Skip to main content
AAN.com

Abstract

Background and Objectives

Alzheimer disease (AD) is primarily associated with accumulations of amyloid plaques and tau tangles in gray matter, however, it is now acknowledged that neuroinflammation, particularly in white matter (WM), significantly contributes to the development and progression of AD. This study aims to investigate WM neuroinflammation in the continuum of AD and its association with AD pathologies and cognition using diffusion-based neuroinflammation imaging (NII).

Methods

This is a cross-sectional, single-center, retrospective evaluation conducted on an observational study of 310 older research participants who were enrolled in the Knight Alzheimer's Disease Research Center cohort. Hindered water ratio (HR), an index of WM neuroinflammation, was quantified by a noninvasive diffusion MRI method, NII. The alterations of NII-HR were investigated at different AD stages, classified based on CSF concentrations of β-amyloid (Aβ) 42/Aβ40 for amyloid and phosphorylated tau181 (p-tau181) for tau. On the voxel and regional levels, the relationship between NII-HR and CSF markers of amyloid, tau, and neuroinflammation were examined, as well as cognition.

Results

This cross-sectional study included 310 participants (mean age 67.1 [±9.1] years), with 52 percent being female. Subgroups included 120 individuals (38.7%) with CSF measures of soluble triggering receptor expressed on myeloid cells 2, 80 participants (25.8%) with CSF measures of chitinase-3–like protein 1, and 110 individuals (35.5%) with longitudinal cognitive measures. The study found that cognitively normal individuals with positive CSF Aβ42/Aβ40 and p-tau181 had higher HR than healthy controls and those with positive CSF Aβ42/Aβ40 but negative p-tau181. WM tracts with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 were primarily located in the posterior brain regions while those with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 connected the posterior and anterior brain regions. A significant negative correlation between NII-HR and CSF Aβ42/Aβ40 was found in individuals with positive CSF Aβ42/Aβ40. Baseline NII-HR correlated with baseline cognitive composite score and predicted longitudinal cognitive decline.

Discussion

Those findings suggest that WM neuroinflammation undergoes alterations before the onset of AD clinical symptoms and that it interacts with amyloidosis. This highlights the potential value of noninvasive monitoring of WM neuroinflammation in AD progression and treatment.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

File (supplementary_figure1.pdf)
File (supplementary_table1.pdf)

