Department of Neurology, University Hospital Ulm, Ulm, Germany.
Swiss Epilepsy Clinic, Klinik Lengg, Zürich, Switzerland.
Neuroimage Clin. 2023;39:103505. doi: 10.1016/j.nicl.2023.103505. Epub 2023 Sep 9.
ALS patients with hexanucleotide expansion in C9orf72 are characterized by a specific clinical phenotype, including more aggressive disease course and cognitive decline. Computerized multiparametric MRI with gray matter volumetry and diffusion tensor imaging (DTI) to analyze white matter structural connectivity is a potential in vivo biomarker.
The objective of this study was to develop a multiparametric MRI signature in a large cohort of ALS patients with C9orf72 mutations. The aim was to investigate how morphological features of C9orf72-associated ALS differ in structural MRI and DTI compared to healthy controls and ALS patients without C9orf72 mutations.
Atlas-based volumetry (ABV) and whole brain-based DTI-based analyses were performed in a cohort of n = 51 ALS patients with C9orf72 mutations and compared with both n = 51 matched healthy controls and n = 51 C9orf72 negative ALS patients, respectively. Subsequently, Spearman correlation analysis of C9orf72 ALS patients' data with clinical parameters (age of onset, sex, ALS-FRS-R, progression rate, survival) as well as ECAS and p-NfH in CSF was performed.
The whole brain voxel-by-voxel comparison of fractional anisotropy (FA) maps between C9orf72 ALS patients and controls showed significant bilateral alterations in axonal structures of the white matter at group level, primarily along the corticospinal tracts and in fibers projecting to the frontal lobes. For the frontal lobes, these alterations were also significant between C9orf72 positive and C9orf72 negative ALS patients. In ABV, patients with C9orf72 mutations showed lower volumes of the frontal, temporal, and parietal lobe, with the lowest values in the gray matter of the superior frontal and the precentral gyrus, but also in hippocampi and amygdala. Compared to C9orf72 negative ALS, the differences were shown to be significant for cerebral gray matter (p = 0.04), especially in the frontal (p = 0.01) and parietal lobe (p = 0.01), and in the thalamus (p = 0.004). A correlation analysis between ECAS and averaged regional FA values revealed significant correlations between cognitive performance in ECAS and frontal association fibers. Lower FA values in the frontal lobes were associated with worse performance in all cognitive domains measured (language, verbal fluency, executive functions, memory and spatial perception). In addition, there were significant negative correlations between age of onset and atlas-based volumetry results for gray matter.
This study demonstrates a distinct pattern of DTI alterations of the white matter and ubiquitous volume reductions of the gray matter early in the disease course of C9orf72-associated ALS. Alterations were closely linked to a more aggressive cognitive phenotype. These results are in line with an expected pTDP43 propagation pattern of cortical affection and thus strengthen the hypothesis that an underlying developmental disorder is present in ALS with C9orf72 expansions. Thus, multiparametric MRI could contribute to the assessment of the disease as an in vivo biomarker even in the early phase of the disease.
具有 C9orf72 六核苷酸扩展的 ALS 患者表现出特定的临床表型,包括更具侵袭性的疾病过程和认知能力下降。使用基于计算机的多参数 MRI 进行灰质容积测量和弥散张量成像(DTI)以分析白质结构连接是一种潜在的体内生物标志物。
本研究旨在为患有 C9orf72 突变的大量 ALS 患者开发一种多参数 MRI 特征。目的是研究与健康对照组和无 C9orf72 突变的 ALS 患者相比,C9orf72 相关 ALS 的形态特征在结构 MRI 和 DTI 中的差异。
在一组 n=51 例患有 C9orf72 突变的 ALS 患者中进行基于图谱的容积测量(ABV)和基于全脑的 DTI 分析,并与 n=51 例匹配的健康对照组和 n=51 例 C9orf72 阴性 ALS 患者进行比较。随后,对 C9orf72 ALS 患者的数据与临床参数(发病年龄、性别、ALS-FRS-R、进展率、生存率)以及 CSF 中的 ECAS 和 p-NfH 进行 Spearman 相关性分析。
C9orf72 ALS 患者与对照组之间的各向异性分数(FA)图的全脑体素比较显示,在组水平上,白质的轴突结构发生了双侧改变,主要沿皮质脊髓束和投射到额叶的纤维。对于额叶,C9orf72 阳性和 C9orf72 阴性 ALS 患者之间也存在显著差异。在 ABV 中,C9orf72 突变患者的额叶、颞叶和顶叶体积较小,额上回和中央前回的灰质体积最小,但也包括海马体和杏仁核。与 C9orf72 阴性 ALS 相比,大脑灰质的差异具有统计学意义(p=0.04),尤其是额叶(p=0.01)和顶叶(p=0.01),以及丘脑(p=0.004)。ECAS 与平均区域 FA 值的相关性分析显示,认知表现与额叶联合纤维之间存在显著相关性。额叶 FA 值较低与所有测量的认知领域(语言、言语流畅性、执行功能、记忆和空间感知)的表现较差相关。此外,发病年龄与基于图谱的灰质容积测量结果之间存在显著的负相关。
本研究表明,在 C9orf72 相关 ALS 的疾病早期,DTI 白质改变和广泛的灰质体积减少具有独特的模式。这些改变与更具侵袭性的认知表型密切相关。这些结果与皮质受累的预期 pTDP43 传播模式一致,因此强化了 C9orf72 扩展的 ALS 中存在潜在发育障碍的假说。因此,多参数 MRI 可以作为一种体内生物标志物,即使在疾病的早期阶段也可以用于评估疾病。