| 21. |
- Manniche, C., et al.
(author)
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Cerebrospinal Fluid Biomarkers to Differentiate Idiopathic Normal Pressure Hydrocephalus from Subcortical Ischemic Vascular Disease
- 2020
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 75:3, s. 937-947
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Journal article (peer-reviewed)abstract
- Background: Idiopathic normal pressure hydrocephalus (iNPH) remains a challenge to differentiate from subcortical ischemic vascular disease (SIVD). Despite major research efforts, the cerebrospinal fluid (CSF) biomarker profiles of the two diseases are still not known in detail. Objective: To determine if novel CSF biomarkers, neurofilament light (NFL) reflecting axonal damage, the synaptic protein neurogranin (NG), and the astroglial marker chitinase-3-like protein 1 (YKL-40), and the core Alzheimer's disease (AD) biomarkers, amyloid-beta 42 (A beta(42)), total tau (t-tau), phosphorylated tau (p-tau), can differentiate iNPH from SIVD. Patients with AD and healthy controls (HC) were included for comparison purposes. Methods: Patients with iNPH (n = 28), SIVD (n = 30), AD (n = 57), and HC (n = 33) were retrospectively included from the Danish Dementia Biobank. All patients with iNPH had effect of shunt surgery with a follow-up period of 4 to 69 months. CSF biomarkers were measured using immunoassays. Results: Lower levels of NFL, NG, A beta(42), and t-tau were found in patients with iNPH versus SIVD, while YKL-40 and p-tau were similar in the two diseases. NFL and A beta(42) were the most reliable biomarkers to differentiate iNPH from SIVD with an area under the curve (AUC) on 0.82 and 0.80, respectively. Combining NFL with A beta(42), t-tau, and p-tau resulted in an AUC of 0.90, which was equivalent to the diagnostic accuracy of all six biomarkers combined. Conclusion: An addition of NFL to the CSF panel of A beta(42), t-tau, and p-tau may improve the differentiation of iNPH from SIVD.
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| 22. |
- Meda, Francisco J, 1997, et al.
(author)
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Analytical and clinical validation of a blood progranulin ELISA in frontotemporal dementias
- 2023
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In: Clinical Chemistry and Laboratory Medicine. - 1434-6621. ; 61:12, s. 2195-2204
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Journal article (peer-reviewed)abstract
- Objectives: Heterozygous mutations in the granulin (GRN) gene may result in haploinsufficiency of progranulin (PGRN), which might lead to frontotemporal dementia (FTD). In this study, we aimed to perform analytical and clinical validation of a commercial progranulin kit for clinical use. Methods: Analytical validation parameters including assay precision, selectivity, measurement range, dilution linearity, interferences and sample stability were tested according to previously described procedures. For clinical validation, PGRN levels were measured in plasma from 32 cognitively healthy individuals, 52 confirmed GRN mutation carriers, 25 C9orf72 mutation carriers and 216 patients with different neurodegenerative diseases of which 70 were confirmed as non-mutation carriers. Results: Among the analytical validation parameters, assay precision and repeatability were very stable (coefficients of variation <7 %). Spike recovery was 96 %, the measurement range was 6.25-400 mu g/L and dilution linearity ranged from 1:50-1:200. Hemolysis did not interfere with progranulin levels, and these were resistant to freeze/thaw cycles and storage at different temperatures. For the clinical validation, the assay was capable of distinguishing GRN mutation carriers from controls and non-GRN mutation carriers with very good sensitivity and specificity at a cut-off of 57 mu g/L (97 %, 100 %, respectively). Conclusions: In this study, we demonstrate robust analytical and diagnostic performance of this commercial progranulin kit for implementation in clinical laboratory practice. This easy-to-use test allows identification of potential GRN mutation carriers, which may guide further evaluation of the patient. This assay might also be used to evaluate the effect of novel PGRN-targeting drugs and therapies.
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| 23. |
- Meda, Francisco J, 1997, et al.
