Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.
Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.
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DOI：
10.1212/wnl.0000000000011848
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发表时间：
2021-05-04
期刊：
影响因子：
9.9
通讯作者：
ALLFTD and GENFI consortia
中科院分区：
文献类型：
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作者：
Rojas JC;Wang P;Staffaroni AM;Heller C;Cobigo Y;Wolf A;Goh SM;Ljubenkov PA;Heuer HW;Fong JC;Taylor JB;Veras E;Song L;Jeromin A;Hanlon D;Yu L;Khinikar A;Sivasankaran R;Kieloch A;Valentin MA;Karydas AM;Mitic LL;Pearlman R;Kornak J;Kramer JH;Miller BL;Kantarci K;Knopman DS;Graff-Radford N;Petrucelli L;Rademakers R;Irwin DJ;Grossman M;Ramos EM;Coppola G;Mendez MF;Bordelon Y;Dickerson BC;Ghoshal N;Huey ED;Mackenzie IR;Appleby BS;Domoto-Reilly K;Hsiung GR;Toga AW;Weintraub S;Kaufer DI;Kerwin D;Litvan I;Onyike CU;Pantelyat A;Roberson ED;Tartaglia MC;Foroud T;Chen W;Czerkowicz J;Graham DL;van Swieten JC;Borroni B;Sanchez-Valle R;Moreno F;Laforce R;Graff C;Synofzik M;Galimberti D;Rowe JB;Masellis M;Finger E;Vandenberghe R;de Mendonça A;Tagliavini F;Santana I;Ducharme S;Butler CR;Gerhard A;Levin J;Danek A;Otto M;Sorbi S;Cash DM;Convery RS;Bocchetta M;Foiani M;Greaves CV;Peakman G;Russell L;Swift I;Todd E;Rohrer JD;Boeve BF;Rosen HJ;Boxer AL;ALLFTD and GENFI consortia
我们检验了血浆神经丝轻链（NfL）识别家族性额颞叶变性（FTLD）的无症状携带者的假设，FTLD导致疾病进展的风险突变。在原始（n = 277）和验证（n = 297）队列中使用单分子阵列测量基线血浆NfL浓度。使用CDR痴呆分期仪加上来自国家阿尔茨海默病协调中心FTLD模块（CDR+NACC-FTLD）的行为和语言领域，将来自相同家族的C9 orf 72、GRN和MAPT突变携带者和非携带者按疾病严重程度（无症状、前驱期和完全表型）分类。线性混合效应模型将NfL与临床变量相关。在两个队列中，与非进展者相比，显示表型转换或疾病进展的无症状突变携带者的基线NfL更高（原始：11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL，p = 0.002;验证：14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL，p = 0.035）。血浆NfL区分有症状的突变携带者和无症状的突变携带者或前驱疾病患者（原始截止值：13.6 pg/mL，灵敏度87.5%，特异性82.7%;验证截止值：19.8 pg/mL，灵敏度87.4%，特异性84.3%）。基线NfL较高与纵向CDR+NACC-FTLD总分、神经心理功能和萎缩较差相关，无论基因型或疾病严重程度如何，包括无症状突变携带者。血浆NfL识别具有短期疾病进展风险的FTLD引起突变的无症状携带者，并且是选择预防临床试验参与者的潜在工具。ClinicalTrials.gov标识符：NCT 02372773和NCT 02365922。这项研究提供了I类证据，即在导致FTLD突变的携带者中，血浆NfL升高可预测临床进展的短期风险。
We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)–causing mutations at risk of disease progression. Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.