Constantinescu Radu, Blennow Kaj, Rosengren Lars, Eriksson Barbro, Gudmundsdottir Thordis, Jansson Yvonne, Johnels Bo, Renck Annika, Bergquist Filip
Department of Neurology, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
Clin Neurol Neurosurg. 2018 Nov;174:174-179. doi: 10.1016/j.clineuro.2018.09.024. Epub 2018 Sep 17.
Cerebrospinal fluid (CSF) markers of neurodegeneration [neurofilament light chain (NFL), total Tau (T-Tau)], tau pathology [phosphorylated tau (p-Tau)], glial cell damage or activation [glial fibrillary acidic protein (GFAP)], and brain amyloidosis [β-amyloid 1-42 (Aβ42)] are useful for diagnosis and prognosis in several neurodegenerative disorders. In this paper we investigate these markers and their relationship to key clinical milestones in patients with advanced Parkinson´s disease (PD) operated at our center with subthalamic nucleus deep brain stimulation (STN-DBS) for at least 15 years ago.
Retrospective analysis of available cerebrospinal fluid and clinical data in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska University Hospital before January 1, 2001, were regularly assessed until January 10, 2018, or until death, or until lost to follow-up.
Twenty three PD patients were operated with STN-DBS. Sixteen of these (six females and ten males) underwent at least one lumbar puncture (LP) immediately prior to or after STN-DBS. Their age at the latest available LP was 64 (55-75) years [median (range)], PD duration 20 (11-33) years, and Hoehn & Yahr (H&Y) stage 3 (2-4). Time between DBS operation and the last LP was 4.5 (0.3-10.8) years. Time from the last LP to the last follow up was 6 (0.1-18) years, and for the entire cohort 115 person-years. On January 10, 2018, four PD-patients (25%) were still alive. All preoperative CSF marker levels were normal. Between two days and six months after DBS, NFL and GFAP levels increased sharply but they normalized thereafter in most patients, and were normal up to almost 11 years after neurosurgery. Over time, all patients deteriorated slowly. At the last follow up, H&Y was 5 (3-5) and 12/16 were demented. There was no significant correlation between postoperative (> 6 months) CSF NFL, GFAP, T-Tau, p-Tau, β-amyloid levels and the presence of dementia, psychosis, inability to walk or need for nursing home at the time for LP, nor for presence of dementia at the last follow up or for death as of January 10, 2018.
CSF protein biomarkers remain normal despite long PD duration, severe disability, and chronic STN-DBS. They cannot be used for PD staging or prognostication but may indicate brain damage caused by other pathological factors.
神经退行性变的脑脊液（CSF）标志物[神经丝轻链（NFL）、总 Tau 蛋白（T-Tau）]、tau 病理改变[磷酸化 tau 蛋白（p-Tau）]、胶质细胞损伤或激活[胶质纤维酸性蛋白（GFAP）]以及脑淀粉样变[β-淀粉样蛋白 1-42（Aβ42）]在多种神经退行性疾病的诊断和预后评估中具有重要作用。在本文中，我们对至少 15 年前在我们中心接受丘脑底核脑深部电刺激（STN-DBS）手术的晚期帕金森病（PD）患者的这些标志物及其与关键临床指标的关系进行了研究。
对接受 STN-DBS 手术 15 年及以上的 PD 患者的现有脑脊液和临床数据进行回顾性分析。所有于 2001 年 1 月 1 日前在萨尔格伦斯卡大学医院植入 STN-DBS 的 PD 患者，均定期接受评估，直至 2018 年 1 月 10 日，或直至死亡，或直至失访。
23 例 PD 患者接受了 STN-DBS 手术。其中 16 例（6 名女性和 10 名男性）在 STN-DBS 手术前后至少接受了一次腰椎穿刺（LP）。他们在最后一次可用 LP 时的年龄为 64（55 - 75）岁[中位数（范围）]，PD 病程为 20（11 - 33）年，Hoehn & Yahr（H&Y）分期为 3（2 - 4）期。DBS 手术与最后一次 LP 之间的时间为 4.5（0.3 - 10.8）年。从最后一次 LP 到最后一次随访的时间为 6（0.1 - 18）年，整个队列的随访时间为 115 人年。2018 年 1 月 10 日，4 例 PD 患者（25%）仍存活。所有术前 CSF 标志物水平均正常。DBS 术后两天至六个月内，NFL 和 GFAP 水平急剧升高，但此后大多数患者恢复正常，直至神经外科手术后近 11 年一直保持正常。随着时间推移，所有患者均缓慢恶化。在最后一次随访时，H&Y 分期为 5（3 - 5）期，16 例中有 12 例出现痴呆。术后（>6 个月）CSF NFL、GFAP、T-Tau、p-Tau、β-淀粉样蛋白水平与 LP 时痴呆、精神病、无法行走或需要入住养老院的情况之间，以及与最后一次随访时痴呆的存在情况或截至 2018 年 1 月 10 日的死亡情况均无显著相关性。
尽管 PD 病程长、残疾严重且长期接受 STN-DBS 治疗，但 CSF 蛋白生物标志物仍保持正常。它们不能用于 PD 分期或预后评估，但可能提示由其他病理因素引起的脑损伤。
