特发性正常压力脑积水神经退行性生物标志物的脑脊液时间趋势。
Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus.
机构信息
Institute of Clinical Medicine -Neurosurgery, University of Eastern Finland and Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland.
UCB, Braine-l'Alleud, Belgium.
出版信息
J Alzheimers Dis. 2021;80(4):1629-1642. doi: 10.3233/JAD-201361.
BACKGROUND
Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.
OBJECTIVE
To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.
METHODS
L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.
RESULTS
All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.
CONCLUSION
Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.
背景
脑脊液（CSF）生物标志物的纵向变化很少被研究。此外，腰椎（L-）和脑室（V-）之间生物标志物梯度的数据似乎存在不一致。
目的
通过脑室分流术检查特发性正常压力脑积水（iNPH）患者中反映阿尔茨海默病（AD）相关淀粉样蛋白-β（Aβ）聚集、tau 病理、神经退行性变和早期突触退化的 CSF 生物标志物的变化，与 AD 相关的脑活检变化相关。此外，比较了 L-和 V-CSF 中的生物标志物水平。
方法
在分流术放置前采集 L-CSF，并在术后 3-73 个月与 V-CSF 一起采集。此后，在基线样本后 3、6 和 18 个月，从 26 例经证实有额皮质脑活检 Aβ斑块的 iNPH 患者和 13 例无 Aβ 病理的 iNPH 患者中，额外采集 CSF 样本。使用定制的 ELISA 分析 CSF 中的 Aβ42、总 tau（T-tau）、磷酸化 tau（P-tau181）、神经丝轻链（NFL）和神经颗粒蛋白（NRGN）。
结果
所有生物标志物（Aβ42 除外）在 L-CSF 中的浓度均显著增加了 140-810%，然后稳定下来。相反，在 L-CSF 中，Aβ 阳性和阴性患者之间的 Aβ42 呈发散性纵向下降，随后 Aβ 阴性 iNPH 患者在 L-和 V-CSF 中均增加。所有五个生物标志物在 V-CSF 和 L-CSF 之间高度相关（Aβ42 R = 0.87、T-tau R = 0.83、P-tau R = 0.92、NFL R = 0.94、NRGN R = 0.9；所有 p 值均<0.0001），但在 V-CSF 中系统较低（Aβ42 低 14%、T-tau 低 22%、P-tau 低 20%、NFL 低 32%、NRGN 低 19%）。按照 APOE 基因型分组，只有非等位基因 ɛ4 携带者的 Aβ42 浓度更高。
结论
纵向随访显示，在术后初期增加后，无论脑活检 Aβ 病理如何，iNPH 患者的 T-tau、P-tau 和 NRGN 均保持稳定，而 NFL 则向分流术前水平正常化。作为生物标志物的 Aβ42 似乎受手术或分流术的影响最小，可能是 iNPH 患者 AD 风险的最佳预测指标。所有生物标志物的浓度在 V-CSF 中均低于 L-CSF，但相关性较强。
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