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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Alawode, Deborah O T, et al.
(författare)
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Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease.
- 2021
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Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 290:3, s. 583-601
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. Whilst these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N), and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre-analytical protocols.
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| 3. |
- Arber, Charles, et al.
(författare)
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Mass spectrometry analysis of tau and amyloid-beta in iPSC-derived models of Alzheimer's disease and dementia.
- 2021
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 159:2, s. 305-317
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Tidskriftsartikel (refereegranskat)abstract
- Induced pluripotent stem cell (iPSC) technology enables the generation of human neurons in vitro, which contain the precise genome of the cell donor, therefore permitting the generation of disease models from individuals with a disease-associated genotype of interest. This approach has been extensively used to model inherited forms of Alzheimer's disease and frontotemporal dementia. The combination of iPSC-derived neuronal models with targeted mass spectrometry analysis has provided unprecedented insights into the regulation of specific proteins in human neuronal physiology and pathology. For example enabling investigations into tau and APP/Aβ, specifically: protein isoform expression, relative levels of cleavage fragments, aggregated species and functionally critical post-translational modifications. The use of mass spectrometry has enabled a determination of how closely iPSC-derived models recapitulate disease profiles observed in the human brain. This review will highlight the progress to date in studies using iPSCs and mass spectrometry to model Alzheimer's disease and dementia. We go on to convey our optimism, as studies in the near future will make use of this precedent, together with novel techniques such as genome editing and stable isotope labelling, to provide real progress towards an in depth understanding of early neurodegenerative processes and development of novel therapeutic agents.
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| 4. |
- Banerjee, Gargi, et al.
(författare)
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Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1189-1201
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Tidskriftsartikel (refereegranskat)abstract
- There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer's disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an "AD-like" profile.CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.
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| 6. |
- Bernardy, Jean-Philippe, 1978, et al.
(författare)
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Parametricity and Dependent Types
- 2010
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Ingår i: SIGPLAN Notices (ACM Special Interest Group on Programming Languages). - : Association for Computing Machinery (ACM). - 0730-8566 .- 0362-1340 .- 1558-1160. ; 45:9, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- Reynolds' abstraction theorem shows how a typing judgement in System F can be translated into a relational statement (in second order predicate logic) about inhabitants of the type. We (in second order predicate logic) about inhabitants of the type. We obtain a similar result for a single lambda calculus (a pure type system), in which terms, types and their relations are expressed. Working within a single system dispenses with the need for an interpretation layer, allowing for an unusually simple presentation. While the unification puts some constraints on the type system (which we spell out), the result applies to many interesting cases, including dependently-typed ones.
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| 7. |
- Bernardy, Jean-Philippe, 1978, et al.
(författare)
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Proofs for Free - Parametricity for dependent types
- 2012
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Ingår i: Journal of Functional Programming. - 1469-7653 .- 0956-7968. ; 22:2, s. 107-152
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Tidskriftsartikel (refereegranskat)abstract
- Reynolds' abstraction theorem shows how a typing judgement in System F can be translated into a relational statement (in second order predicate logic) about inhabitants of the type.We obtain a similar result for pure type systems: for any PTS used as a programming language, there is a PTS that can be used as a logic for parametricity. Types in the source PTS are translated to relations (expressed as types) in the target. Similarly, values of a given type are translated to proofs that the values satisfy the relational interpretation. We extend the result to inductive families.We also show that the assumption that every term satisfies the parametricity condition generated by its type is consistent with the generated logic. Our proof gives a computationally meaningful way to interpret that assumption.
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| 8. |
- Coenen, Mirthe, et al.
(författare)
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Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts
- 2023
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Ingår i: NeuroImage. Clinical. - 2213-1582. ; 40
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.
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| 9. |
- 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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