Ikeda Masaki, Kodaira Sayaka, Kasahara Hiroo, Takai Eriko, Nagashima Kazuaki, Fujita Yukio, Makioka Kouki, Hirayanagi Kimitoshi, Furuta Natsumi, Furuta Minori, Sanada Etsuko, Kobayashi Ayumi, Harigaya Yasuo, Nagamine Shun, Hattori Noriaki, Tashiro Yuichi, Kishi Kazuhiro, Shimada Hirotaka, Suto Takayuki, Tanaka Hisashi, Sakai Yasujiro, Yamazaki Tsuneo, Tanaka Yukiko, Aihara Yuko, Amari Masakuni, Yamaguchi Haruyasu, Okamoto Koichi, Takatama Masamitsu, Ishii Kenji, Higuchi Tetsuya, Tsushima Yoshito, Ikeda Yoshio
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Department of Neurology, Geriatrics Research Institute and Hospital, Maebashi, Japan.
Front Neurol. 2021 Apr 6;12:543866. doi: 10.3389/fneur.2021.543866. eCollection 2021.
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 Tc-ethyl cysteinate dimer single photon emission computerized tomography (Tc ECD-SPECT), as well as the mean cortical standard uptake value ratio by C-labeled Pittsburgh Compound B-positron emission tomography (C 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.
阿尔茨海默病（AD）中的脑叶脑微出血（CMBs）与脑血管淀粉样β（Aβ）沉积所致的脑淀粉样血管病（CAA）相关。然而，脑叶CMBs与AD临床亚型之间的关系仍不清楚。在此，我们纳入了符合AD标准的早发型和晚发型遗忘型主导AD、原发性进行性失语的语言减少型变异（lvPPA）和后皮质萎缩（PCA）患者。然后，我们检测了脑脊液（CSF）生物标志物的水平[Aβ1-42、Aβ1-40、Aβ1-38、磷酸化tau 181（P-Tau）、总tau（T-Tau）、神经丝轻链（NFL）和几丁质酶3样1蛋白（YKL-40）]，分析了CMBs的数量和定位，并通过锝-乙基半胱氨酸二聚体单光子发射计算机断层扫描（Tc ECD-SPECT）测量脑血流量（CBF），以及通过碳-标记的匹兹堡化合物B-正电子发射断层扫描（C PiB-PET）测量平均皮质标准摄取值比率。lvPPA中的脑叶CMBs分布于颞叶、额叶和顶叶，以左侧为主，而lvPPA中左颞区的CBF显著降低，该区域脑叶CMBs的数量与CBF呈显著负相关。与其他AD亚型和非痴呆受试者相比，lvPPA中CSF的NFL水平显著更高。在所有AD患者中，脑叶CMBs的数量显著增加了CSF的NFL水平，此外，在AD亚型中，lvPPA中CSF的NFL水平主要随着脑叶CMBs数量的增加而升高。另一方面，在所有AD患者中，随着脑叶CMBs数量的增加，CSF的Aβ1-38、Aβ1-40、Aβ1-42、P-Tau和T-Tau水平降低。这些发现可能表明，lvPPA中异常的脑灌注不足源于神经退行性变导致的脑萎缩，可能还涉及脑叶CMBs和脑血管损伤引起的异常微循环，以左侧为主，从而导致语言减少型变异的临床表型。
