Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations

Cullen, Nicholas; Leuzy, Antoine; Palmqvist, Sebastian; Bateman, Randall J.; Stomrud, Erik; Pesini, Pedro; Sarasa, Leticia; Allué, José Antonio; Proctor, Nicholas K.; Zetterberg, Henrik; Dage, Jeffrey L.; Blennow, Kaj; Mattsson‐Carlgren, Niklas; Hansson, Oskar

doi:10.1038/s43587-020-00003-5

Cited by 115 publications

(130 citation statements)

References 32 publications

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“…Our findings have strong implications for the use of inflammatory proteins as biomarkers to identify or track the progression of AD, particularly as plasma assays for the core AD biomarkers appear to have strong performance in both prognostic and clinical trial scenarios 29,30 . In terms of drug discovery, our results point out a group of inflammatory pathways whose further study could illuminate the role of inflammation in AD pathogenesis.…”

Section: Discussionmentioning

confidence: 91%

Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition

Cullen

Mälarstig

Stomrud

et al. 2021

Sci Rep

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It is unclear how pathological aging of the inflammatory system relates to Alzheimer’s disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ− CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer’s disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone (“inflammatory age”) differed significantly from true chronological age. Aβ− individuals with subjective cognitive decline (Aβ− SCD; n = 125) or MCI (Aβ− MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ− CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ− SCD and validation Aβ− CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ− MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ− CU and Aβ− SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.

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Section: Discussionmentioning

confidence: 91%

Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition

Cullen

Mälarstig

Stomrud

et al. 2021

Sci Rep

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“…Our work in MCI patients showed a greater effect of plasma Aβ42/Aβ40 by using a mass-spectrometry method, indicating that a more effective plasma assay could lead to greater value. 39 However, such data was not widely available in this cohort. Further work is needed to compare performance of CSF and plasma biomarkers in CU individuals using different assays, as recent studies suggest that the difference between CSF and plasma biomarkers is less pronounced in MCI individuals.…”

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

“…Further work is needed to compare performance of CSF and plasma biomarkers in CU individuals using different assays, as recent studies suggest that the difference between CSF and plasma biomarkers is less pronounced in MCI individuals. 39 The strengths of this study include the standardized collection and measurement of relevant biomarkers in both plasma and CSF-which allowed for direct comparison between biomarkers and across the two modalities-and the availability of multi-year follow-up data in a large number of participants. Our study improves in particular on previous studies linking novel plasma tau levels on their own with cognitive decline and neurodegeneration in similar populations 43,44 .…”

Section: Discussionmentioning

confidence: 99%

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Plasma biomarkers of Alzheimer’s disease predict cognitive decline and could improve clinical trials in the cognitively unimpaired elderly

Leuzy

Bateman

et al. 2021

Preprint

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Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly indviduals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ±1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in the cognition (Pre-Alzheimer’s Clinical Composite; R2=0.14, 95% CI [0.12-0.17]; P<0.0001) and subsequent AD dementia (AUC=0.82, 95% CI [0.77-0.91], P<0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54-81]; P<0.001) with cognition as trial endpoint, and by 63% (95% CI [53-70], P<0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.

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“…Second, the more widespread availability and site-to-site standardization of high-quality automated assays (e.g., Roche Elecsys [208]) has put the measurement of some widely-used fluid biomarkers on a firmer footing. Third, it is now possible to measure from blood plasma a number of analytes previously requiring a CSF draw; these include Aβ and tau species, along with NfL [209][210][211][212][213][214][215].…”

Section: Imaging In the Context Of Fluid Biomarkersmentioning

confidence: 99%

The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders

Schwarz

2021

Neurotherapeutics

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Imaging biomarkers play a wide-ranging role in clinical trials for neurological disorders. This includes selecting the appropriate trial participants, establishing target engagement and mechanism-related pharmacodynamic effect, monitoring safety, and providing evidence of disease modification. In the early stages of clinical drug development, evidence of target engagement and/or downstream pharmacodynamic effect—especially with a clear relationship to dose—can provide confidence that the therapeutic candidate should be advanced to larger and more expensive trials, and can inform the selection of the dose(s) to be further tested, i.e., to “de-risk” the drug development program. In these later-phase trials, evidence that the therapeutic candidate is altering disease-related biomarkers can provide important evidence that the clinical benefit of the compound (if observed) is grounded in meaningful biological changes. The interpretation of disease-related imaging markers, and comparability across different trials and imaging tools, is greatly improved when standardized outcome measures are defined. This standardization should not impinge on scientific advances in the imaging tools per se but provides a common language in which the results generated by these tools are expressed. PET markers of pathological protein aggregates and structural imaging of brain atrophy are common disease-related elements across many neurological disorders. However, PET tracers for pathologies beyond amyloid β and tau are needed, and the interpretability of structural imaging can be enhanced by some simple considerations to guard against the possible confound of pseudo-atrophy. Learnings from much-studied conditions such as Alzheimer’s disease and multiple sclerosis will be beneficial as the field embraces rarer diseases.

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Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations

Cited by 115 publications

References 32 publications

Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition

Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition

Plasma biomarkers of Alzheimer’s disease predict cognitive decline and could improve clinical trials in the cognitively unimpaired elderly

The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders

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