To test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury.
We recruited 47 patients with mild (n = 20), moderate (n = 9), ...or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort.
The patients with severe COVID-19 had higher plasma concentrations of GFAp (
= 0.001) and NfL (
< 0.001) than controls, while GFAp was also increased in patients with moderate disease (
= 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (
< 0.01), while NfL showed a sustained increase from first to last follow-up (
< 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury.
We show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19-related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients.
Purpose
In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer’s disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap ...Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)—with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology.
Methods
A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop.
Results
By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability.
Conclusions
Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.
Purpose
The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential ...diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers.
Methods
A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers.
Results
Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aβ remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aβ, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria.
Conclusions
Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 – with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.
Exclusive enteral nutrition (EEN) is the first line therapy for paediatric Crohn's disease, providing a complete nutritional feed whilst simultaneously inducing remission in up to 80% of cases. The ...effect of EEN on systemic/local intestinal immune function and subsequent inflammation (including barrier permeability, direct anti-inflammatory effects and cytokine signalling pathways), alongside changes in the microbiome (specific species and broad taxonomic shifts, functional changes) are becoming clearer, however the exact mechanism for induction of remission in Crohn's disease remains uncertain. The evidence of efficacy in paediatric Crohn's disease is strong, with selected adult populations also benefiting from EEN. However despite recommendations from all major societies (ECCO, ESPGHAN, NASPGHAN and ESPEN) first-line use of EEN is varied and Europe/Australasia/Canada show significantly more routine use than other parts of North America. Growth and nutritional status are significantly improved with EEN compared to corticosteroids but long-term outcomes are sparse. This review discusses the evidence underlying the use of EEN, highlighting the mechanisms thought to underlie how EEN induces remission in Crohn's disease, when and how to use EEN, including practical issues in both paediatric and adult practice (formulation, compliance, volumes and administration), and summarises the ongoing research priorities.
Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification ...of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.
Paediatric inflammatory bowel disease (PIBD), comprising Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU) is a complex and multifactorial condition ...with increasing incidence. An accurate diagnosis of PIBD is necessary for a prompt and effective treatment. This study utilises machine learning (ML) to classify disease using endoscopic and histological data for 287 children diagnosed with PIBD. Data were used to develop, train, test and validate a ML model to classify disease subtype. Unsupervised models revealed overlap of CD/UC with broad clustering but no clear subtype delineation, whereas hierarchical clustering identified four novel subgroups characterised by differing colonic involvement. Three supervised ML models were developed utilising endoscopic data only, histological only and combined endoscopic/histological data yielding classification accuracy of 71.0%, 76.9% and 82.7% respectively. The optimal combined model was tested on a statistically independent cohort of 48 PIBD patients from the same clinic, accurately classifying 83.3% of patients. This study employs mathematical modelling of endoscopic and histological data to aid diagnostic accuracy. While unsupervised modelling categorises patients into four subgroups, supervised approaches confirm the need of both endoscopic and histological evidence for an accurate diagnosis. Overall, this paper provides a blueprint for ML use with clinical data.
Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal ...studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.
The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at ...threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (
n
= 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by
18
FMK-6240 positron emission tomography (PET), and brain amyloidosis by
18
FAZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous
18
FAZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.
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