| 1. |
- Ashton, Nicholas J., et al.
(författare)
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A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer's disease.
- 2019
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- A blood-based assessment of preclinical disease would have huge potential in the enrichment of participants for Alzheimer's disease (AD) therapeutic trials. In this study, cognitively unimpaired individuals from the AIBL and KARVIAH cohorts were defined as Aβ negative or Aβ positive by positron emission tomography. Nontargeted proteomic analysis that incorporated peptide fractionation and high-resolution mass spectrometry quantified relative protein abundances in plasma samples from all participants. A protein classifier model was trained to predict Aβ-positive participants using feature selection and machine learning in AIBL and independently assessed in KARVIAH. A 12-feature model for predicting Aβ-positive participants was established and demonstrated high accuracy (testing area under the receiver operator characteristic curve = 0.891, sensitivity = 0.78, and specificity = 0.77). This extensive plasma proteomic study has unbiasedly highlighted putative and novel candidates for AD pathology that should be further validated with automated methodologies.
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| 2. |
- Ashton, Nicholas J., et al.
(författare)
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An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.
- 2020
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Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 16
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Forskningsöversikt (refereegranskat)abstract
- Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.
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| 3. |
- Ashton, Nicholas J., et al.
(författare)
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Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.
- 2021
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 141:5, s. 709-724
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Tidskriftsartikel (refereegranskat)abstract
- The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer's disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92-0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2-4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3-4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I-II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.
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| 4. |
- Blennow, Kaj, 1958, et al.
(författare)
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Amyloid biomarkers in Alzheimer's disease.
- 2015
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Ingår i: Trends in pharmacological sciences. - : Elsevier BV. - 1873-3735 .- 0165-6147. ; 36:5
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation of amyloid-β (Aβ) into oligomers, fibrils, and plaques is central in the molecular pathogenesis of Alzheimer's disease (AD), and is the main focus of AD drug development. Biomarkers to monitor Aβ metabolism and aggregation directly in patients are important for further detailed study of the involvement of Aβ in disease pathogenesis and to monitor the biochemical effect of drugs targeting Aβ in clinical trials. Furthermore, if anti-Aβ disease-modifying drugs prove to be effective clinically, amyloid biomarkers will be of special value in the clinic to identify patients with brain amyloid deposition at risk for progression to AD dementia, to enable initiation of treatment before neurodegeneration is too severe, and to monitor drug effects on Aβ metabolism or pathology to guide dosage. Two types of amyloid biomarker have been developed: Aβ-binding ligands for use in positron emission tomography (PET) and assays to measure Aβ42 in cerebrospinal fluid (CSF). In this review, we present the rationales behind these biomarkers and compare their ability to measure Aβ plaque load in the brain. We also review possible shortcomings and the need of standardization of both biomarkers, as well as their implementation in the clinic.
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| 5. |
- Cedres, N., et al.
(författare)
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Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:15, s. E1619-E1629
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. Methods The contribution of amyloid and tau pathology was assessed through CSF levels of the A beta(42/40) ratio and phosphorylated tau (p-tau). CSF A beta(38) levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE epsilon 4 carriership were also included in the analysis as variables of interest. Results We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of A beta(38) and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The A beta(42/40) ratio did not contribute notably to the models (IncMSE<3.0%). APOE epsilon 4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T-201 = -1.55; p = 0.123). Discussion In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.
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| 6. |
- Chong, J. R., et al.
(författare)
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Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer's disease: a focused review on recent advances
- 2021
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:11, s. 1231-1241
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Forskningsöversikt (refereegranskat)abstract
- Discovery and development of clinically useful biomarkers for Alzheimer's disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-beta (A beta) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring A beta and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish A beta and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of A beta peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.
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| 7. |
- Chong, J. R., et al.
