| 1351. |
- Palmqvist, Sebastian, et al.
(författare)
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Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity.
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer's disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of Aβ accumulation is already evident in individuals with normal Aβ42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF Aβ42. The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.
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| 1352. |
- Palmqvist, Sebastian, et al.
(författare)
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Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 76:9, s. 1060-1069
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Tidskriftsartikel (refereegranskat)abstract
- Key PointsQuestionDo plasma levels of beta -amyloid 42, beta -amyloid 40, and tau detect cerebral beta -amyloid status when measured using fully automated immunoassays? FindingsIn 2 cross-sectional studies, plasma beta -amyloid 42 to beta -amyloid 40 ratio, measured using immunoassay, accurately predicted cerebral beta -amyloid status in all stages of Alzheimer disease in the BioFINDER cohort (n=842) and in an independent validation cohort (n=237). The diagnostic accuracy was further increased by analyzing APOE genotype. MeaningBlood-based beta -amyloid 42 and beta -amyloid 40 ratio together with APOE genotype may be used as prescreening tests in primary care and in clinical Alzheimer disease trials to lower the costs and number of positron emission tomography scans and lumbar punctures. This corss-sectional diagnostic study evaluates the accuracy of fully automated plasma assays in measuring plasma beta -amyloid and tau in patients with and without cognitive impairment in the Swedish BioFINDER study and an independent validation cohort. ImportanceAccurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. ObjectiveTo examine the accuracy of plasma beta -amyloid (A beta) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral A beta. Design, Setting, and ParticipantsTwo prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study. Main Outcome and MeasuresThe cerebrospinal fluid (CSF) A beta 42/A beta 40 ratio was used as the reference standard for brain A beta status. Plasma A beta 42, A beta 40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of A beta status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1. ResultsThe mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma A beta 42 and A beta 40 predicted A beta status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to A beta 42, A beta 40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma A beta 42 and A beta 40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma A beta 42, A beta 40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. Conclusions and RelevancePlasma A beta 42 and A beta 40 measured using Elecsys immunoassays predict A beta status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of A beta positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.
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| 1353. |
- Palmqvist, Sebastian, et al.
(författare)
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Prediction of future Alzheimer's disease dementia using plasma phospho-tau combined with other accessible measures
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27
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Tidskriftsartikel (refereegranskat)abstract
- Plasma P-tau, in combination with clinical measures, predicts future Alzheimer's disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists. A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer's disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma A beta 42/A beta 40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90-0.91 in both cohorts. Using cerebrospinal fluid P-tau, A beta 42/A beta 40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials.
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| 1354. |
- Palpatzis, Eleni, et al.
(författare)
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Lifetime Stressful Events Associated with Alzheimer's Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort
- 2024
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Ingår i: ANNALS OF NEUROLOGY. - 0364-5134 .- 1531-8249.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD.MethodsThis cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and A beta 1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods.ResultsWithin the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower A beta 1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively.InterpretationWe did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024
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| 1355. |
- Pan, X. B., et al.
(författare)
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Cerebrospinal Fluid Spermidine, Glutamine and Putrescine Predict Postoperative Delirium Following Elective Orthopaedic Surgery
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (>= 65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 <= 0.56; Q2 <= 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF A beta 42 (ROC > 0.8), and spermidine significantly correlated with A beta 42 (pearson r = -0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with A beta 42, and this requires further investigation.
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| 1356. |
- Pan, Xiaobei, et al.
(författare)
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Plasma metabolites distinguish dementia with Lewy bodies from Alzheimer's disease: a cross-sectional metabolomic analysis
- 2024
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Ingår i: FRONTIERS IN AGING NEUROSCIENCE. - 1663-4365. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn multifactorial diseases, alterations in the concentration of metabolites can identify novel pathological mechanisms at the intersection between genetic and environmental influences. This study aimed to profile the plasma metabolome of patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), two neurodegenerative disorders for which our understanding of the pathophysiology is incomplete. In the clinical setting, DLB is often mistaken for AD, highlighting a need for accurate diagnostic biomarkers. We therefore also aimed to determine the overlapping and differentiating metabolite patterns associated with each and establish whether identification of these patterns could be leveraged as biomarkers to support clinical diagnosis.MethodsA panel of 630 metabolites (Biocrates MxP Quant 500) and a further 232 metabolism indicators (biologically informative sums and ratios calculated from measured metabolites, each indicative for a specific pathway or synthesis; MetaboINDICATOR) were analyzed in plasma from patients with probable DLB (n = 15; age 77.6 +/- 8.2 years), probable AD (n = 15; 76.1 +/- 6.4 years), and age-matched cognitively healthy controls (HC; n = 15; 75.2 +/- 6.9 years). Metabolites were quantified using a reversed-phase ultra-performance liquid chromatography column and triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, or by using flow injection analysis in MRM mode. Data underwent multivariate (PCA analysis), univariate and receiving operator characteristic (ROC) analysis. Metabolite data were also correlated (Spearman r) with the collected clinical neuroimaging and protein biomarker data.ResultsThe PCA plot separated DLB, AD and HC groups (R2 = 0.518, Q2 = 0.348). Significant alterations in 17 detected metabolite parameters were identified (q <= 0.05), including neurotransmitters, amino acids and glycerophospholipids. Glutamine (Glu; q = 0.045) concentrations and indicators of sphingomyelin hydroxylation (q = 0.039) distinguished AD and DLB, and these significantly correlated with semi-quantitative measurement of cardiac sympathetic denervation. The most promising biomarker differentiating AD from DLB was Glu:lysophosphatidylcholine (lysoPC a 24:0) ratio (AUC = 0.92; 95%CI 0.809-0.996; sensitivity = 0.90; specificity = 0.90).DiscussionSeveral plasma metabolomic aberrations are shared by both DLB and AD, but a rise in plasma glutamine was specific to DLB. When measured against plasma lysoPC a C24:0, glutamine could differentiate DLB from AD, and the reproducibility of this biomarker should be investigated in larger cohorts.
