肌少症與力弱症於體顯性腦動脈血管病變合併皮質下腦梗塞及腦白質病變病人的盛行率與相關因子

Prevalence and Associated Factors of Sarcopenia and Dynapenia in Patients with CADASIL

呂旻益(Min-Yi Lu)

指導教授 ： 湯頌君

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2022年)

https://doi.org/10.6342/NTU202203603

摘要

背景：
腦部小血管疾病 (Cerebral small vessel disease (CSVD)) 是一種影響大腦內小血管的疾病，通常為直徑小於 1 毫米的血管。 CSVD佔所有腦中風原因的20~30%，也是40~50%失智症的原因。體顯性腦動脈血管病變合併皮質下腦梗塞及腦白質病變「Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)」是CSVD最常見的單一基因突變疾病，由NOTCH3基因突變引起。然而除了基因以外，哪些因素促成了疾病表現的嚴重性仍然未知。另一方面，肌少症(sarcopenia)是一種退化過程，其特徵是肌肉總量減少和肌肉力量下降，力弱症(dynapenia)這一名詞則用於描述減少肌肉力量而不損失肌肉總量的情形。肌肉總量或力量下降都會導致生活品質受損。肌少症或力弱症與 CSVD 之間的關係仍不清楚。在本研究中，我們探討了肌少症或力弱症與 CSVD 之間的關係。我們比較了 CADASIL 組和非基因 CSVD 組，以研究NOTCH3 基因突變是否與肌少症或力弱症有關。
方法：
我們收錄了符合臨床表現和腦部 MRI 診斷的 CSVD 患者，並安排 NOTCH3基因分析，依據結果分成CADASIL組及非基因CSVD組。另有收非CSVD 對照組，其組成為參加台大健康管理中心健康檢查的顧客。 非基因CSVD組和CADASIL組均有測量握力、5 次椅子站坐測試和步行速度，以及腦部 MRI和病例數據。在非CSVD 對照組、非基因CSVD組、和CADASIL組中，我們通過生物電阻抗分析 (BIA) 評估了附肢骨骼肌 (ASM)數據。另外ASM除上身高的平方變成附肢骨骼肌肉總量指數(appendicular skeletal muscle mass index(ASMI))
結果：
本實驗篩選了101 名CADASIL 患者和378名非基因 CSVD患者，在去除無參與研究意願和缺少腦部影像數據或肌肉功能數據後各剩下61位和62位，另外還有45位非CSVD 對照組。ASM和ASMI在 CADASIL、非基因 CSVD 和非CSVD 對照組之間沒有顯著差異。非基因CSVD組和CADASIL組相比，初始臨床表現(P：0.02)和腦部白質病變之Fazekas評分(P<0.01)存在差異。通過對年齡、性別、初始臨床表現進行調整的邏輯回歸分析，CADASIL 組患者的 5 次椅子站坐測試顯著延長(OR：1.05(1.01-1.11)；P=0.04)。在 CADASIL 患者中，強健(Robust，無肌少症和無肌無力)和非強健病人的次分析上可見，年齡(67.9 ±7.81 vs. 58.2 ±10.00；P<0.001)和腔隙(lacune)數量(4.57 ±3.81 vs.2.61 ±3.33；P=0.04)是顯著不同的，但調整年齡和性別後未發現具體差別。
結論：
CADASIL 相較非基因 CSVD 組在握力、5次椅子站坐測試延長、4米步行試驗(m/sec)的步行速度(m/sec)中有較差的趨勢。調整了年齡、性別和臨床表現後CADASIL 組患者的 5 次椅子站坐測試顯著延長。這結果對未來CADASIL的研究方向，及臨床治療提供了方向。

關鍵字

肌少症 ； 力弱症 ； 體顯性腦動脈血管病變合併皮質下腦梗塞及腦白質病變 ； 相關因子

並列摘要

Background:
Cerebral small vessel disease (CSVD) is a heterogenous group of disease which primarily affects small vessels in the brain. The disease burden of CSVD is huge, constituting up to 20~30% of stroke and 40~50% of dementia. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary form of CSVD, which is caused by mutation of the NOTCH3 gene. However, what factors contribute to the disease manifestation are still unknown. On the other hand, sarcopenia is a degenerative process characterized by loss of muscle mass and decreasing muscle strength. Besides, dynapenia is used for decreasing muscle strength without loss of muscle mass. The relationship between CSVD and sarcopenia or dynapenia is still unclear. In this proposal, we explored the relationship between sarcopenia or dynapenia and CSVD, with special focus on the genetic form of CSVD. We compared the CADASIL group and non-genetic CSVD group to investigate whether sarcopenia or dynapenia is associated with the NOTCH3 gene mutation.
Methods:
Patients with clinical features and brain MRI suggestive of CSVD were recruited and NOTCH3 genetic analysis were performed on them. Patients who had detectable NOTCH3 mutation were assigned to the CADASIL group, while those with no NOTCH3 mutation were in the non-genetic CSVD group. Besides, a non-CSVD control group were recruited from the National Taiwan University Hospital Health Management Center. Both the CADASIL and non-genetic CSVD groups received the handgrip strength test, 5-time chair standing test, and walking speed test. All three groups also received the bioelectrical impedance analysis (BIA) for the appendicular skeletal muscle mass, and the appendicular skeletal mass index (ASMI) was calculated by dividing the appendicular skeletal mass with their height (ASM/m2). Features of CSVD on brain MRI were assessed and recorded.
Result:
We identified 101 CADASIL patients and 378 non-genetic CSVD patients. After excluding patients who did not provide consents, had no available brain MRI studies, or were unable to finish all muscle function tests (handgrip strength, 5-time chair standing test, and walking speed), 61 patients and 62 patients were finally included. Besides, 45 participants were recruited in the non-CSVD control group. There were no significant differences of ASMI　between the CADASIL, non-genetic CSVD, and non-CSVD control groups. The initial clinical presentation (P=0.02) and Fazekas scores of the white matter hyperintensity (P<0.01) were different between the CADASIL and non-genetic CSVD groups. The 5-time chair stand test was significant prolonged (OR: 1.05 (1.01- 1.11); P=0.04) in the CADASIL group compared to the non-genetic CSVD group after adjustment with age, sex, and initial clinical presentation. In the subgroup analysis of the CADASIL patients, age (67.9 ±7.81 vs. 58.2 ±10.00; P<0.001) and lacunar number (4.57 ±3.81 vs. 2.61 ±3.33; P=0.04) were different between the robust (no sarcopenia and no dynapenia) and no-robust patients; however, the difference became non-significant after adjustment for age and sex.
Conclusion:
CADASIL group had worse performance of handgrip strength, 5-time chair standing test, and walking speed comparing to non-genetic CSVD group. After adjustment of age, gender, initial clinical presentation, regression analyses showed significant prolonged of 5-time chair stand test in CADASIL group. It may suggest, NOTCH3 mutation still cause deterioration of muscle function. It may give some hints for further treatment of CADASIL patient.

並列關鍵字

Sarcopenia ； Dynapenia ； CADASIL ； Cerebral small vessel disease ； Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

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