References

1.
Bronzuoli MR, Iacomino A, Steardo L, Scuderi C. Targeting neuroinflammation in Alzheimer's disease. J Inflamm Res. 2016;9:199-208.
2.
Hamelin L, Lagarde J, Dorothee G, et al. Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain. 2016;139(pt 4):1252-1264.
3.
Suridjan I, Pollock BG, Verhoeff NP, et al. In-vivo imaging of grey and white matter neuroinflammation in Alzheimer's disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA. Mol Psychiatry. 2015;20(12):1579-1587.
4.
Raj D, Yin Z, Breur M, et al. Increased white matter inflammation in aging- and Alzheimer's disease brain. Front Mol Neurosci. 2017;10:206.
5.
Ihara M, Polvikoski TM, Hall R, et al. Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies. Acta Neuropathol. 2010;119(5):579-589.
6.
Sjobeck M, Englund E. Glial levels determine severity of white matter disease in Alzheimer's disease: a neuropathological study of glial changes. Neuropathol Appl Neurobiol. 2003;29(2):159-169.
7.
Zhang H, Schneider T, Wheeler-Kingshott CA, Alexander DC. NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage. 2012;61(4):1000-1016.
8.
Pasternak O, Sochen N, Gur Y, Intrator N, Assaf Y. Free water elimination and mapping from diffusion MRI. Magn Reson Med. 2009;62(3):717-730.
9.
Wang Y, Sun P, Wang Q, et al. Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis. Brain. 2015;138(pt 5):1223-1238.
10.
Wang Y, Wang Q, Haldar JP, et al. Quantification of increased cellularity during inflammatory demyelination. Brain. 2011;134(pt 12):3590-3601.
11.
Yi SY, Barnett BR, Torres-Velazquez M, et al. Detecting microglial density with quantitative multi-compartment diffusion MRI. Front Neurosci. 2019;13:81.
12.
Pasternak O, Kubicki M, Shenton ME. In vivo imaging of neuroinflammation in schizophrenia. Schizophr Res. 2016;173(3):200-212.
13.
Dumont M, Roy M, Jodoin PM, et al. Free water in white matter differentiates MCI and AD from control subjects. Front Aging Neurosci. 2019;11:270.
14.
Chiang CW, Wang Y, Sun P, et al. Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. Neuroimage. 2014;101:310-319.
15.
Wang Q, Wang Y, Liu J, et al. Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer's disease. Neuroimage Clin. 2019;22:101767.
16.
Cross AH, Song SK. A new imaging modality to non-invasively assess multiple sclerosis pathology. J Neuroimmunol. 2017;304:81-85.
17.
Zhan J, Lin TH, Libbey JE, et al. Diffusion basis spectrum and diffusion tensor imaging detect hippocampal inflammation and dendritic injury in a virus-induced mouse model of epilepsy. Front Neurosci. 2018;12:77.
18.
Samara A, Murphy T, Strain J, et al. Neuroinflammation and white matter alterations in obesity assessed by diffusion basis spectrum imaging. Front Hum Neurosci. 2019;13:464.
19.
Ly M, Raji CA, Yu GZ, et al. Obesity and white matter neuroinflammation related edema in Alzheimer's disease dementia biomarker negative cognitively normal individuals. J Alzheimers Dis. 2021;79(4):1801-1811.
20.
Zhou R, Ji B, Kong Y, et al. PET imaging of neuroinflammation in Alzheimer's disease. Front Immunol. 2021;12:739130.
21.
Vipin A, Ng KK, Ji F, et al. Amyloid burden accelerates white matter degradation in cognitively normal elderly individuals. Hum Brain Mapp. 2019;40(7):2065-2075.
22.
Berg L, McKeel DW Jr, Miller JP, et al. Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol. 1998;55(3):326-335.
23.
Morris JC, Weintraub S, Chui HC, et al. The Uniform Data Set (UDS): clinical and cognitive variables and descriptive data from Alzheimer Disease Centers. Alzheimer Dis Assoc Disord. 2006;20(4):210-216.
24.
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):270-279.
25.
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.
26.
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412-2414.
27.
von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453-1457.
28.
Talbot C, Lendon C, Craddock N, Shears S, Morris JC, Goate A. Protection against Alzheimer's disease with apoE epsilon 2. Lancet. 1994;343(8910):1432-1433.
29.
Wang Q, Chen GS, Schindler SE, et al. Baseline microglial activation correlates with brain amyloidosis and longitudinal cognitive decline in Alzheimer disease. Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1152.
30.
Donohue MC, Sperling RA, Salmon DP, et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 2014;71(8):961-970.
31.
Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid A beta(42) in humans. Ann Neurol. 2006;59(3):512-519.
32.
Deming Y, Filipello F, Cignarella F, et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk. Sci Transl Med. 2019;11(505):eaau2291.
33.
Winkler AM, Ridgway GR, Webster MA, Smith SM, Nichols TE. Permutation inference for the general linear model. Neuroimage. 2014;92(100):381-397.
34.
Volluz KE, Schindler SE, Henson RL, et al. Correspondence of CSF biomarkers measured by Lumipulse assays with amyloid PET. Alzheimers Dement. 2021 17(S5):e051085.
35.
Longford NT. Random coefficient models. In: Arminger G, Clogg CC, Sobel ME, eds. Handbook of Statistical Modeling for the Social and Behavioral Sciences. Springer; 1995.
36.
Brier MR, Gordon B, Friedrichsen K, et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease. Sci Transl Med. 2016;8(338):338ra366.
37.
Suarez-Calvet M, Kleinberger G, Araque Caballero MA, et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. EMBO Mol Med. 2016;8(5):466-476.
38.
Takata F, Nakagawa S, Matsumoto J, Dohgu S. Blood-brain barrier dysfunction amplifies the development of neuroinflammation: understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction. Front Cell Neurosci. 2021;15:661838.
39.
Stokum JA, Kurland DB, Gerzanich V, Simard JM. Mechanisms of astrocyte-mediated cerebral edema. Neurochem Res. 2015;40(2):317-328.
40.
Silva I, Silva J, Ferreira R, Trigo D. Glymphatic system, AQP4, and their implications in Alzheimer's disease. Neurol Res Pract. 2021;3(1):5.
41.
Kester MI, Teunissen CE, Sutphen C, et al. Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer's disease in a memory clinic cohort. Alzheimers Res Ther. 2015;7(1):59.
42.
Schindler SE, Li Y, Todd KW, et al. Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease. Alzheimers Dement. 2019;15(5):655-665.
43.
Suarez-Calvet M, Araque Caballero MA, Kleinberger G, et al. Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci Transl Med. 2016;8(369):369ra178.
44.
Suarez-Calvet M, Morenas-Rodriguez E, Kleinberger G, et al. Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology. Mol Neurodegener. 2019;14:1.
45.
Brickman AM, Meier IB, Korgaonkar MS, et al. Testing the white matter retrogenesis hypothesis of cognitive aging. Neurobiol Aging. 2012;33(8):1699-1715.
46.
Zhu QY, Bi SW, Yao XT, et al. Disruption of thalamic connectivity in Alzheimer's disease: a diffusion tensor imaging study. Metab Brain Dis. 2015;30(5):1295-1308.
47.
Maller JJ, Welton T, Middione M, Callaghan FM, Rosenfeld JV, Grieve SM. Revealing the hippocampal connectome through super-resolution 1150-direction diffusion MRI. Sci Rep. 2019;9(1):2418.
48.
Englund E. Neuropathology of white matter changes in Alzheimer's disease and vascular dementia. Dement Geriatr Cogn Disord. 1998;9(suppl 1):6-12.
49.
Fan Z, Brooks DJ, Okello A, Edison P. An early and late peak in microglial activation in Alzheimer's disease trajectory. Brain. 2017;140(3):792-803.
50.
Pichet Binette A, Theaud G, Rheault F, et al. Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer's disease. Elife. 2021;10:e62929.