(författare)
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Brain atrophy and white matter hyperintensities are independently associated with plasma neurofilament light chain in an Asian cohort of cognitively impaired patients with concomitant cerebral small vessel disease
- 2023
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Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionPlasma neurofilament light chain (NfL) is a potential biomarker for neurodegeneration in Alzheimer's disease (AD), ischemic stroke, and non-dementia cohorts with cerebral small vessel disease (CSVD). However, studies of AD in populations with high prevalence of concomitant CSVD to evaluate associations of brain atrophy, CSVD, and amyloid beta (A beta) burden on plasma NfL are lacking. MethodsAssociations were tested between plasma NfL and brain A beta, medial temporal lobe atrophy (MTA) as well as neuroimaging features of CSVD, including white matter hyperintensities (WMH), lacunes, and cerebral microbleeds. ResultsWe found that participants with either MTA (defined as MTA score >= 2; neurodegeneration [N]+WMH-) or WMH (cut-off for log-transformed WMH volume at 50th percentile; N-WMH+) manifested increased plasma NfL levels. Participants with both pathologies (N+WMH+) showed the highest NfL compared to N+WMH-, N-WMH+, and N-WMH- individuals. DiscussionPlasma NfL has potential utility in stratifying individual and combined contributions of AD pathology and CSVD to cognitive impairment.
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| 8. |
- Dittrich, Anna, 1972, et al.
(författare)
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Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg.
- 2023
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Ingår i: Neurology. - 1526-632X. ; 101:3, s. e277-e288
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Tidskriftsartikel (refereegranskat)abstract
- Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relationship between kidney function, blood, CSF, and structural brain MRI markers of neurodegeneration in a sample including individuals with and without CKD.Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR), and structural brain MRI were included. Participants were invited to also have the CSF collected. The primary endpoint of this study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR, and CSF-derived and MRI-derived markers of neurodegeneration and Alzheimer disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, and white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, and NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3-6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model.We included 744 participants, 668 without CKD (age 71 [70-71] years, 50% males) and 76 with CKD (age 71 [70-71] years, 39% males). Biomarkers from the CSF were analyzed in 313 participants. A total of 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 [76; 77] years, 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 vs 14.1 pg/mL, p < 0.001), while MRI and CSF markers were similar between the groups. P-NfL was independently associated with CKD after adjustment for confounding variables, including hypertension and diabetes (OR; 3.231, p < 0.001), in a logistic regression model. eGFR and CSF Aβ 42/40: R = 0.23, p = 0.004 correlated in participants with Aβ42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.39 [1.21: 4.72]).In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.
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| 9. |
- Dittrich, Anna, 1972, et al.
(författare)
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Plasma and CSF NfL are differentially associated with biomarker evidence of neurodegeneration in a community-based sample of 70-year-olds
- 2022
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Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilament light protein (NfL) in cerebrospinal fluid (CSF) and plasma (P) are suggested to be interchangeable markers of neurodegeneration. However, evidence is scarce from community-based samples. NfL was examined in a small-scale sample of 287 individuals from the Gothenburg H70 Birth cohort 1944 study, using linear models in relation to CSF and magnetic resonance imaging (MRI) biomarker evidence of neurodegeneration. CSF-NfL and P-NfL present distinct associations with biomarker evidence of Alzheimer's disease (AD) pathology and neurodegeneration. P-NfL was associated with several markers that are characteristic of AD, including smaller hippocampal volumes, amyloid beta (A beta)(42), A beta(42/40), and A beta(42)/t-tau (total tau). CSF-NfL demonstrated associations with measures of synaptic and neurodegeneration, including t-tau, phosphorylated tau (p-tau), and neurogranin. Our findings suggest that P-NfL and CSF-NfL may exert different effects on markers of neurodegeneration in a small-scale community-based sample of 70-year-olds.
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| 10. |
- Franzmeier, Nicolai, et al.
(författare)
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Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer's disease.
- 2024
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Ingår i: Nature communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity. We therefore tested whether Aβ-related GAP-43 increases, as a marker of synaptic changes, drive tau spreading in 93 patients across the aging and Alzheimer's spectrum with available CSF GAP-43, amyloid-PET and longitudinal tau-PET assessments. We found that (1) higher GAP-43 was associated with faster Aβ-related tau accumulation, specifically in brain regions connected closest to subject-specific tau epicenters and (2) that higher GAP-43 strengthened the association between Aβ and connectivity-associated tau spread. This suggests that GAP-43-related synaptic changes are linked to faster Aβ-related tau spread across connected regions and that synapses could be key targets for preventing tau spreading in Alzheimer's disease.
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