目的:纵向表征有遗传性朊病毒疾病风险的个体的疾病相关CSF和血浆生物标志物,直至疾病转化。
方法:这项单中心纵向队列研究追踪了已知的PRNP致病变异携带者,有近亲死于遗传性朊病毒病但没有接受预测性基因检测的个体,和控制。所有参与者在第一次访问时无症状,并大致每年返回。我们确定了PRNP基因型,测量血浆中的NfL和GFAP,和RT-QuIC,总PrP,NFL,T-tau,和脑脊液中的β-突触核蛋白。
结果:在注册的41个运营商和21个对照中,28人(68%)和15人(71%)为女性,平均年龄为47.5岁和46.1岁。在基线,所有个体均无症状.我们观察到3名无症状E200K携带者的CSF中的RT-QuIC接种活性,这些携带者随后转化为有症状并死于朊病毒病。1P102L携带者通过症状转化保持RT-QuIC阴性。没有其他个体出现症状。从检测RT-QuIC阳性到疾病发作的前驱窗口在PRNP密码子129处的E200K个体纯合(V/V)中为1年,在2个密码子129杂合子(M/V)中为2.5年和3.1年。在发病前观察到神经退行性和神经炎性标志物的变化,在4/4转换器中观察到等离子体NfL的增加,和血浆GFAP,CSFNFL,CSFT-tau,和脑脊液β-突触核蛋白各自在2/4转换器中,尽管对于这些标志物中的任何一个,相对于年龄的值和相对于个体基线的倍数变化都不显著。CSFPrP在长达6年的所有个体中纵向稳定,平均变异系数为9.0%,包括在RT-QuIC阳性时间点转换个体的数据。
结论:CSF病毒接种活性可能是E200K携带者中最早可检测到的前驱症状。神经元损伤和神经炎症标志物在前驱阶段显示有限的敏感性。即使在存在RT-QuIC接种活性的情况下,CSFPrP水平仍保持稳定。
背景:ClinicalTrials.govNCT05124392发布了2017-12-01,更新于2023-01-27。
OBJECTIVE: To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion.
METHODS: This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF.
RESULTS: Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints.
CONCLUSIONS: CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity.
BACKGROUND: ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.