IRCCS Istituto delle Scienze Neurologiche di Bologna, Bellaria Hospital, Via Altura 1/8, 40139, Bologna, Italy.
Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
Fluids Barriers CNS. 2022 Sep 7;19(1):71. doi: 10.1186/s12987-022-00368-2.
Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome of elderly individuals likely sustained by different neurodegenerative changes as copathologies. Since iNPH is a potentially reversible condition, assessing neurodegenerative pathologies in vitam through CSF biomarkers and their influence on clinical features and surgical outcome represents crucial steps.
We measured α-synuclein seeding activity related to Lewy body (LB) pathology by the real-time quaking-induced conversion assay (RT-QuIC) and Alzheimer disease core biomarkers (proteins total-tau, phospho-tau, and amyloid-beta) by immunoassays in the cerebrospinal fluid (CSF) of 293 iNPH patients from two independent cohorts. To compare the prevalence of LB copathology between iNPH participants and a control group representative of the general population, we searched for α-synuclein seeding activity in 89 age-matched individuals who died of Creutzfeldt-Jakob disease (CJD). Finally, in one of the iNPH cohorts, we also measured the CSF levels of neurofilament light chain protein (NfL) and evaluated the association between all CSF biomarkers, baseline clinical features, and surgery outcome at 6 months.
Sixty (20.5%) iNPH patients showed α-synuclein seeding activity with no significant difference between cohorts. In contrast, the prevalence observed in CJD was only 6.7% (p = 0.002). Overall, 24.0% of iNPH participants showed an amyloid-positive (A+) status, indicating a brain co-pathology related to Aβ deposition. At baseline, in the Italian cohort, α-synuclein RT-QuIC positivity was associated with higher scores on axial and upper limb rigidity (p = 0.003 and p = 0.011, respectively) and lower MMSEc scores (p = 0.003). A+ patients showed lower scores on the MMSEc (p = 0.037) than A- patients. Higher NfL levels were also associated with lower scores on the MMSEc (rho = -0.213; p = 0.021). There were no significant associations between CSF biomarkers and surgical outcome at 6 months (i.e. responders defined by decrease of 1 point on the mRankin scale).
Prevalent LB- and AD-related neurodegenerative pathologies affect a significant proportion of iNPH patients and contribute to cognitive decline (both) and motor impairment (only LB pathology) but do not significantly influence the surgical outcome at 6 months. Their effect on the clinical benefit after surgery over a more extended period remains to be determined.
特发性正常压力脑积水（iNPH）是一种临床和影像学综合征，主要发生在老年人身上，可能与不同的神经退行性改变有关。由于 iNPH 是一种潜在可逆转的疾病，因此通过 CSF 生物标志物评估 Vitam 中的神经退行性病变及其对临床特征和手术结果的影响是至关重要的步骤。
我们通过实时震颤诱导转化测定法（RT-QuIC）测量了与路易体（LB）病理学相关的α-突触核蛋白种籽活性，并通过免疫测定法测量了 293 名来自两个独立队列的 iNPH 患者的脑脊液（CSF）中的阿尔茨海默病核心生物标志物（总 tau、磷酸化 tau 和淀粉样β）。为了比较 iNPH 参与者和代表一般人群的对照组中 LB 共病的患病率，我们在 89 名年龄匹配的死于克雅氏病（CJD）的个体中搜索了α-突触核蛋白种籽活性。最后，在其中一个 iNPH 队列中，我们还测量了神经丝轻链蛋白（NfL）的 CSF 水平，并评估了所有 CSF 生物标志物、基线临床特征和 6 个月时手术结果之间的关联。
60 名（20.5%）iNPH 患者显示出α-突触核蛋白种籽活性，但两个队列之间没有显著差异。相比之下，CJD 中的患病率仅为 6.7%（p=0.002）。总的来说，24.0%的 iNPH 参与者表现出淀粉样阳性（A+）状态，表明存在与 Aβ 沉积有关的脑共病。在基线时，在意大利队列中，α-突触核蛋白 RT-QuIC 阳性与轴向和上肢僵硬的更高评分（p=0.003 和 p=0.011，分别）和更低的 MMSEc 评分（p=0.003）相关。A+患者的 MMSEc 评分（p=0.037）低于 A-患者。更高的 NfL 水平也与 MMSEc 评分较低相关（rho=-0.213；p=0.021）。CSF 生物标志物与 6 个月时的手术结果（即通过 mRankin 量表下降 1 分定义的应答者）之间没有显著关联。
普遍存在的 LB 和 AD 相关神经退行性病变影响了相当一部分 iNPH 患者，并导致认知能力下降（两者）和运动障碍（仅 LB 病理学），但对 6 个月时的手术结果没有显著影响。它们对手术后更长时间内的临床获益的影响仍有待确定。
