| 11. |
- Heywood, W. E., et al.
(författare)
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Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment
- 2022
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Ingår i: F1000Research. - : F1000 Research Ltd. - 2046-1402. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT. © 2022 Iwan K et al.
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| 12. |
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| 13. |
- Hallqvist, Jenny, et al.
(författare)
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A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning
- 2023
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Ingår i: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 24:18
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Tidskriftsartikel (refereegranskat)abstract
- As disease-modifying therapies are now available for Alzheimer's disease (AD), accessible, accurate and affordable biomarkers to support diagnosis are urgently needed. We sought to develop a mass spectrometry-based urine test as a high-throughput screening tool for diagnosing AD. We collected urine from a discovery cohort (n = 11) of well-characterised individuals with AD (n = 6) and their asymptomatic, CSF biomarker-negative study partners (n = 5) and used untargeted proteomics for biomarker discovery. Protein biomarkers identified were taken forward to develop a high-throughput, multiplexed and targeted proteomic assay which was tested on an independent cohort (n = 21). The panel of proteins identified are known to be involved in AD pathogenesis. In comparing AD and controls, a panel of proteins including MIEN1, TNFB, VCAM1, REG1B and ABCA7 had a classification accuracy of 86%. These proteins have been previously implicated in AD pathogenesis. This suggests that urine-targeted mass spectrometry has potential utility as a diagnostic screening tool in AD.
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| 14. |
- Heslegrave, A. J., et al.
(författare)
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A Selected reaction monitoring protocol for the measurement of sTREM2 in cerebrospinal fluid
- 2018
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Ingår i: Biomarkers for Preclinical Alzheimer’s Disease. Perneczky R. (red.). - New York, NY : Springer. - 0893-2336. - 9781493976744 ; , s. 169-177
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Bokkapitel (refereegranskat)abstract
- Mass spectrometry plays an increasingly important role in the biomarker field with the advent of targeted proteomics. Tryptic peptides from a protein of interest can be used to create a targeted assay to interrogate cerebrospinal fluid (CSF) for biomarkers. Since heterozygous mutations in the TREM2 gene have been associated with an increased risk of Alzheimer’s disease, measuring this soluble protein in CSF has become a priority. This chapter demonstrates the development, optimization, and validation of a method to measure soluble TREM2 using a single reaction monitoring (SRM) targeted mass spectrometry assay. © 2018, Springer Science+Business Media, LLC.
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| 15. |
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| 16. |
- Murray, C. E., et al.
(författare)
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The presubiculum is preserved from neurodegenerative changes in Alzheimer's disease
- 2018
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 6:62
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Tidskriftsartikel (refereegranskat)abstract
- In the majority of affected brain regions the pathological hallmarks of Alzheimer's disease (AD) are beta-amyloid (A beta) deposits in the form of diffuse and neuritic plaques, tau pathology in the form of neurofibrillary tangles, neuropil threads and plaque-associated abnormal neurites in combination with an inflammatory response. However, the anatomical area of the presubiculum, is characterised by the presence of a single large evenly distributed 'lake-like' A beta deposit with minimal tau deposition or accumulation of inflammatory markers. Post-mortem brain samples from sporadic AD (SAD) and familial AD (FAD) and two hereditary cerebral amyloid diseases, familial British dementia (FBD) and familial Danish dementia (FDD) were used to compare the morphology of the extracellular proteins deposited in the presubiculum compared to the entorhinal cortex. The level of tau pathology and the extent of microglial activation were quantitated in the two brain regions in SAD and FAD. Frozen tissue was used to investigate the A beta species and proteomic differences between the two regions. Consistent with our previous investigations of FBD and FDD cases we were able to establish that the 'lake-like' pre-amyloid deposits of the presubiculum were not a unique feature of AD but they also found two non-A beta amyloidosis. Comparing the presubiculum to the entorhinal cortex the number of neurofibrillary tangles and tau load were significantly reduced; there was a reduction in microglial activation; there were differences in the A beta profiles and the investigation of the whole proteome showed significant changes in different protein pathways. In summary, understanding why the presubiculum has a different morphological appearance, biochemical and proteomic makeup compared to surrounding brain regions severely affected by neurodegeneration could lead us to understanding protective mechanisms in neurodegenerative diseases.
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| 17. |
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