(author)
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Neurofilament light oligomers in neurodegenerative diseases: quantification by homogeneous immunoassay in cerebrospinal fluid
- 2023
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In: BMJ NEUROLOGY OPEN. - : BMJ. - 2632-6140. ; 5:1
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Journal article (peer-reviewed)abstract
- Background Neurofilament light (NfL) is a widely used biomarker for neurodegeneration. NfL is prone to oligomerisation, but available assays do not reveal the exact molecular nature of the protein variant measured. The objective of this study was to develop a homogeneous ELISA capable of quantifying oligomeric NfL (oNfL) in cerebrospinal fluid (CSF). Methods A homogeneous ELISA, based on the same capture and detection antibody (NfL21), was developed and used to quantify oNfL in samples from patients with behavioural variant frontotemporal dementia (bvFTD, n=28), non-fluent variant primary progressive aphasia (nfvPPA, n=23), semantic variant PPA (svPPA, n=10), Alzheimer's disease (AD, n=20) and healthy controls (n=20). The nature of NfL in CSF, and the recombinant protein calibrator, was also characterised by size exclusion chromatography (SEC). Results CSF concentration of oNfL was significantly higher in nfvPPA (p<0.0001) and svPPA patients (p<0.05) compared with controls. CSF oNfL concentration was also significantly higher in nfvPPA compared with bvFTD (p<0.001) and AD (p<0.01) patients. SEC data showed a peak fraction compatible with a full-length dimer (similar to 135 kDa) in the in-house calibrator. For CSF, the peak was found in a fraction of lower molecular weight (similar to 53 kDa), suggesting dimerisation of NfL fragments. Conclusions The homogeneous ELISA and SEC data suggest that most of the NfL in both the calibrator and human CSF is present as a dimer. In CSF, the dimer appears to be truncated. Further studies are needed to determine its precise molecular composition.
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| 24. |
- Mens, H., et al.
(author)
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Neurofilament Light in Cerebrospinal Fluid is Associated With Disease Staging in European Lyme Neuroborreliosis
- 2022
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In: Journal of Central Nervous System Disease. - : SAGE Publications. - 1179-5735. ; 14
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Journal article (peer-reviewed)abstract
- BACKGROUND: Drivers of differences in disease presentation and symptom duration in Lyme neuroborreliosis (LNB) are currently unknown. OBJECTIVES: We hypothesized that neurofilament light (NfL) in cerebrospinal fluid (CSF) would predict disease location and sequelae in a historic LNB cohort. DESIGN: Using a cross-sectional design and archived CSF samples from 185 patients diagnosed with LNB, we evaluated the content of NfL in the total cohort and in a subgroup of 84 patients with available clinical and paraclinical information. METHODS: Individuals were categorized according to disease location: a. Central nervous system (CNS) with stroke (N=3), b. CNS without stroke (N=11), c. Peripheral nervous system (PNS) with cranial nerve palsy (CNP) (N=40) d. PNS without CNP (N=30). Patients with hospital follow-up more than 6 months after completed antibiotic therapy were categorized as having LNB associated sequelae (N=15). RESULTS: At diagnosis concentration of NfL exceeded the upper reference level in 60% (105/185), especially among individuals above 30 years. Age-adjusted NfL was not found to be associated with symptom duration. Age-adjusted NfL was significantly higher among individuals with CNS involvement. Category a. (stroke) had significantly higher NfL concentrations in CSF compared to all other categories, category b. (CNS involvement without stroke) had significantly higher values compared to the categories of PNS involvement. We found no significant difference between the categories with PNS involvement (with or without CNP). Significantly higher NfL was found among patients with follow-up in hospital setting. CONCLUSION: Comparison of NfL concentrations between the 4 groups of LNB disease manifestations based on clinical information revealed a hierarchy of neuron damage according to disease location and suggested evolving mechanisms with accelerated injury especially when disease is complicated by stroke. Higher values of NfL among patients with need of follow-up in hospital setting suggest NfL could be useful to identify rehabilitative needs.
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| 25. |
- Mens, H., et al.
