Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease

Qing Wang; Gengsheng Chen; Suzanne E Schindler; Jon Christensen; Nicole S McKay; Jingxia Liu; Sicheng Wang; Zhexian Sun; Jason Hassenstab; Yi Su; Shaney Flores; Russ Hornbeck; Lisa Cash; Carlos Cruchaga; Anne M Fagan; Zhude Tu; John C Morris; Mark A Mintun; Yong Wang; Tammie L S Benzinger

doi:10.1212/NXI.0000000000001152

Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease

Neurol Neuroimmunol Neuroinflamm. 2022 Mar 8;9(3):e1152. doi: 10.1212/NXI.0000000000001152. Print 2022 May.

Authors

Qing Wang¹, Gengsheng Chen², Suzanne E Schindler², Jon Christensen², Nicole S McKay¹, Jingxia Liu², Sicheng Wang¹, Zhexian Sun², Jason Hassenstab², Yi Su², Shaney Flores², Russ Hornbeck², Lisa Cash², Carlos Cruchaga², Anne M Fagan², Zhude Tu², John C Morris², Mark A Mintun², Yong Wang¹, Tammie L S Benzinger²

Affiliations

¹ From the Mallinckrodt Institute of Radiology (Q.W., G.C., J.C., S.F., R.H., Z.T., Y.W., T.L.S.B.), Washington University School of Medicine; Knight Alzheimer Disease Research Center (Q.W., G.C., S.E.S., J.H., L.C., A.M.F., J.C.M., T.L.S.B.), Washington University School of Medicine; Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Washington University School of Medicine; Department of Surgery (J.L.), Washington University School of Medicine; Department of Electrical and System Engineering (S.W., Y.W.), Washington University School of Med-icine; Department of Biomedical Engineering (Z.S., Y.W.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimer's Institute and Arizona Alzheimer's Consortium (Y.S.), Phoenix, AZ; Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Avid Radiopharmaceuticals (M.A.M.), Philadelphia, PA; Department of Obstetrics and Gynecology (Y.W.), Washington University School of Medicine; and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO. wangyong@wustl.edu.
² From the Mallinckrodt Institute of Radiology (Q.W., G.C., J.C., S.F., R.H., Z.T., Y.W., T.L.S.B.), Washington University School of Medicine; Knight Alzheimer Disease Research Center (Q.W., G.C., S.E.S., J.H., L.C., A.M.F., J.C.M., T.L.S.B.), Washington University School of Medicine; Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Washington University School of Medicine; Department of Surgery (J.L.), Washington University School of Medicine; Department of Electrical and System Engineering (S.W., Y.W.), Washington University School of Med-icine; Department of Biomedical Engineering (Z.S., Y.W.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimer's Institute and Arizona Alzheimer's Consortium (Y.S.), Phoenix, AZ; Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Avid Radiopharmaceuticals (M.A.M.), Philadelphia, PA; Department of Obstetrics and Gynecology (Y.W.), Washington University School of Medicine; and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO.

Abstract

Background and objectives: This study aims to quantify microglial activation in individuals with Alzheimer disease (AD) using the 18-kDa translocator protein (TSPO) PET imaging in the hippocampus and precuneus, the 2 AD-vulnerable regions, and to evaluate the association of baseline neuroinflammation with amyloidosis, tau, and longitudinal cognitive decline.

Methods: Twenty-four participants from the Knight Alzheimer Disease Research Center (Knight ADRC) were enrolled and classified into stable cognitively normal, progressor, and symptomatic AD groups based on clinical dementia rating (CDR) at 2 or more clinical assessments. The baseline TSPO radiotracer [11C]PK11195 was used to image microglial activation. Baseline CSF concentrations of Aβ42, Aβ42/Aβ40 ratio, tau phosphorylated at position 181 (p-tau181), and total tau (t-tau) were measured. Clinical and cognitive decline were examined with longitudinal CDR and cognitive composite scores (Global and Knight ADRC-Preclinical Alzheimer Cognitive Composite [Knight ADRC-PACC] Score).

Results: Participants in the progressor and symptomatic AD groups had significantly elevated [11C]PK11195 standard uptake value ratios (SUVRs) in the hippocampus but not in the precuneus region. In the subcohort with CSF biomarkers (16 of the 24), significant negative correlations between CSF Aβ42 or Aβ42/Aβ40 and [11C]PK11195 SUVR were observed in the hippocampus and precuneus. No correlations were observed between [11C]PK11195 SUVR and CSF p-tau181 or t-tau at baseline in those regions. Higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions predicted longitudinal decline on cognitive tests.

Discussion: Microglial activation is increased in individuals with brain amyloidosis and predicts worsening cognition in AD.

Classification of evidence: This study provides Class II evidence that in patients with AD, higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions was associated with longitudinal decline on cognitive tests.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / metabolism
Amyloidosis* / complications
Amyloidosis* / diagnostic imaging
Amyloidosis* / metabolism
Brain / diagnostic imaging
Brain / metabolism
Cognitive Dysfunction* / diagnostic imaging
Cognitive Dysfunction* / etiology
Humans
Microglia / metabolism
Receptors, GABA / metabolism

Substances

Receptors, GABA
TSPO protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding