•Ultrasensitive measurement techniques have made blood biomarkers for neurodegeneration a reality.•The most robust blood biomarker for neurodegeneration is plasma/serum NfL.•Results look promising ...for plasma Aβ42/40 ratio as a blood biomarker for cerebral Aβ pathology.•Plasma tau biomarkers require additional work.
Cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) are in clinical use in many parts of the world and show good to excellent diagnostic accuracy in regards to identifying cerebral amyloid β (Aβ) and tau pathology irrespective of the clinical stage of the disease. However, CSF sampling is more difficult than a blood draw and a procedure only rarely performed by general practitioners. Since AD is such a common disease and since intense research on novel treatments that hopefully will be directed against underlying pathologies is moving forward, it would be excellent if the CSF tests for AD could be transformed into blood tests, as well as if novel blood biomarkers could be discovered. Brain-derived molecules are, however, present at much lower concentrations in blood than in CSF, which poses an analytical challenge. There are also additional issues with blood as a biofluid in which to measure biomarkers for central nervous system disease. Nevertheless, the past few years have seen an enormous development in the field of ultrasensitive measurement techniques. There is also much better availability of deeply phenotyped clinical cohorts for biomarker discovery and validation. This review gives an updated account of the current state of research on blood biomarkers for AD and related neurodegenerative dementias with special emphasis on findings that have been replicated by more than one research group.
In the current issue of Neuron, Bacioglu, Maia, and colleagues show that neurofilament light concentrations in body fluids reflect pathology and symptoms in mouse models of cerebral proteopathies and ...that these findings translate to human disease (Bacioglu et al., 2016).
In the current issue of Neuron, Bacioglu, Maia, and colleagues show that neurofilament light concentrations in body fluids reflect pathology and symptoms in mouse models of cerebral proteopathies and that these findings translate to human disease.
Clinical trial results presented in 2019 suggest that antibody-based removal of cerebral amyloid β (Aβ) plaques may possibly clear tau tangles and modestly slow cognitive decline in symptomatic ...Alzheimer's disease (AD). Although regulatory approval of this approach is still pending, preparing the healthcare system for the advent of disease-modifying therapies against AD is imperative. In particular, it will be necessary to identify the most suitable biomarkers to facilitate appropriate treatment of AD. Here, we give an update on recent developments in fluid and imaging biomarkers for AD-related pathologies and discuss potential approaches that could be adopted to screen for and clarify the underlying pathology in people seeking medical advice because of cognitive symptoms. We succinctly review recent data regarding biomarkers for Aβ and tau pathology, neurodegeneration, synaptic dysfunction, and inflammation, highlight the need for further research into common copathologies, and suggest how different biomarkers could be used (most likely in combination) to facilitate the development and clinical implementation of novel drug candidates against AD.
Four fluid-based biomarkers have been developed into diagnostic tests for Alzheimer's disease (AD) pathology: the ratio of 42 to 40 amino acid-long amyloid β, a marker of plaque pathology; total-tau ...and phosphorylated tau, markers of AD-related changes in tau metabolism and secretion; and neurofilament light, a marker of neurodegeneration. When measured in cerebrospinal fluid, these biomarkers can be used in clinical practice to support a diagnosis of mild cognitive impairment or dementia due to AD. Recently, technological breakthroughs have made it possible to measure them in standard blood samples as well. Here, we give an updated account of the current state of the fluid-based AD biomarker research field. We discuss how the new blood tests may be used in research and clinical practice, and what role they may play in relation to more established diagnostic tests, such as CSF biomarkers and amyloid and tau positron emission tomography, to facilitate the effective implementation of future disease-modifying therapies.
To evaluate whether the axonal protein neurofilament light (NFL) in serum is a sensitive biomarker to detect subtle brain injury or concussion in contact sports athletes.
Two prospective cohort ...studies involving (1) 14 Swedish amateur boxers who underwent fluid biomarker assessments at 7-10 days after bout and after 3 months of rest from boxing and (2) 35 Swedish professional hockey players who underwent blood biomarker assessment at 1, 12, 36, and 144 hours after concussion and when the players returned to play were performed. Fourteen healthy nonathletic controls and 12 athletic controls were also enrolled. Serum NFL was measured using ultrasensitive single molecule array technology.
