1. |
- Boulo, S., et al.
(author)
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First amyloid β1-42 certified reference material for re-calibrating commercial immunoassays
- 2020
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:11, s. 1493-1503
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Journal article (peer-reviewed)abstract
- Introduction: Reference materials based on human cerebrospinal fluid were certified for the mass concentration of amyloid beta (Aβ)1-42 (Aβ42). They are intended to be used to calibrate diagnostic assays for Aβ42. Methods: The three certified reference materials (CRMs), ERM-DA480/IFCC, ERM-DA481/IFCC and ERM-DA482/IFCC, were prepared at three concentration levels and characterized using isotope dilution mass spectrometry methods. Roche, EUROIMMUN, and Fujirebio used the three CRMs to re-calibrate their immunoassays. Results: The certified Aβ42 mass concentrations in ERM-DA480/IFCC, ERM-DA481/IFCC, and ERM-DA482/IFCC are 0.45, 0.72, and 1.22μg/L, respectively, with expanded uncertainties (k=2) of 0.07, 0.11, and 0.18μg/L, respectively. Before re-calibration, a good correlation (Pearson's r>0.97), yet large biases, were observed between results from different commercial assays. After re-calibration the between-assay bias was reduced to<5%. Discussion: The Aβ42 CRMs can ensure the equivalence of results between methods and across platforms for the measurement of Aβ42. © 2020 the Alzheimer's Association
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2. |
- Minta, Karolina, et al.
(author)
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Dynamics of cerebrospinal fluid levels of matrix metalloproteinases in human traumatic brain injury
- 2020
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 18075-
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Journal article (peer-reviewed)abstract
- Matrix metalloproteinases (MMPs) are extracellular enzymes involved in the degradation of extracellular matrix (ECM) proteins. Increased expression of MMPs have been described in traumatic brain injury (TBI) and may contribute to additional tissue injury and blood–brain barrier damage. The objectives of this study were to determine longitudinal changes in cerebrospinal fluid (CSF) concentrations of MMPs after acute TBI and in relation to clinical outcomes, with patients with idiopathic normal pressure hydrocephalus (iNPH) serving as a contrast group. The study included 33 TBI patients with ventricular CSF serially sampled, and 38 iNPH patients in the contrast group. Magnetic bead-based immunoassays were utilized to measure the concentrations of eight MMPs in ventricular human CSF. CSF concentrations of MMP-1, MMP-3 and MMP-10 were increased in TBI patients (at baseline) compared with the iNPH group (p < 0.001), while MMP-2, MMP-9 and MMP-12 did not differ between the groups. MMP-1, MMP-3 and MMP-10 concentrations decreased with time after trauma (p = 0.001–0.04). Increased concentrations of MMP-2 and MMP-10 in CSF at baseline were associated with an unfavourable TBI outcome (p = 0.002–0.02). Observed variable pattern of changes in MMP concentrations indicates that specific MMPs serve different roles in the pathophysiology following TBI, and are in turn associated with clinical outcomes.
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3. |
- Pujol-Calderón, Fani, et al.
(author)
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Prediction of Outcome After Endovascular Embolectomy in Anterior Circulation Stroke Using Biomarkers.
- 2022
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In: Translational stroke research. - : Springer Science and Business Media LLC. - 1868-601X .- 1868-4483. ; 13, s. 65-76
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Journal article (peer-reviewed)abstract
- Stroke is a major public health problem that can cause a long-term disability or death due to brain damage. Serious stroke is frequently caused by a large vessel occlusion in the anterior circulation, which should be treated by endovascular embolectomy if possible. In this study, we investigated the use of the brain damage biomarkers tau, NFL, NSE, GFAp, and S100B to understand the progression of nervous tissue damage and their relationship to outcome in such stroke after endovascular treatment. Blood samples were taken from 90 patients pre-treatment and 2 h, 24 h, 48 h, 72 h and 3 months after endovascular treatment. Stroke-related neurological deficit was estimated using the National Institute of Health Stroke Scale (NIHSS) at admission and at 24 h. Neurological outcome was evaluated at 3 months. After stroke, tau, NFL, GFAp and S100B increased in a time dependent manner, while NSE remained constant over time. At 3 months, tau and GFAp levels were back to normal whereas NFL was still high. Tau, NFL and GFAp correlated well to outcome, as well as to infarct volume and NIHSS at 24 h. The best time for prediction of poor outcome was different for each biomarker. However, the combination of NIHSS at 24 h with either tau, NFL or GFAp at 48 h gave the best prediction. The use of biomarkers in the early setting after endovascular treatment of stroke will lead to a simplified and standardized way to estimate the nervous tissue damage and possibly complement the clinical judgement in foreseeing the need of rehabilitation measures.
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5. |
- Alic, I., et al.
(author)
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Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
- 2021
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10, s. 5766-5788
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Journal article (peer-reviewed)abstract
- A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of beta-amyloid-(A beta)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A beta deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical beta and gamma-secretase inhibition. We found that T21 organoids secrete increased proportions of A beta-preventing (A beta 1-19) and A beta-degradation products (A beta 1-20 and A beta 1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in similar to 30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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6. |
- Arber, C., et al.
(author)
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Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta
- 2020
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 25:11, s. 2919-2931
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Journal article (peer-reviewed)abstract
- Familial Alzheimer’s disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD. © 2019, Springer Nature Limited.
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7. |
- Behzadi, Arvin, et al.
(author)
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Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics.
- 2021
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n=234), ALS mimics (n=44) and controls (n=9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HREmutations had significantly higher plasma NFL levels than patients withSOD1mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. Allthree biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.
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8. |
- Blennow, Kaj, et al.
(author)
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Cerebrospinal fluid tau fragment correlates with tau PET : a candidate biomarker for tangle pathology
- 2020
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 143:2, s. 650-660
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Journal article (peer-reviewed)abstract
- To date, there is no validated fluid biomarker for tau pathology in Alzheimer's disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer's disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer's disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer's disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer's disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer's disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer's disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer's disease and other tauopathies.
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9. |
- Gkanatsiou, Eleni, et al.
(author)
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Amyloid pathology and synaptic loss in pathological aging
- 2021
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 159:2, s. 258-272
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid beta (A beta) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and A beta peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion A beta peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of A beta 40 was higher in AD while for A beta 42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of A beta 40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of A beta.
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10. |
- Gkanatsiou, Eleni, et al.
(author)
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Characterization of monomeric and soluble aggregated Aβ in Down's syndrome and Alzheimer's disease brains.
- 2021
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In: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 754
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Journal article (peer-reviewed)abstract
- The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10+4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
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