Neuroinflammation is linked to dementia risk in Parkinson's disease.
Neuroinflammation is linked to dementia risk in Parkinson's disease.
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神经炎症与帕金森病的痴呆风险有关。
DOI：
10.1093/brain/awad322
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Kouli A
中科院分区：
文献类型：
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作者：
Kouli A
痴呆症的发展是帕金森病（PD）的一个破坏性方面，在诊断后10年内影响了近一半的患者。 对于预防和减缓PD痴呆（PDD）进展的有效疗法，需要了解决定为什么一些PD患者发展为早期痴呆而其他人保持认知不受影响的关键机制。神经炎症和tau蛋白积聚已在死后PD脑中以及在导致痴呆的许多其他神经退行性疾病中得到证实。然而，这些过程是否在PD病程早期介导痴呆风险尚未确定。为此，我们使用PET神经成像与11 C-PK 11195来指示早期PD患者的神经炎症，并使用18 F-AV-1451来指示错误折叠的tau蛋白，根据我们的“帕金森病痴呆中的神经炎症和Tau蛋白累积”（NET-PDD）研究中的痴呆风险进行分层。NET-PDD研究纵向评估了低和高痴呆风险的两个亚组中新诊断的PD患者（基于五边形复制，语义流畅性，MAPT基因型分层），并与年龄和性别匹配的对照组进行比较。在43个脑区（Hammers' parcellation）中的非可置换结合电位（BPND）在组间进行比较（成对检验），并且BPND与所测试的示踪剂之间的关联（线性混合效应模型）。我们假设，痴呆风险较高的人在显著的认知能力下降之前有更大的炎症和/或tau蛋白积累。我们发现，与对照组相比，高痴呆风险组的多个皮质下和受限皮质区域的神经炎症（11 C-PK 11195 BPND）显著升高，而在低风险组中，这仅限于两个皮质区域。高痴呆风险组也显示出比低风险组更大的神经炎症，集中在皮质下和基底节区域。这些区域中的大多数神经炎症与更差的认知表现（Addenbrooke认知检查-III评分）相关。总体神经炎症负荷也与促炎细胞因子的血清水平相关。相反，PD患者18F-AV-1451（tau）BPND的增加仅限于皮质下区域，在那里通常可以看到脱靶结合，与认知无关。全脑18F-AV-1451负荷与血清磷酸化tau 181水平相关。尽管PD患者的局部tau蛋白蓄积最少，但PD参与者的局部神经炎症和tau蛋白负荷相关，在高痴呆风险组中相关性最强，表明这些病理可能存在共定位。总之，我们的研究结果表明，在早期PD显着的区域神经炎症可能支持PDD发展的风险较高，表明神经炎症作为一个假定的早期可修改的病因病理学疾病因素，以防止或减缓痴呆的发展，使用免疫调节策略。
The development of dementia is a devastating aspect of Parkinson’s disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with11C-PK11195 to index neuroinflammation and18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our ‘Neuroinflammation and Tau Accumulation in Parkinson’s Disease Dementia’ (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency,MAPTgenotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers’ parcellation) was compared between groups (pairwiset-tests), and associations between BPNDof the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke’s Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in18F-AV-1451 (tau) BPNDin PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies.