| 1. |
- Knorr, Ulla, et al.
(författare)
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Alzheimer's disease related biomarkers in bipolar disorder - A longitudinal one-year case-control study.
- 2022
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Ingår i: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 297, s. 623-633
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a heterogeneous mental disorder characterized by recurrent relapses of affective episodes: Subgroups of patients with BD have cognitive deficits, and an increased risk of dementia.This prospective, longitudinal, one-year follow-up, case-control study investigated biomarkers for AD and neurodegenerative diseases, namely: cerebrospinal fluid (CSF) amyloid beta (Aβ) isoforms and ratios (Aβ42, Aβ40, Aβ38), CSF soluble amyloid precursor protein (sAPP) α and β, CSF total (t-tau) and phosphorylated tau (p-tau), CSF neurofilament-light (NF-L), CSF neurogranin (NG), plasma-isoforms Aβ42 and Aβ40, plasma-tau, plasma-NF-L, and serum S100B, in patients with BD (N=62, aged 18-60) and gender-and-age-matched healthy control individuals (N=40). CSF and plasma/serum samples were collected at baseline, during and after an affective episode, if it occurred, and after a year. Data were analyzed in mixed models.Levels of CSF Aβ42 decreased in patients with BD who had an episode during follow-up (BD-E) (N=22) compared to patients without an episode (BD-NE) (N=25) during follow-up (P=0.002). Stable levels were seen for all other markers in BD-E compared to BD-NE during the one-year follow-up. We found no statistically significant differences between patients with BD and HC at T0 and T3 for Aβ42, Aβ40, Aβ38, Aβ42/38, Aβ42/40, sAPPα, sAPPβ, t-tau, p-tau, p-tau /t-tau, NF-L, NG in CSF and further Aβ40, Aβ42, Aβ42/40, t-tau, NF-L in plasma, S100B in serum, and APOE-status. Furthermore, all 18 biomarkers were stable in HC during the one-year follow-up from T0 to T3.A panel of biomarkers of Alzheimer's and neurodegeneration show no differences between patients with BD and HC. There were abnormalities of amyloid production/clearance during an acute BD episode. The abnormalities mimic the pattern seen in AD namely decreasing CSF Aβ42 and may suggest an association with brain amyloidosis.
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| 2. |
- Steen Jensen, Camilla, et al.
(författare)
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Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease.
- 2016
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 42:3-4, s. 146-158
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Tidskriftsartikel (refereegranskat)abstract
- Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical activity.The objective of this study was to elucidate the effect of 16 weeks of moderate- to high-intensity physical exercise on the biomarkers of AD, with special emphasis on the amyloidogenic pathway.From a total of 53 patients with AD participating in the Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients for apolipoprotein E ε4 (ApoE ε4) genotype.We found no effect of 16 weeks of physical exercise on the selected biomarkers, and no effect of ApoE ε4 genotype.Our findings suggest that the possible effect of physical exercise on cognition in patients with AD is not due to modulation of Aβ, t-tau, p-tau and sAPP species.
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| 3. |
- Bocchetta, Martina, et al.
(författare)
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The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey.
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 11:2, s. 195-206
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
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| 4. |
- Brinkmalm, Gunnar, et al.
(författare)
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A Parallel Reaction Monitoring Mass Spectrometric Method for Analysis of Potential CSF Biomarkers for Alzheimer's Disease.
- 2018
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Ingår i: Proteomics. Clinical applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to develop and evaluate a parallel reaction monitoring mass spectrometry (PRM-MS) assay consisting of a panel of potential protein biomarkers in cerebrospinal fluid (CSF).Thirteen proteins were selected based on their association with neurodegenerative diseases and involvement in synaptic function, secretory vesicle function, or innate immune system. CSF samples were digested and two to three peptides per protein were quantified using stable isotope-labeled peptide standards.Coefficients of variation were generally below 15%. Clinical evaluation was performed on a cohort of 10 patients with Alzheimer's disease (AD) and 15 healthy subjects. Investigated proteins of the granin family exhibited the largest difference between the patient groups. Secretogranin-2 (p<0.005) and neurosecretory protein VGF (p<0.001) concentrations were lowered in AD. For chromogranin A, two of three peptides had significantly lowered AD concentrations (p<0.01). The concentrations of the synaptic proteins neurexin-1 and neuronal pentraxin-1, as well as neurofascin were also significantly lowered in AD (p<0.05). The other investigated proteins, β2-microglobulin, cystatin C, amyloid precursor protein, lysozyme C, neurexin-2, neurexin-3, and neurocan core protein, were not significantly altered.PRM-MS of protein panels is a valuable tool to evaluate biomarker candidates for neurodegenerative disorders.
