From the Sorbonne Université (G.C., C.D.-F., E.P., S.S., L.D., P.C., R.K., R.H., H.H., J.-C.L., M.-L.W., P.P., A.B., S.T.d.M., A.D.), Paris Brain Institute, Inserm, CNRS, INRIA, APHP; CATI (C.F., M.C., J.-F.M.), US52-UAR2031, CEA, Paris Brain Institute, Sorbonne Université, CNRS, INSERM, APHP; Sorbonne Université (M.N., I.A.), Inserm, CNRS, Institut de la Vision; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (M.N., I.A.), National Rare Disease Center REFERET and INSERM-DGOS CIC 1423; Sorbonne Université (P.G.), Inserm, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique; Sorbonne Université (K.D.), Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (CIMI-Paris), France; P3lab (P.D.), Louvain-la-Neuve, Belgique; Clinical Metabolomic Department (A.L.), Assistance Publique-Hôpitaux de Paris, Saint Antoine Hospital, Saint-Antoine Research Center, Sorbonne University, France; Ionis Pharmaceuticals (R.L.), Carlsbad, CA; and Service de Neurophysiologie (B.G.), University Hospital Pitié-Salpêtrière, Paris, France.
Neurology. 2024 Sep 10;103(5):e209749. doi: 10.1212/WNL.0000000000209749. Epub 2024 Aug 12.
Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year.
We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year.
We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, = 0.78), as well the sex ( = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, < 0.01). Pons and medulla volumes were smaller in SCAs ( < 0.05) and cerebellum volume only in SCA2 ( = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm) and cerebellum (-1,508 ± 580 mm) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 μm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7.
Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase.
ClinicalTrials.gov NCT04288128.
在共济失调发作前的横断面研究中，大多数多聚谷氨酰胺脊髓小脑共济失调患者的脑 MRI 异常和神经丝轻链（NfL）增加。我们的研究旨在确定脊髓小脑共济失调（SCA）2 和 SCA7 携带者在 1 年内的生物、临床和/或影像学生物标志物的纵向变化。
我们在巴黎脑研究所研究了 SCA2 和 SCA7 携带者和对照（无扩张亲属）。纳入标准包括 SARA 评分在 0 到 15 之间。基线、6 个月和 12 个月的评估包括神经病学、生活质量、口面运动、神经心理学和眼科检查，以及步态和眼动记录、脑 MRI、CSF 和血液采样。主要结局是 1 年内这些评估的纵向变化。
我们纳入了 2020 年 5 月至 2021 年 4 月的 15 名 SCA2 携带者、15 名 SCA7 携带者和 10 名对照。基线时，年龄相似（SCA2 为 41 [37，46]，SCA7 为 38 [28.5，39.8]，对照为 39.5 [31，54.5]，=0.78），性别也相似（=0.61）；SARA 评分较低但不同（SCA2 为 4 [1.25，6.5]，SCA7 为 2 [0，11.5]，对照为 0，<0.01）。桥脑和延髓体积在 SCA 中较小（<0.05），而小脑体积仅在 SCA2 中较小（=0.01）。SCA 参与者的血浆 NfL 水平较高（SCA2：14.2 pg/mL [11.52，15.89]，SCA7：15.53 [13.27，23.23]），低于对照组（4.88 [3.56，6.17]，<0.001）。在 1 年的随访后，SCA2 患者的桥脑（-144 ± 60 mm）和小脑（-1508 ± 580 mm）体积明显减少，步态评估恶化；SCA7 患者的 SARA 评分显著增加（+1.3 ± 0.4），外视网膜核层厚度减少（-15.4 ± 1.6 μm）；两组 SCA 的口面运动评估均明显恶化。对于前共济失调和早期共济失调携带者，SCA2 中的口面运动和 SCA7 中的视网膜厚度是纵向恶化最严重的指标。
尽管样本量小的限制，我们在脑 MRI 成像、临床评分、步态参数和视网膜厚度方面检测到前共济失调和早期共济失调 SCA 个体的年度变化。这些参数可能作为未来前共济失调阶段治疗试验的潜在终点。
ClinicalTrials.gov NCT04288128。