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| 1357. |
- Pannee, Josef, 1979, et al.
(författare)
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A selected reaction monitoring (SRM)-based method for absolute quantification of Aβ38, Aβ40, and Aβ42 in cerebrospinal fluid of Alzheimer's Disease patients and healthy controls.
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 33:4, s. 1021-32
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in research centers, clinical trials, and clinical settings. However, their broad-scale use is hampered by lack of standardization across analytical platforms and by interference from binding of amyloid-β (Aβ) to matrix proteins as well as self-aggregation. Here, we report on a matrix effect-resistant method for the measurement of the AD-associated 42 amino acid species of Aβ (Aβ42), together with Aβ40 and Aβ38 in human CSF based on mass spectrometric quantification using selected reaction monitoring (SRM). Samples were prepared by solid-phase extraction and quantification was performed using stable-isotope labeled Aβ peptides as internal standards. The diagnostic performance of the method was evaluated on two independent clinical materials with research volunteers who were cognitively normal and AD patients with mild to moderate dementia. Analytical characteristics of the method include a lower limit of quantification of 62.5 pg/mL for Aβ42 and coefficients of variations below 10%. In a pilot study on AD patients and controls, we verified disease-association with decreased levels of Aβ42 similar to that obtained by ELISA and even better separation was obtained using the Aβ42/Aβ40 ratio. The developed assay is sensitive and is not influenced by matrix effects, enabling absolute quantification of Aβ42, Aβ40, and Aβ38 in CSF, while it retains the ability to distinguish AD patients from controls. We suggest this SRM-based method for Aβ peptide quantification in human CSF valuable for clinical research and trials.
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| 1358. |
- Pannee, Josef, 1979, et al.
(författare)
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Abeta CSF LC-MS
- 2021
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Ingår i: Cerebrospinal Fluid Biomarkers. Teunissen C.E., Zetterberg H. (eds). - New York, NY : Springer. - 0893-2336. - 9781071613184 ; , s. 55-69
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- In this chapter, a method using an antibody independent approach based on solid phase extraction (SPE) and liquid chromatography (LC)-tandem mass spectrometry (MS/MS) is described for the analysis of Aβ isoforms in cerebrospinal fluid (CSF). Stable isotope-labeled Aβ peptides are used as internal standards, enabling absolute quantification. A high-resolution quadrupole-Orbitrap hybrid instrument was used for measurements. The method allows quantification of CSF Aβ1-42 between 150 and 4000 pg/mL. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.
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| 1359. |
- Pannee, Josef, 1979, et al.
(författare)
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Absolute Quantification of Aβ1-42 in CSF Using a Mass Spectrometric Reference Measurement Procedure.
- 2017
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Ingår i: Journal of visualized experiments : JoVE. - : MyJove Corporation. - 1940-087X. ; :121
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly and accounts for 60-80% of all cases of dementia. Currently, the diagnosis of AD is based on cognitive tests and mental state exams, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used in clinical trials and settings. As for most protein and peptide biomarkers, quantification is performed using antibody-based techniques, such as enzyme-linked immunosorbent assay (ELISA). However, intra- and inter-laboratory variability in these assays hamper its use as a diagnostic marker in clinical routine. An antibody-independent Reference Measurement Procedure (RMP) was developed based on solid-phase extraction (SPE) and liquid chromatography (LC)-tandem mass spectrometry (MS/MS), where stable, isotope-labeled Aβ peptides were used as internal standards, enabling absolute quantification. A high-resolution quadrupole-orbitrap hybrid instrument was used for the measurements. The method allows for the quantification of CSF Aβ1-42 between 150-4,000 pg/mL.
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| 1360. |
- Pannee, Josef, 1979, et al.
(författare)
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Round robin test on quantification of amyloid-β 1-42 in cerebrospinal fluid by mass spectrometry.
- 2016
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ42) is an important biomarker for Alzheimer's disease, both in diagnostics and to monitor disease-modifying therapies. However, there is a great need for standardization of methods used for quantification. To overcome problems associated with immunoassays, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a critical orthogonal alternative.
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