Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.
Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.
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DOI：
10.1016/s1474-4422(14)70324-2
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Binetti G
中科院分区：
文献类型：
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作者：
Rohrer JD;Nicholas JM;Cash DM;van Swieten J;Dopper E;Jiskoot L;van Minkelen R;Rombouts SA;Cardoso MJ;Clegg S;Espak M;Mead S;Thomas DL;De Vita E;Masellis M;Black SE;Freedman M;Keren R;MacIntosh BJ;Rogaeva E;Tang-Wai D;Tartaglia MC;Laforce R Jr;Tagliavini F;Tiraboschi P;Redaelli V;Prioni S;Grisoli M;Borroni B;Padovani A;Galimberti D;Scarpini E;Arighi A;Fumagalli G;Rowe JB;Coyle-Gilchrist I;Graff C;Fallström M;Jelic V;Ståhlbom AK;Andersson C;Thonberg H;Lilius L;Frisoni GB;Pievani M;Bocchetta M;Benussi L;Ghidoni R;Finger E;Sorbi S;Nacmias B;Lombardi G;Polito C;Warren JD;Ourselin S;Fox NC;Rossor MN;Binetti G
额颞叶痴呆是一种高度遗传性的神经退行性疾病。在大约三分之一的患者中，这种疾病是由常染色体显性遗传突变引起的，通常发生在三个基因中的一个：原颗粒蛋白(GRN)、微管相关蛋白tau(MAPT)或染色体9开放阅读框架72(C9orf72)。对其他遗传性痴呆的研究结果显示，在症状出现之前，神经成像和认知发生了变化，我们的目标是确定这种变化是否可以在额颞部痴呆中表现出来。我们招募了这项多中心研究的参与者，他们要么是已知的GRN、MAPT或C9orf72致病突变的携带者，要么因为一级亲属是已知的症状携带者而面临携带突变的风险。我们根据评估时年龄与家庭内平均发病年龄之间的差值来计算预期发病时间。参与者接受了标准化的临床评估和神经心理测试。我们做了MRI，并使用体积T1加权扫描的分割来生成皮质和皮质下体积。我们使用线性混合效应模型来检验在突变携带者和非携带者之间，神经心理学和影像测量与预期症状出现的时间之间的关联是否有所不同。在2012年1月30日至2013年9月15日期间，我们从英国、意大利、荷兰、瑞典和加拿大的11个研究地点招募了参与者。我们分析了220名参与者的数据：118名突变携带者(40名有症状，78名无症状)和102名非携带者。对于神经心理学指标，我们注意到突变携带者和非携带者在预期发病前5年最早出现显著差异，当时除即刻回忆和语言流畅性测试外，所有指标的差异均显著。我们注意到，在预期发病前5年，携带者和非携带者在命名(波士顿命名测试-0.7；SE0.3)和执行功能(追踪测试B部分，数字跨度倒退和数字符号任务，ALL-0.5，SE0.2)测试中Z分差异最大。在影像测量方面，我们注意到最早的差异是脑岛(在预期症状出现前10年，突变携带者的平均体积占总颅内体积的百分比为0.80%，非携带者为0.84%；差异-0.04，SE为0.02)，其次是颞叶(在预期症状出现前的10年，突变携带者的平均体积占总颅内体积的百分比为8.1%，非携带者为8.3%；差异-0.2，SE为0·1)。在有遗传性额颞叶痴呆风险的无症状成人中，结构成像和认知改变可以在预期症状出现前5-10年确定。这些发现可能有助于定义可以诊断症状前疾病和跟踪疾病进展的生物标记物，这对未来的治疗试验将是重要的。神经退行性变卓越中心。
Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test –0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all –0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference –0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference –0·2, SE 0·1). Structural imaging and cognitive changes can be identified 5–10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Centres of Excellence in Neurodegeneration.