Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes

Marks, Jordan D.; Syrjanen, Jeremy; Graff‐Radford, Jonathan; Petersen, Ronald C.; Machulda, Mary M.; Campbell, Michelle R.; Algeciras‐Schimnich, Alicia; Lowe, Val J.; Knopman, David S.; Jack, Clifford R.; Vemuri, Prashanthi; Mielke, Michelle M.

doi:10.1186/s13195-021-00944-y

Cited by 55 publications

(88 citation statements)

References 44 publications

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“…Other groups are developing similar diagnostic testing, the Quanterix SIMOA system which, by reaction with monoclonal antibodies, determines phosphorylated Tau with a 90% sensitivity in AD [19]. A later study noted that neurofilament light chain may even be a better predictor of AD amyloid formation [20]. Even now, accuracies as high as 90% to 95% are being claimed.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer’s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid β assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)–a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-naïve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0–35), 5 had intermediate risk (APS 36–57) and 10 had high risk (APS 58–100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate AD biomarker—may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.

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Section: Discussionmentioning

confidence: 99%

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

et al. 2022

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“…More recently, however, there has been a shift in conceptualizing Alzheimer’s disease within an ATN [amyloid (A), tau (T) and neurodegeneration (N)] framework, which defines disease based on A and T, and characterizes progression based on N. 12 , 13 This advance was facilitated by development of biomarkers reflecting the underlying biology of Alzheimer’s disease, initially CSF measures of A and T, but more recently PET ligands that permit in vivo imaging of both A and T. N is determined via MRI measures of brain atrophy or hypometabolism on fluorodeoxyglucose PET, and potentially by elevation of CSF or blood neurofilament light chain (NfL). 14 Indeed, plasma NfL is elevated 6.8 estimated years before symptom onset (EYO) of familial Alzheimer’s disease, and trajectories of NfL among mutation carriers diverge from non-mutation carriers ∼16 years before EYO. 15 Layered on top of this underlying biological classification is staging by clinical features that, while correlated with ATN state, is independent of the biological framework.…”

Section: Pre-symptomatic Neurodegenerative Diseasesmentioning

confidence: 99%

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases

Benatar

Wuu

McHutchison

et al. 2021

Brain

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Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), spinal muscular atrophy, and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in ALS. The development of biomarkers reflecting amyloid and tau has led to a shift in defining AD based on inferred underlying histopathology. PD is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM-sleep behavior disorder. HD benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. SMA clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in FTD illustrate the differential role of biomarkers based on genotype. Similar advances in ALS would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic ALS relies upon a clear conceptual framework for defining the earliest stages of disease. Clinically manifest ALS may emerge abruptly, especially among those who harbor genetic mutations associated with rapidly progressive ALS. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioral impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioral impairment before progression to ALS. Biomarkers are critically important to studying pre-symptomatic ALS and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counseling, informed consent, communication of results, and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counseling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building upon what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from ALS gene mutation carriers—we present a roadmap to early intervention, and perhaps even disease prevention, for all forms of ALS.

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“…Peripheral measures of tau biology in AD include p-tau 181, p-tau 217, and p-tau 231 [ 37 ]. Total tau is measurable in plasma, and CSF and may reflect cell death and neurodegeneration [ 38 ]. Visinin-like protein-1 (VILIP-1) is an additional cell death reporter detectable in CSF [ 39 ].…”

Section: Biomarker Definition and Classificationmentioning

confidence: 99%

Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

Cummings

Kinney

2022

Medicina

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Background and Objectives: The US Food and Drug Administration (FDA) defines a biomarker as a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention. Biomarkers may be used in clinical care or as drug development tools (DDTs) in clinical trials. The goal of this review and perspective is to provide insight into the regulatory guidance for the use of biomarkers in clinical trials and clinical care. Materials and Methods: We reviewed FDA guidances relevant to biomarker use in clinical trials and their transition to use in clinical care. We identified instructive examples of these biomarkers in Alzheimer’s disease (AD) drug development and their application in clinical practice. Results: For use in clinical trials, biomarkers must have a defined context of use (COU) as a risk/susceptibility, diagnostic, monitoring, predictive, prognostic, pharmacodynamic, or safety biomarker. A four-stage process defines the pathway to establish the regulatory acceptance of the COU for a biomarker including submission of a letter of intent, description of the qualification plan, submission of a full qualification package, and acceptance through a qualification recommendation. Biomarkers used in clinical care may be companion biomarkers, in vitro diagnostic devices (IVDs), or laboratory developed tests (LDTs). A five-phase biomarker development process has been proposed to structure the biomarker development process. Conclusions: Biomarkers are increasingly important in drug development and clinical care. Adherence to regulatory guidance for biomarkers used in clinical trials and patient care is required to advance these important drug development and clinical tools.

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Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes

Cited by 55 publications

References 44 publications

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer’s Disease

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases

Biomarkers for Alzheimer’s Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation

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