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| 5. |
- Knorr, Ulla, et al.
(författare)
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Biomarkers for neurodegeneration impact cognitive function: a longitudinal 1-year case–control study of patients with bipolar disorder and healthy control individuals
- 2024
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Ingår i: International Journal of Bipolar Disorders. - 2194-7511. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Abnormalities in cerebrospinal fluid (CSF)-amyloid-beta (Aβ)42, CSF-Aβ40, CSF-Aβ38, CSF-soluble amyloid precursor proteins α and β, CSF-total-tau, CSF-phosphorylated-tau, CSF-neurofilament light protein (NF-L), CSF-neurogranin, plasma-Aβ42, plasma-Aβ40, plasma-total-tau, plasma-NF-L and, serum-S100B during affective episodes may reflect brain changes that could impact cognitive function in patients with bipolar disorder (BD). The study aimed to investigate the association between these biomarkers indicative of Alzheimer’s disease and those reflecting neurodegeneration alongside their impact on cognitive function in patients with BD and healthy control individuals (HC). The primary hypothesis was that GL and VL would increase with increasing levels of CSF-Aβ42 based on data from T0 and T3 in BD and HC jointly. Methods: In a prospective, longitudinal case–control study euthymic patients with BD (N = 85) and HC (N = 44) were evaluated with clinical assessment and neuropsychological testing at baseline (T0) and during euthymia after a year (T3). Patients’ affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. If an episode occurred during follow-up, the patient was also assessed in post-episode euthymia. Cognitive performance was measured as a global cognitive score (GL) for four cognitive domains including verbal learning and memory (VL). Results: Estimated in a linear mixed model GL increased with 0.001 for each increase of 1pg/ml of CSF-Aβ42 (97.5%, CI 0.00043–0.0018, adjusted-p = 0.0005) while VL increased by 0.00089 (97.5%, CI 0.00015–0.0018, adjusted-p = 0.045) in BD and HC jointly. The association was weak, however stronger in patients with BD compared to HC. Associations between other biomarkers including CSF-neurogranin, and cognitive domains were overall weak, and none remained significant after adjustment for multiple testing. Limitations: Modest sample size. A complete data set regarding both CSF-AB-42 and cognitive test scores was obtained from merely 61 patients with BD and 38 HC individuals. Conclusion: CSF-Aβ42 may be associated with cognitive dysfunction in patients with BD and HC individuals. The association appeared to be stronger in BD but with overlapping confidence intervals. Hence it remains uncertain whether the association is a general phenomenon or driven by BD.
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| 6. |
- Knorr, Ulla, et al.
(författare)
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Cerebrospinal fluid synaptic biomarker changes in bipolar disorder - A longitudinal case-control study.
- 2024
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Ingår i: Journal of affective disorders. - 1573-2517. ; 358, s. 250-259
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Tidskriftsartikel (refereegranskat)abstract
- This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections.Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14-3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes.The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up.It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect.This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.
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| 7. |
- Leuzy, Antoine, et al.
(författare)
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Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study.
- 2016
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 139:Pt 9, s. 2540-53
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally measured cerebrospinal fluid amyloid-β42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β42 to amyloid-β40 Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer's and Parkinson's Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer's disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β42 and amyloid-β40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer's disease, while more variable results were observed for cognitively normal and non-Alzheimer's disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference measurement procedure findings was further improved when using amyloid-β42/40 Agreement between Pittsburgh compound B visual ratings and Centiloids was near complete. Despite improved agreement between Pittsburgh compound B and centrally analysed cerebrospinal fluid, a minority of subjects showed discordant findings. While future studies are needed, our results suggest that amyloid biomarker results may not be interchangeable in some individuals.
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| 8. |
- Travassos, Maria, et al.
(författare)
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Does Caffeine Consumption Modify Cerebrospinal Fluid Amyloid-β Levels in Patients with Alzheimer's Disease?