(author)
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Plasma neurofilament light significantly decreases following treatment in Lyme neuroborreliosis and is not associated with persistent symptoms
- 2023
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 30:5, s. 1371-1377
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Journal article (peer-reviewed)abstract
- Background and purpose: Currently there is an unmet need for a highly standardized blood biomarker test to monitor treatment response in Lyme neuroborreliosis (LNB). Differentiating between active or past infection is challenged by the relatively high frequency of persistent symptoms after the end of antibiotic treatment (estimated 15%-20%), the variable clinical course and the long-lasting Borrelia burgdorferi antibodies. The aim was therefore to evaluate plasma neurofilament light chain (pNfL) as a marker for disease activity in LNB.Methods: This was a prospective cohort of definite LNB (N = 36) with blood samples and clinical evaluation including Glasgow Outcome Score at treatment initiation and 3 and 6 months' follow-up. Consecutive plasma was retrospectively analysed for the content of neurofilament light chain by Quanterix (R) kits (Simoa (R) NF-light Kit).Results: Plasma neurofilament light chain significantly decreased between treatment initiation and the 3-month follow-up (median 83 pg/ml vs. median 14 pg/ml (25 pairs), p < 0.0001). No significant change was observed between 3 and 6 months' follow-up (median 14 pg/ml vs. median 12 pg/ml (21 pairs), p = 0.33). At treatment initiation 90% had pNfL above the age-defined reference compared to only 23% and 7% respectively at 3 and 6 months' follow-up. Decreases in pNfL were mirrored by increasing Glasgow Outcome Score. Reporting persistent symptoms at the 6-month follow-up was not associated with pNfL (relative change from reference or actual values) at baseline or at 6 months' follow-up.Conclusion: Plasma neurofilament light chain decreases following antibiotic treatment in LNB and is not associated with reporting persistent symptoms. It was therefore speculated that it may prove useful as a treatment response biomarker in LNB.
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| 26. |
- Minta, Karolina, et al.
(author)
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Brevican and Neurocan Peptides as Potential Cerebrospinal Fluid Biomarkers for Differentiation Between Vascular Dementia and Alzheimer's Disease
- 2021
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In: Journal of Alzheimer's disease : JAD. - 1387-2877 .- 1875-8908. ; 79:2, s. 729-741
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Journal article (peer-reviewed)abstract
- BACKGROUND: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF).OBJECTIVE: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer's disease (AD) and vascular dementia (VaD) compared with controls.METHODS: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry.RESULTS: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p≤0.05) and as compared with the control group (AUC = 0.79.0.87, p ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p ≤ 0.05) and to controls (AUC = 0.80.0.82, p ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p > 0.05). No peptides differed between AD and controls.CONCLUSION: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.
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| 27. |
- Minta, Karolina, et al.
(author)
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Cerebrospinal fluid brevican and neurocan fragment patterns in human traumatic brain injury.
- 2021
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In: Clinica chimica acta; international journal of clinical chemistry. - : Elsevier BV. - 1873-3492 .- 0009-8981. ; 512, s. 74-83
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Journal article (peer-reviewed)abstract
- Altered levels of two extracellular matrix (ECM) proteoglycans, brevican and neurocan, have been found in brain injury models; however, their proteolytic processing in traumatic brain injury (TBI) remains unexplored. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a possible contributor to ECM remodelling following TBI. The aims of this study were to evaluate proteolytic brevican/neurocan patterns and ADAMTS-like activity in cerebrospinal fluid (CSF) in the context of TBI.Forty-two acute TBI patients and 37 idiopathic normal pressure hydrocephalus (iNPH) patients were included in the analysis of tryptic brevican and neurocan peptides in CSF using parallel reaction monitoring mass spectrometry. Twenty-nine TBI and 36 iNPH patients were analysed for ADAMTS-like activity in CSF using a quenched fluorescent substrate.The majority of CSF concentrations of brevican peptides significantly decreased in TBI patients compared with the iNPH group (p≤0.002), while ADAMTS-like activity increased (p<0.0001). Two C-terminal brevican peptides strongly correlated with unfavourable outcome of TBI patients (rho=0.85-0.93, p≤0.001).The decreased CSF concentrations of brevican peptides in TBI are associated with their increased degradation by ADAMTS enzymes. Furthermore, the N- and C- terminal parts of brevican are differentially regulated following TBI and may serve as outcome markers.
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| 28. |
- 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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| 29. |
- Minta, Karolina, et al.
(author)
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Lumbar and ventricular CSF concentrations of extracellular matrix proteins before and after shunt surgery in idiopathic normal pressure hydrocephalus
- 2021
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In: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 18:1
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Journal article (peer-reviewed)abstract
- Background: Idiopathic normal pressure hydrocephalus (iNPH) is a reversible CNS disease characterized by disturbed cerebrospinal fluid (CSF) dynamics. Changes in the extracellular matrix (ECM) composition might be involved in the pathophysiology of iNPH. The aim of this study was to explore possible differences between lumbar and ventricular CSF concentrations of the ECM markers brevican and neurocan, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and their relation to clinical symptoms in iNPH patients before and after shunt surgery. Methods: Paired lumbar and ventricular CSF was collected from 31 iNPH patients, before and four months after shunt surgery. CSF was analysed for concentrations of tryptic peptides originating from brevican and neurocan using a mass spectrometry-based panel, and for MMP-1, -2, -9, -10 and TIMP-1 using fluorescent or electrochemiluminescent immunoassays. Results: Brevican and neurocan peptide levels were not influenced by CSF origin, but MMP-1, -2, -10 and TIMP-1 were increased (p ≤ 0.0005), and MMP-9 decreased (p ≤ 0.0003) in lumbar CSF compared with ventricular CSF. There was a general trend of ECM proteins to increase following shunt surgery. Ventricular TIMP-1 was inversely correlated with overall symptoms (rho = − 0.62, p < 0.0001). CSF concentrations of the majority of brevican and neurocan peptides were increased in iNPH patients with a history of cardiovascular disease (p ≤ 0.001, AUC = 0.84–0.94) compared with those without. Conclusion: Levels of the CNS-specific proteins brevican and neurocan did not differ between the lumbar and ventricular CSF, whereas the increase of several CNS-unspecific MMPs and TIMP-1 in lumbar CSF suggests contribution from peripheral tissues. The increase of ECM proteins in CSF following shunt surgery could indicate disturbed ECM dynamics in iNPH that are restored by restitution of CSF dynamics. © 2021, The Author(s).
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| 30. |
- Minta, Karolina, et al.
(author)
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Quantification of total apolipoprotein E and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases
- 2020
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12
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Journal article (peer-reviewed)abstract
- Background The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: epsilon 2, epsilon 3, and epsilon 4 that give rise to amino acid substitutions. APOE-epsilon 4 is a strong risk factor of sporadic Alzheimer's disease (AD) but the reason why is still unknown despite intense research for more than 20 years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes. Methods Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry. In total, 1820 individuals were involved in the study including clinically diagnosed AD patients (n = 228), cognitively unimpaired (CU) patients (n = 896), and patients with other neurodegenerative disorders (n = 696). Follow-up data was available for 100 individuals, assessed at two time points. Subjects were dichotomized based on an A beta(42/40) CSF concentration ratio cut-off into A beta positive (A beta+, < 0.091) and A beta negative (A beta-, > 0.091) groups. Results Even though there was a significant increase of total apoE in the amyloid beta-positive (A beta+) group compared with amyloid beta-negative (A beta-) individuals (p < 0.001), the magnitude of the effect was very small (AUC = 0.55). Moreover, CSF total apoE concentrations did not differ between A beta- CU controls and clinically diagnosed AD patients. There was a difference in concentration between isoforms in heterozygous individuals in an isoform-dependent manner (E2 < E3 < E4) (p < 0.001, AUC = 0.64-0.69), and these associations remained when dichotomizing the samples into A beta+ and A beta- groups (p < 0.01, AUC = 0.63-0.74). In the cohort with follow-up samples, neither total apoE nor isoform-specific apoE concentrations differed between the two time points (p > 0.05). Conclusions The results indicate that neither the concentrations of total apoE nor the different apoE isoforms in CSF are associated with APOE-epsilon 4 carrier status, A beta status, or clinical dementia diagnoses.
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