Cerebral Microbleeds, Cerebrospinal Fluid, and Neuroimaging Markers in Clinical Subtypes of Alzheimer's Disease

Masaki Ikeda,Koichi Okamoto,Etsuko Sanada,Masamitsu Takatama,Kouki Makioka,Yoshito Tsushima,Masakuni Amari,Hisashi Tanaka,Yasuo Harigaya,Hiroo Kasahara,Kazuhiro Kishi,Kimitoshi Hirayanagi,Tsuneo Yamazaki,Yuichi Tashiro,Yukiko Tanaka,Sayaka Kodaira,Natsumi Furuta,Kenji Ishii,Yoshio Ikeda,Eriko Takai,Shun Nagamine,Tetsuya Higuchi,Noriaki Hattori,Yukio Fujita,Kazuaki Nagashima,Yasuo Aihara ,Yusuke Sakai ,Masaya Furuta ,Hideyo Yamaguchi ,Hironori Shimada ,Akito Kobayashi ,Takayuki Sakai

doi:10.3389/fneur.2021.543866

Abstract

Lobar cerebral microbleeds (CMBs) in Alzheimer's disease (AD) are associated with cerebral amyloid angiopathy (CAA) due to vascular amyloid beta (Aβ) deposits. However, the relationship between lobar CMBs and clinical subtypes of AD remains unknown. Here, we enrolled patients with early- and late-onset amnestic dominant AD, logopenic variant of primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA) who were compatible with the AD criteria. We then examined the levels of cerebrospinal fluid (CSF) biomarkers [Aβ1-42, Aβ1-40, Aβ1-38, phosphorylated tau 181 (P-Tau), total tau (T-Tau), neurofilament light chain (NFL), and chitinase 3-like 1 protein (YKL-40)], analyzed the number and localization of CMBs, and measured the cerebral blood flow (CBF) volume by 99mTc-ethyl cysteinate dimer single photon emission computerized tomography (99mTc ECD-SPECT), as well as the mean cortical standard uptake value ratio by 11C-labeled Pittsburgh Compound B-positron emission tomography (11C PiB-PET). Lobar CMBs in lvPPA were distributed in the temporal, frontal, and parietal lobes with the left side predominance, while the CBF volume in lvPPA significantly decreased in the left temporal area, where the number of lobar CMBs and the CBF volumes showed a significant inversely correlation. The CSF levels of NFL in lvPPA were significantly higher compared to the other AD subtypes and non-demented subjects. The numbers of lobar CMBs significantly increased the CSF levels of NFL in the total AD patients, additionally, among AD subtypes, the CSF levels of NFL in lvPPA predominantly were higher by increasing number of lobar CMBs. On the other hand, the CSF levels of Aβ1-38, Aβ1-40, Aβ1-42, P-Tau, and T-Tau were lower by increasing number of lobar CMBs in the total AD patients. These findings may suggest that aberrant brain hypoperfusion in lvPPA was derived from the brain atrophy due to neurodegeneration, and possibly may involve the aberrant microcirculation causing by lobar CMBs and cerebrovascular injuries, with the left side dominance, consequently leading to a clinical phenotype of logopenic variant.

Highlights

Cerebral amyloid angiopathy (CAA) is caused by amyloid beta (Aβ) accumulation and is characterized by several pathological changes in the walls of small cortical and leptomeningeal capillaries, arterioles, and arteries [1,2,3,4]
cerebrospinal fluid (CSF) biomarkers were analyzed in 18 patients with logopenic variant type of primary progressive aphasia (lvPPA), 12 with posterior cortical atrophy (PCA), 34 with EOAD, and 38 with LOAD, in addition to
The CSF levels of Aβ1-42 were significantly lower in combined the typical Alzheimer’s disease (AD) group and the atypical AD than in the ND, while the CSF levels of phosphorylated tau 181 (P-Tau), total tau (T-Tau), neurofilament light chain (NFL), and YKL-40 were significantly higher in the typical AD and atypical AD groups compared to the ND group

Summary

Introduction

Cerebral amyloid angiopathy (CAA) is caused by amyloid beta (Aβ) accumulation and is characterized by several pathological changes in the walls of small cortical and leptomeningeal capillaries, arterioles, and arteries [1,2,3,4]. CSF levels of Aβ1-38 was reported to be lower in the CAA patients than the AD patients and the control, while CSF NFL of CAA and AD patients was higher than control cases [28], they were not atypical AD phenotypes From these findings, we postulated that differences might exist in the CSF levels of NFL, YKL-40, and Aβ1-38, the number and distribution of cortical areas, the lateral predominance (left-right difference) of lobar CMBs localization, as well as the regional CBF (cerebral blood flow) volume and 11C PiB retention may be apparent between the four subtypes of AD. We formulated the following hypotheses: [1] typical amnestic AD and atypical AD exhibit unique clinical characteristics, CSF biomarkers, and frequency of apolipoprotein E gene (APOE)

Methods

Results

Conclusion