Information & Authors

Information

Published In

Neurology®
Volume 102Number 4February 27, 2024
PubMed: 38315956

Publication History

Received: June 1, 2023
Accepted: October 13, 2023
Published online: February 5, 2024
Published in print: February 27, 2024

Permissions

Request permissions for this article.

Disclosure

Q. Wang is the inventor on the patent application PCT/US2017/030161. S.E. Washington, University of Indiana, and St. Luke's Hospital; is a board member of Greater Missouri Alzheimer's Association; and received data on behalf of Washington University from C2N Diagnostics at no cost. G. Chen, N.S. McKay, A. McCullough, S. Flores, J. Liu, Z. Sun, S. Wang, and W. Wang report no disclosures relevant to the manuscript. J. Hassenstab is a paid consultant for Lundbeck, Biogen, Roche, and Takeda. C. Cruchaga has received research support from: GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C. Cruchaga is a member of the advisory board of Vivid Genomics and Circular Genomics and owns Stocks. R. Perrin reports no disclosures relevant to the manuscript. A.M. Fagan received consulting fees from DiamiR and Siemens Healthcare Diagnostics Inc. and participated on an advisory board at Roche Diagnostics, Genentech, and Diadem. J.C. Morris received consulting fees from Barcelona Brain Research Center and TS Srinivasan Advisory Board; received payment or honoraria from Montefiore Grand Rounds and Tetra-Inst ADRC seminar series; and participated on an advisory board at Cure Alzheimer's Fund. Y. Wang is the inventor on the patent application PCT/US2017/030161. T.L.S. Benzinger is the inventor on the patent application PCT/US2017/030161 and has investigator-initiated research funding from NIH, Alzheimer's Association, Barnes-Jewish Hospital foundation, and Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Biogen, Eisai, Janssen, and Roche; serves as an unpaid consultant to Eisai and Siemens; and is on the Speaker's Bureau for Biogen. Go to Neurology.org/N for full disclosures.

Study Funding

This study was supported, in part, by grants from the NIH including the National Institutes on Aging (NIA) P01AG027276 (Antecedent Biomarkers of AD: The Adult Children Study, PI: J.C. Morris); NIA P01AG003991 (Healthy Aging and Senile Dementia, PI: J.C. Morris); NIA P30AG066444 (Alzheimer Disease Research Center, PI: J.C. Morris); and NIA R01AG054567-01A1(PIs: T.L.S. Benzinger and Y. Wang). Q. Wang is supported by NIA R03AG072375-01 (PI: Q. Wang) and NIA R01AG074909 (PI: Q. Wang). S.E. Schindler is supported by NIA R01AG070941 (PI: S.E. Schindler). Additional support was generously provided by the Charles and Joanne Knight Alzheimer's Research Initiative and by the Fred Simmons and Olga Mohan Fund and the Paula and Rodger Riney Fund.

