up study.
- 2020
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer's disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development.Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study).We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score.We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.
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| 2. |
- Baldacci, Filippo, et al.
(författare)
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Two-level diagnostic classification using cerebrospinal fluid YKL-40 in Alzheimer's disease.
- 2017
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 13:9, s. 993-1003
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) YKL-40 in discriminating (1) clinical Alzheimer's disease (AD) from cognitively healthy controls (HCs) and frontotemporal dementia (FTD) (level I) and (2) patients stratified by different pathophysiological profiles from HCs and FTD following a novel unbiased/descriptive categorization based on CSF biomarkers, independent of cognitive impairment severity (level II).YKL-40 was compared among HCs (n=21), mild cognitive impairment (n=41), AD (n=35), and FTD (n=9) (level I) and among HCs (n=21), AD pathophysiology (tau and amyloid-β) negative (n=15), tau positive (n=15), amyloid-β positive (n=13), AD pathophysiology positive (n=33), and FTD (n=9) (level II).Level I: YKL-40 discriminated AD from HC and FTD (area under the receiver operating characteristic curves [AUROCs]=0.69, 0.71). Level II: YKL-40 discriminated tau-positive individuals and AD pathophysiology-positive individuals from HC, AD pathophysiology-positive patients from FTD (AUROCs=0.76, 0.72, 0.73).YKL-40 demonstrates fair performance in distinguishing tau-positive patients from HCs, suggesting it may aid clinical diagnosis and support a biomarker-guided pathophysiological stratification.
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| 3. |
- Blennow, Kaj, 1958, et al.
(författare)
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Biomarkers in Amyloid-β Immunotherapy Trials in Alzheimer's Disease.
- 2014
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aβ drug as disease modifying.Neuropsychopharmacology advance online publication, 17 July 2013; doi:10.1038/npp.2013.154.
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| 4. |
- Blennow, Kaj, 1958, et al.
(författare)
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Cerebrospinal fluid and plasma biomarkers in Alzheimer disease
- 2010
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Ingår i: Nature reviews. Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 6:3, s. 131-44
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Forskningsöversikt (refereegranskat)abstract
- Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-beta immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-beta. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.
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| 5. |
- Blennow, Kaj, 1958, et al.
(författare)
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Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease.
- 2015
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 11:1, s. 58-69
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Tidskriftsartikel (refereegranskat)abstract
- Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD.
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| 6. |
- Bos, Isabelle, et al.
(författare)
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The frequency and influence of dementia risk factors in prodromal Alzheimer's disease
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 56, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.
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| 9. |
- Buerger, Katharina, et al.
(författare)
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Prediction of Alzheimer's disease using midregional proadrenomedullin and midregional proatrial natriuretic peptide: a retrospective analysis of 134 patients with mild cognitive impairment.
- 2011
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Ingår i: The Journal of clinical psychiatry. - 1555-2101 .- 0160-6689. ; 72:4, s. 556-63
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Development of biomarkers for early detection of Alzheimer's disease (AD) is a major clinical research goal. On the basis of the hypothesis that cardiovascular risk factors contribute to the pathogenesis of AD, we investigated whether the cardiovascular risk markers midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP) predict a major clinical milestone, ie, conversion from predementia mild cognitive impairment (MCI) to manifest AD. METHOD: A group of 134 MCI patients, among 137 originally prospectively recruited at the memory disorder clinic at Malmö University Hospital, Malmö, Sweden, between July 1998 and June 2001, was clinically followed for 4-6 years. We determined whether plasma concentrations of MR-proADM and MR-proANP at baseline predicted time to conversion from MCI to clinically diagnosed AD (DSM-III-R). MCI was diagnosed according to Petersen criteria. RESULTS: During follow-up, 41.8% of MCI patients remained cognitively stable, 42.5% converted to possible and probable AD, and 15.7% converted to other forms of dementia (MCI-other). MCI converters and MCI-other patients showed increased concentrations of MR-proANP and MR-proADM compared to the stable MCI patients (P = .0001). At a cutoff of 87 pmol/L, MR-proANP yielded a sensitivity of 73.7% and a specificity of 64.3% for predicting conversion to AD. The survival analysis showed that higher values of MR-proANP and MR-proADM were associated with progression to AD. In a multivariate Cox regression model including known risk factors, MR-proANP and MR-proADM remained independent risk factors for conversion to AD for patients below the age of 72 years. CONCLUSIONS: Our study shows that plasma concentrations of MR-proANP and MR-proADM have predictive value in the progression from predementia MCI to clinical AD. Sensitivity was particularly high, which may recommend this test for first-stage screening in patients at risk for AD.
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| 10. |
- Buerger, Katharina, et al.
(författare)
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Validation of Alzheimer's disease CSF and plasma biological markers: the multicentre reliability study of the pilot European Alzheimer's Disease Neuroimaging Initiative (E-ADNI).
- 2009
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Ingår i: Experimental gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 44:9, s. 579-85
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported. METHODS: Six academic EADC centres recruited 49 subjects (healthy controls, subjects with mild cognitive impairment (MCI) and AD). We measured CSF beta-amyloid 42 (CSF Abeta42), total tau-protein (t-tau), phosphorylated tau-proteins (P-tau181, P-tau231), plasma beta-amyloid 40 and 42 (Abeta40/Abeta42). Immediate fresh shipment was compared to freezing and later shipment on dry ice. RESULTS: CSF T-tau (fresh samples) was increased in AD versus controls (p=0.049), CSF Abeta42 (frozen samples) was decreased in MCI and AD (p=0.02), as well as plasma Abeta40 (fresh and frozen samples) in AD (p=0.049 and p=0.016). Pooled values of neurochemical parameters and ratios thereof were different between centres (p<0.005). Analysis of frozen samples yielded higher diagnostic accuracy than immediate fresh shipment with 100% (fresh: 100%) correctly classified in control subjects, 100% (78%) in MCI, 91% (91%) in AD. CONCLUSION: The use of frozen rather than fresh samples renders higher diagnostic accuracy within a multicentre context. We confirmed the feasibility of a multicentre AD biomarker programme for future clinical trials.
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