Serum NFL concentrations were increased in boxers 7-10 days after bout as compared to the levels after 3 months rest as well as compared with controls (
= 0.0007 and
< 0.0001, respectively). NFL decreased following 3 months of rest, but was still higher than in controls (
< 0.0001). Boxers who received many (>15) hits to the head or were groggy after bout had higher concentrations of serum NFL as compared to those who received fewer hits to the head (
= 0.0023). Serum NFL increased over time in hockey players, and the levels returned to normal at return to play. Importantly, serum NFL could separate players with rapidly resolving postconcussion symptoms (PCS) from those with prolonged PCS.
The results from these 2 independent cohort studies suggest that serum NFL is a highly sensitive biomarker for concussion.
Background
Neurofilament proteins have been extensively studied in relapsing–remitting multiple sclerosis, where they are promising biomarkers of disease activity and treatment response. Their role ...in progressive multiple sclerosis, where there is a particularly urgent need for improved biomarkers, is less clear. The objectives of this systematic review are to summarise the literature on neurofilament light and heavy in progressive multiple sclerosis, addressing key questions.
Methods
A systematic search of PubMed, Embase, Web of Science and Scopus identified 355 potential sources. 76 relevant sources were qualitatively reviewed using QUADAS-2 criteria, and 17 were identified as at low risk of bias. We summarise the findings from all relevant sources, and separately from the 17 high-quality studies.
Results
Differences in neurofilament light between relapsing–remitting and progressive multiple sclerosis appear to be explained by differences in covariates. Neurofilament light is consistently associated with current inflammatory activity and future brain atrophy in progressive multiple sclerosis, and is consistently shown to be a marker of treatment response with immunosuppressive disease-modifying therapies. Associations with current or future disability are inconsistent, and there is no evidence of NFL being a responsive marker of purportedly neuroprotective treatments. Evidence on neurofilament heavy is more limited and inconsistent.
Conclusions
Neurofilament light has shown consistent utility as a biomarker of neuroinflammation, future brain atrophy and immunosuppressive treatment response at a
group
level. Neither neurofilament light or heavy has shown a consistent treatment response to neuroprotective disease-modifying therapies, which will require further data from successful randomised controlled trials.
The acute and long-term consequences of traumatic brain injury (TBI) have received increased attention in recent years. In this Review, we discuss the neuropathology and neural mechanisms associated ...with TBI, drawing on findings from sports-induced TBI in athletes, in whom acute TBI damages axons and elicits both regenerative and degenerative tissue responses in the brain and in whom repeated concussions may initiate a long-term neurodegenerative process called dementia pugilistica or chronic traumatic encephalopathy (CTE). We also consider how the neuropathology and neurobiology of CTE in many ways resembles other neurodegenerative illnesses such as Alzheimer’s disease, particularly with respect to mismetabolism and aggregation of tau, β-amyloid, and TDP-43. Finally, we explore how translational research in animal models of acceleration/deceleration types of injury relevant for concussion together with clinical studies employing imaging and biochemical markers may further elucidate the neurobiology of TBI and CTE.
The acute and long-term consequences of traumatic brain injury (TBI) have received increased attention in recent years. In this Review, Blennow et al. discuss the neuropathology and neural mechanisms associated with TBI and consider how these mechanisms resemble other neurodegenerative illnesses.
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.
A major barrier to the effective conduct of clinical trials of new drug candidates against Alzheimer's disease (AD) and to identifying patients for receiving future disease-modifying treatments is ...the limited capacity of the current health system to find and diagnose patients with early AD pathology. This may be related in part to the limited capacity of the current health systems to select those people likely to have AD pathology in order to confirm the diagnosis with available cerebrospinal fluid and imaging biomarkers at memory clinics. In the current narrative review, we summarize the literature on candidate blood tests for AD that could be implemented in primary care settings and used for the effective identification of individuals at increased risk of AD pathology, who could be referred for potential inclusion in clinical trials or future approved treatments following additional testing. We give an updated account of blood-based candidate biomarkers and biomarker panels for AD-related brain changes. Our analysis centres on biomarker candidates that have been replicated in more than one study and discusses the need of further studies to achieve the goal of a primary care-based screening algorithm for AD.
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