Authors

Affiliations & Disclosures

From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
2.
NONE
Research Support:
1.
Governmental - NIH/NIA (P01AG027276): Antecedent Biomarkers of AD: The Adult Children Study, PI J. C. Morris
2.
Governmental - NIH/NIA (P01AG003991 ): Healthy Aging and Senile Dementia, PI J. C. Morris
3.
Governmental - NIH/NIA (P30AG066444 ): Alzheimer Disease Research Center, PI J. C. Morris
4.
Governmental - NIH/NIA (R01AG054567-01A1): Quantification of Neuroinflammation in Alzheimer's Disease Using Diffusion Basis Spectrum Imaging, PIs T.L.S. Benzinger and Y. Wang
5.
Governmental - NIH/NIA (R01AG074909): Quantitative Endogenous MRI Imaging of Neuroinflammation in Alzheimer Disease, PI Q. Wang
6.
Governmental - NIH/NIA (R03AG072375-01 ): Characterization of the Neuroinflammation in Autosomal Dominant Alzheimer Disease Using Neuro-Inflammation Imaging, PI, Q. Wang
7.
Governmental - NIH/NIA (R01AG070941): Staging Alzheimer disease with blood-based biomarkers, PI S. E. Schindler
8.
society - the Charles and Joanne Knight Alzheimer's Research Initiative (N/A): the Charles and Joanne Knight Alzheimer's Research Initiative
9.
society - the Fred Simmons and Olga Mohan Fund and the Paula and Rodger Riney Fund (N/A): the Fred Simmons and Olga Mohan Fund and the Paula and Rodger Riney Fund
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Suzanne E. Schindler, MD, PhD https://orcid.org/0000-0002-1680-1465
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
Served on a scientific advisory board - Eisai
Research Support:
1.
Governmental - National Institute on Aging (R01AG070941): Novel CSF and plasma biomarker assays
2.
Governmental - National Institute on Aging (K23AG053426): Novel CSF and plasma biomarker assays
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
Foundation - Alzheimer's Association (AARF-21-722077): Postdoctoral support for research aims.
2.
Foundation - BrightFocus (A2022013F): Postdoctoral support for research aims.
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Austin McCullough, PhD
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
Governmental - NIH (5T32AG078117): T32 Translational Imaging Research Program in Radiopharmaceutical Sciences
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
Served as a consultant - Roche
2.
Served as a consultant - Parabon Nanolabs
3.
Served as a consultant - Prothena
4.
Served as a consultant - AlzPath
Research Support:
1.
Governmental - National Institutes of Health (R01AG081394): DS-ARC: A remote digital cognitive assessment for Down Syndrome-Associated Alzheimer's Disease
2.
Governmental - National Institutes of Health (R01AG057840): Optimizing Cognitive Assessment in DIAN with Smartphone-based Burst Testing
3.
Governmental - National Institutes of Health (U19AG032438): DIAN is an international study of autosomal dominantly inherited Alzheimer's disease. The aims of the study are to create a registry of pedigrees with known AD causing mutations and to measure clinical and psychometric performance with imaging, CSF, and blood biomarkers
4.
Governmental - National Institutes of Health (R01AG068319): The DIAN-TU Next Generation Tau Prevention Trial
5.
Governmental - National Institutes of Health (U01AG059798): DIAN-TU: Primary Prevention Trial
6.
Governmental - National Institutes of Health (P50AG005681): Alzheimer's Disease Research Center (ADRC) Major Goals: The goal of this project is the interdisciplinary neurobiological research and clinical analysis of Alzheimer's disease and other dementias.
7.
Governmental - National Institutes of Health (P01AG003991): Healthy Aging and Senile Dementia (HASD) Major Goals: The overall goal of this project is the investigation of the natural history of senile dementia of the Alzheimer type (SDAT) including neurologic, psychiatric, psychometric and imaging data. Project 4 will use a smartphone application to test cognition rapidly and repeatedly in an effort to characterize preclinical AD and the transition to symptomatic AD.
8.
Governmental - National Institutes of Health (R61AG083581): Digital Assessment of Long Term Forgetting in Autosomal-Dominant Alzheimer's Disease
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Richard J. Perrin, MD, PhD https://orcid.org/0000-0002-3443-7716
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
Governmental entities - NIH (R01AG053267): The DIAN-TU Next Generation Prevention Trial
2.
Governmental entities - NIH (R01AG054567): Quantification of Neuroinflammation in Alzheimer's Disease Using Diffusion Basis Spectrum Imaging
3.
Governmental entities - NIH (R01AG052550): Imaging Tauopathy in The Dominantly Inherited Alzheimer Network (DIAN)
4.
Governmental entities - NIH (P01AG003991): to study the clinical and biomedical correlates of the clinical course of SDAT in comparison to healthy aging
5.
Governmental entities - NIH (U19AG032438): Dominantly Inherited Alzheimer Network (DIAN)
6.
Governmental entities - NIH (U19AG032438-09S1): DIAN Supplement- Neuropath Core expansion into Latin America
7.
