Department of Nuclear Medicine, LMU University Hospital, LMU Munich, University of Munich, Marchioninstraße 15, 81377, Munich, Germany.
Department of Radiology, LMU University Hospital, LMU Munich, Munich, Germany.
J Neuroinflammation. 2024 Jan 23;21(1):30. doi: 10.1186/s12974-024-03020-y.
18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between β-amyloid-accumulation and microglial activation in AD.
49 patients with AD (29 females, all Aβ-positive) and 15 Aβ-negative CN (8 female) underwent TSPO-PET ([F]GE-180) and β-amyloid-PET ([F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aβ-PET on TSPO-PET was used to determine the Aβ-plaque-dependent microglial response (slope) and the Aβ-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI).
In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aβ-PET z-scores were similar. The Aβ-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD - 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aβ-plaque-dependent microglial response was not different between sexes. The Aβ-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aβ-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F = 3.077, p = 0.005).
While microglia response to fibrillar Aβ is similar between sexes, women with AD show a stronger Aβ-plaque-independent microglia response. This sex difference in Aβ-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aβ-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.
18 kDa 转位蛋白正电子发射断层扫描（TSPO-PET）成像技术用于评估阿尔茨海默病（AD）研究中的神经炎症的体内情况。在认知正常的人群中，已经有研究报道了性别和肥胖对 TSPO-PET 结合的影响，但在 AD 患者中，尚未对这些影响进行系统评估。因此，我们旨在研究性别和肥胖对 AD 患者中β-淀粉样蛋白蓄积与小胶质细胞激活之间关系的影响。
49 名 AD 患者（29 名女性，均为 Aβ 阳性）和 15 名 Aβ 阴性的认知正常对照（8 名女性）接受了 TSPO-PET([F]GE-180)和β-淀粉样蛋白-PET([F]flutemetamol)成像。在 24 名 AD 患者（14 名女性）中，还进行了 tau-PET([F]PI-2620)成像。将大脑分为 218 个皮质区域，并计算标准化摄取值比（SUVr，小脑参考）。对于 AD 与 CN，每个区域和示踪剂，均计算了 AD 患者的局部 PET SUVr（z 分数）相对于 CN 的增加。通过 AD 患者的局部 Aβ-PET 与 TSPO-PET 的回归得出的线性效应，用于确定 Aβ 斑块依赖性小胶质细胞反应（斜率）和 Aβ 斑块非依赖性小胶质细胞反应（截距）。比较所有的结果，并测试性别对与体重指数（BMI）相关的关联的调节作用。
在 AD 患者中，女性的平均皮质 TSPO-PET z 分数更高（0.91±0.49；男性为 0.30±0.75；p=0.002），而 Aβ-PET z 分数相似。AD 女性的 Aβ 斑块非依赖性小胶质细胞反应更强（+0.37±0.38；AD 男性为-0.33±0.87；p=0.006），且在疾病的前驱期更为明显。相反，性别之间的 Aβ 斑块依赖性小胶质细胞反应没有差异。Aβ 斑块非依赖性小胶质细胞反应与 AD 女性的 tau-PET 显著相关（Braak-II 区域：r=0.757，p=0.003），但与 AD 男性无关。BMI 与 Aβ 斑块非依赖性小胶质细胞反应在 AD 女性中显著相关（r=0.44，p=0.018），但在 AD 男性中不相关（BMI*性别交互作用：F=3.077，p=0.005）。
虽然性别之间小胶质细胞对纤维状 Aβ 的反应相似，但 AD 女性表现出更强的 Aβ 斑块非依赖性小胶质细胞反应。这种 AD 中 Aβ 非依赖性小胶质细胞激活的性别差异可能与 tau 蓄积有关。在 AD 女性中，BMI 与 Aβ 斑块非依赖性小胶质细胞反应呈正相关，但在 AD 男性中不相关，这表明在研究 AD 中的神经炎症时，需要考虑性别和肥胖因素。
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