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. 2024 Jul 9;10(3):e12490.
doi: 10.1002/trc2.12490. eCollection 2024 Jul-Sep.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients

Dawn C Matthews  1 , Jefferson W Kinney  2 , Aaron Ritter  3 , Randolph D Andrews  1 , Erin N Toledano Strom  4 , Ana S Lukic  1 , Lauren N Koenig  1 , Carolyn Revta  5 , Howard M Fillit  6 , Kate Zhong  7 , Babak Tousi  8 , James B Leverenz  9 , Howard H Feldman  5   10 , Jeffrey Cummings  4
Affiliations

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients

Dawn C Matthews et al. Alzheimers Dement (N Y). .

Abstract

Introduction: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population.

Methods: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years).

Results: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group.

Discussion: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age.

Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Keywords: A/T/N; Alzheimer's disease; FDG PET; GFAP; Inflammation; NfL; Tau PET; flortaucipir; pTau‐181; plasma biomarkers; volumetric MRI.

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Conflict of interest statement

Dawn Matthews is CEO of ADM Diagnostics, Inc., Scientific Advisor to the Alzheimer's Drug Development Foundation, and Co‐Chair of the Radiological Society of North America PET Tau Profile Working Group and PET Amyloid Profile Working Group, and reports that ADM Diagnostics received grant funding (2R44AG060861‐02) from the National Institutes of Aging, University of Arizona subaward (R01 AG063826), and University of Arizona subaward (R01 AG075122‐01 during the conduct of this work. She reports support for attending meetings and/or travel hotel and registration fees from Alzheimer's Drug Discovery Foundation, and stock or stock options in ADM Diagnostics and Abiant. Jefferson Kinney reports a grant from the National Institutes of General Medical Sciences (NIGMS) COBRE grant #P20GM109025, along with grants NIH NIA R01 AG074392‐01, NIH NIA P20 AG068053‐01, and R01AG062762‐01A1. Aaron Ritter reports payment from Corium Pharmaceuticals and Lundbeck/Otsuka for speaker board and advertisement board. He also has a leadership role in Alzheimer's Association Orange County Board and Alzheimer's Family Center. Ana Lukic, Randolph Andrews, and Lauren Koenig are employees of ADM Diagnostics, Inc. Carolyn Revta has nothing to disclose. Babak Tousi received a grant from the Alzheimer's Drug Discovery Foundation during the study, and has received consulting fees from Eisai, Biogen, Lilly, GE Healthcare, Kisbee, and Otsuka. He received honoraria from Eisai and Lily, support for attending meetings or travel from Novo Nordisk, and participated in a Data Safety Monitoring Board or Advisory Board at Eisai and Lilly. James Leverenz reports the grant P30AG072959, a Scientific Advisory leadership role for the Lewy Body Dementia Association, and receipt of ligands and software for imaging from GE Healthcare. Howard Fillit founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation, which funded the rasagiline clinical trial, and has provided consulting support to the following pharmaceutical companies: Otsuka, LifeWorx, and Alector. He reports royalties from Icahn School of Medicine at Mount Sinai, and participation in a DSMB at Alector. He reports stock or stock options at CarePredict, and other non‐financial interests with the Lilly GERAS study and Roche Genentech Claims study. Howard Feldman reports a service agreement through UCSD with the Cleveland Clinic for data management and biostatistics during the conduct of the original study; grants from Annovis (QR Pharma), Vivoryon (Probiodrug), AC Immune, Biohaven Pharmaceuticals, and LuMind Foundation, and service agreements through UCSD for consulting with LuMind Foundation, Novo Nordisk, Arrowhead Pharmaceuticals, and Axon Neurosciences Roche/Genentech Pharmaceuticals. He reports support for attending meetings and/or travel for Novo Nordisk, and Royal Society of Canada; participation in DMC and DSMB for Tau Consortium, Rooche/Genentech Pharmaceuticals, and Janssen Research and Development; and philanthropic support for Alzheimer therapeutic research. Jeffrey Cummings reports grants from the National Institutes of General Medical Sciences (NIGMS) COBRE grant #P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P30AG072959; NIA grant R35AG71476; NIA R25 AG083721‐01; Alzheimer's Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; Joy Chambers‐Grundy Endowment during the conduct of the study. He reports consulting fees from Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol‐Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, ONO, Optoceutics, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He reports participation in Data Safety Monitoring Board or Advisory Board for Acadia, Biogen, Genentech, Grifols, Janssen, Karuna, Otsuka, reMYND, Roche, Signant Health and stock or stock options for Artery, Vaxxinity, Behrens, Alzheon, MedAvante‐Prophase, and Acumen. Finally, outside the submitted work he is Chief Scientific Advisor to CNS Innovations, LLC and owns the copyright for the Neuropsychiatric Inventory (NPI). Kate Zhong and Erin Toledano Strom have nothing to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Imaging and plasma biomarker distributions and relationships to MMSE and age. (A) Flortaucipir SUVR images for three subjects of varying age and tau spatial extent. (B‐D) Relationships between tau PET, volume, and FDG PET with MMSE score, stratified by age‐decade (57‐69, blue; 70‐79, red; 80‐90, green). (E) Relationships of pTau‐181, NfL, and GFAP to MMSE stratified by age‐decade (same color table). Overall correlations are apparent as well as an age effect within the biomarker‐clinical severity relationships despite adjustment for normal aging. The unfilled green circle is for one participant in the 80‐ to 90‐year group whose plasma values were outliers and are not included in the line of fit. “n.s.” = not significant (p‐values between 0.05 and 0.12 listed as a trend).
FIGURE 2
FIGURE 2
Relationships between tau PET and other imaging and plasma biomarkers. Relationship between tau PET in (A) total cortical, (B) inferior parietal, and (C) left inferior temporal regions as compared to pTau‐181log10, GFAPlog10, regional FDG SUVR, and regional volumes. Correlation coefficients are shown for the three age‐decade groups: (1) 57–69 years (blue), (2) 70–79 years (red), (3) 80–90 years (green). (D, E) The relationships between hemispheric asymmetry in the inferior iemporal region for tau PET as compared to volume and FDG PET, respectively.
FIGURE 3
FIGURE 3
Plasma biomarker relationships. Plasma biomarker relationships are shown by age group (A‐H) and in an overall comparison that includes imaging biomarkers shown for the 70‐ to 79‐year age group (I). (“_t” in variable names indicates log10 transformation).
See this image and copyright information in PMC

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