- 2015
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 47:4, s. 1069-78
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Tidskriftsartikel (refereegranskat)abstract
- Caffeine may be protective against Alzheimer's disease (AD) by modulating amyloid-β (Aβ) metabolic pathways. The present work aimed to study a possible association of caffeine consumption with the cerebrospinal fluid (CSF) biomarkers, particularly Aβ. The study included 88 patients with AD or mild cognitive impairment. The consumption of caffeine and theobromine was evaluated using a validated food questionnaire. Quantification of caffeine and main active metabolites was performed with liquid chromatography coupled to tandem mass spectrometry. The levels of A(1-42), total tau, and phosphorylated tau in the CSF were determined using sandwich ELISA methods and other Aβ species, Aβ(X-38), Aβ(X-40), and Aβ(X-42), with the MSD Aβ Triplex assay. The concentration of caffeine was 0.79±1.15 μg/mL in the CSF and 1.20±1.88 μg/mL in the plasma. No correlation was found between caffeine consumption and Aβ42 in the CSF. However, a significant positive correlation was found between the concentrations of theobromine, both in the CSF and in the plasma, with Aβ42 in the CSF. Theobromine in the CSF was positively correlated with the levels of other xanthines in the CSF, but not in the plasma, suggesting that it may be formed by central metabolic pathways. In conclusion, caffeine consumption does not modify the levels of CSF biomarkers, and does not require to be controlled for when measuring CSF biomarkers in a clinical setting. Since theobromine is associated with a favorable Aβ profile in the CSF, the possibility that it might have a protective role in AD should be further investigated.
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| 9. |
- Vandenberghe, Rik, et al.
(författare)
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Binary classification of F-18-flutemetamol PET using machine learning: Comparison with visual reads and structural MRI
- 2013
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Ingår i: NeuroImage. - : Elsevier BV. - 1095-9572 .- 1053-8119. ; 64, s. 517-525
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Tidskriftsartikel (refereegranskat)abstract
- F-18-flutemetamol is a positron emission tomography (PET) tracer for in vivo amyloid imaging. The ability to classify amyloid scans in a binary manner as 'normal' versus 'Alzheimer-like', is of high clinical relevance. We evaluated whether a supervised machine learning technique, support vector machines (SVM), can replicate the assignments made by visual readers blind to the clinical diagnosis, which image components have highest diagnostic value according to SVM and how F-18-flutemetamol-based classification using SVM relates to structural MRI-based classification using SVM within the same subjects. By means of SVM with a linear kernel, we analyzed F-18-flutemetamol scans and volumetric MRI scans from 72 cases from the F-18-flutemetamol phase 2 study (27 clinically probable Alzheimer's disease (AD), 20 amnestic mild cognitive impairment (MCI), 25 controls). In a leave-one-out approach, we trained the F-18-flutemetamol based classifier by means of the visual reads and tested whether the classifier was able to reproduce the assignment based on visual reads and which voxels had the highest feature weights. The F-18-flutemetamol based classifier was able to replicate the assignments obtained by visual reads with 100% accuracy. The voxels with highest feature weights were in the striatum, precuneus, cingulate and middle frontal gyrus. Second, to determine concordance between the gray matter volume- and the F-18-flutemetamol-based classification, we trained the classifier with the clinical diagnosis as gold standard. Overall sensitivity of the F-18-flutemetamol- and the gray matter volume-based classifiers were identical (85.2%), albeit with discordant classification in three cases. Specificity of the F-18-flutemetamol based classifier was 92% compared to 68% for MRI. In the MCI group, the F-18-flutemetamol based classifier distinguished more reliably between converters and non-converters than the gray matter-based classifier. The visual read-based binary classification of F-18-flutemetamol scans can be replicated using SVM. In this sample the specificity of F-18-flutemetamol based SVM for distinguishing AD from controls is higher than that of gray matter volume-based SVM. (C) 2012 Elsevier Inc. All rights reserved.
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| 10. |
- Vandenberghe, Rik, et al.
(författare)
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F-18-Flutemetamol Amyloid Imaging in Alzheimer Disease and Mild Cognitive Impairment A Phase 2 Trial
- 2010
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 68:3, s. 319-329
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The most widely studied positron emission tomography ligand for in vivo P-amyloid imaging is C-11-Pittsburgh compound B (C-11-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the F-18-labeled PIB derivative F-18-flutemetamol could significantly enhance access to this novel technology. Methods: Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of F-18-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for F-18-flutemetamol and its parent molecule C-11-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of F-18-flutemetamol SUVRs in 5 of the AD subjects. Results: Blinded visual assessments of F-18-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical F-18-flutemetamol SUVRs and C-11-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%. Interpretation: F-18-Flutemetamol performs similarly to the C-11-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use. ANN NEUROL 2010;68:319-329
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