Governmental entities - NIH (P30AG066444): Alzheimer's Disease Research Center (ADRC)
8.
Governmental entities - NIH (R01AG068319): The DIAN-TU Next Generation Tau Prevention Trial
9.
Governmental entities - NIH (R01AG070883): The Neighborhoods Study: Contextual Disadvantage and Alzheimer's Disease and Related Dementia (ADRD)
10.
Governmental entities - NIH (U19AG069701): Biology and Pathobiology of ApoE in Aging and Alzheimer's Disease
11.
Governmental entities - NIH (U19NS110456): multi-institutional collaborative study to develop Positron Emission Tomography (PET) ligands for imaging synucleinopathies and 4R tauopathies
12.
Governmental entities - NIH (R01NS075321): Investigations of Dementia in Parkinson Disease
13.
Governmental entities - NIH (R01AG058676): Investigating Alzheimer's dementia onset and progression in international cohorts
14.
Governmental entities - NIH (U19 AG024904-16): Alzheimer's Disease Neuroimaging Initiative (ADNI4)
15.
Governmental entities - NIH (R01NS097799): Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease<br>(16) Governmental entities - NIH (R01AG074909): Quantitative Endogenous MRI Imaging of Neuroinflammation in AD
16.
Governmental entities - NIH (U19 AG07879): Centrally-linked longitudinal peripheral biomarkers of AD in multi-ethnic populations (CLEAR-AD)
17.
Foundation - American Parkinson Disease Association (Perlmutter J, PI): to support Parkinson disease research including PET, physiological and genetic studies as well as support services for PD
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
Served as a consultant - Diadem
2.
Served as a consultant - Siemens Healthcare Diagnostic, Inc.
3.
Served as a consultant - Cyclo Therapeutics, Inc.
4.
Served on a scientific advisory board - Roche Diagnostics
5.
Served on a scientific advisory board - Genentech
6.
Served on a scientific advisory board - Diadem
7.
Received funding for travel - AAIC
8.
Received funding for travel - South Texas Alzheimer's Disease Research Center (ADRC)
Research Support:
1.
NONE
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
honorarium - Cure Alzheimer's Fund, Research Strategy Council
2.
honorarium - NIA-funded LEADS study
3.
consultant - Barcelona Beta Brain Research Center (BBRC)
4.
editorial advisory board - Brain & Life
5.
editorial advisory board - Alzheimer & Dementia
Research Support:
1.
NIH - National Institute of Aging (P30 AG066444; P01AG003991; P01AG026276; U19AG032438): grant support
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
Served as a consultant - EP Solution
2.
Served as a consultant - Medtronic
Research Support:
1.
Governmental - NIH (R01-AG054567): R01 grant to support this work
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE
Tammie L.S. Benzinger, MD, PhD https://orcid.org/0000-0002-8114-0552
From the Mallinckrodt Institute of Radiology (Q.W., G.C., N.S.M., A.M., S.F., Y.W., T.L.S.B.), Knight Alzheimer Disease Research Center (Q.W., S.E.S., G.C., N.S.M., A.M., J.H., R.J.P., A.M.F., J.C.M., T.L.S.B.), Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Department of Surgery (J.L.), Department of Biomedical Engineering (Z.S.), Department of Electrical and System Engineering (S.W., W.W., Y.W.), Department of Psychiatry (C.C.), Department of Pathology & Immunology (R.J.P.), Department of Obstetrics & Gynecology (Y.W.), and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.
Disclosure
Financial Disclosure:
1.
Served on a scientific advisory board or data safety monitoring board - Eisai
2.
Served on a scientific advisory board or data safety monitoring board - Biogen
3.
Served on a scientific advisory board or data safety monitoring board - Bristol-Myers Squibb
4.
Served on a scientific advisory board of data safety monitoring board - Jaansen
Research Support:
1.
Commercial - Siemens Healtineers: Prior investigator initiated research examining 3D post processing for volumetric MRI segmentation. Work is completed and not related to this publication.
2.
Governmental - NIH: Multiple NIH grants (PI and coI)
Stock, Stock Options & Royalties:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. Q. Wang [email protected] or Dr. Y. Wang [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Associate Editor Linda Hershey, MD, PhD, FAAN.
*
These authors contributed equally to this work.

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

Cited By
  1. White Matter Neuroinflammation Matters in Early Alzheimer Disease, Neurology, 102, 4, (2024)./doi/10.1212/WNL.0000000000208090
    Abstract
Loading...

View Options

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.

If you need immediate support or to place an order, please call or email customer service:

  • 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
  • 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
  • [email protected]

We appreciate your patience during this time and apologize for any inconvenience.

View options

Short Form

View Short Form

Full Text

View Full Text

Full Text HTML

View Full Text HTML

Media

Figures

Other

Tables

Share

Share

Share article link

Share