Abstract
摘要:家族性澱粉樣多發性神經病變 (familial amyloid polyneuropathy,簡稱「類澱粉神經病變」)是因轉運蛋白(transthyretin)突變造成的神經退化疾病。在台灣,類澱粉神經病變是原發性周邊神經退化疾病(idiopathic neuropathy)中最常見、重要的病因。儘管類澱粉神經病變臨床表現 (包括運動,感覺和自主神經缺失)都已經有廣泛描述,仍然有一個關鍵的症狀與未解決的研究議題,即是「神經退化導致神經痛的機制與生物標記」。神經損傷會引起神經發炎,包括巨噬細胞的浸潤,而發炎細胞產生的細胞激素會惡化神經損傷並加重神經性疼痛。這些議題過去僅見於實驗動物系統,以機械性損傷所造成之神經痛探討,只有少數人類神經病變的觀察意味著神經退化伴隨神經發炎的可能性,類澱粉神經病變對於這一現象的研究,更是闕如。類澱粉神經病變一向被認為是周邊神經系統的疾病,近年來有些觀察,意味著腦部也可能受到影響,這些包括:(1)於類澱粉神經病變患者,腦膜血管及大腦表淺層皮質有類澱粉沈積,(2)對於接受肝臟移植病人的臨床分析,類澱粉神經病變患者比一般人有較高的中樞神經功能缺損。我們先前的研究顯示,在糖尿病神經病變患者,其大腦激活模式與正常人有所不同。這些觀察意味著類澱粉神經病變很可能不全然只有周邊神經退化,但是類澱粉神經病變對於「中樞神經系統可能的改變」這一主題一直缺少系統性地研究。這一研究計畫,將探討類澱粉神經病變的(1)周邊神經發炎以及(2)大腦神經影像的變化。在第一年,我們將研究神經之發炎細胞的浸潤以及熱誘發之功能性磁振造影。在第二年,這一計畫將檢查發炎分子於神經之表達以及的靜息態功能性磁振造影。預期這一計畫的研究結果應為評估神經退化引起的神經性疼痛的機制與生物標記,並提供治療策略的新方向。
Abstract: Familial amyloid polyneuropathy (amyloid neuropathy) is a neurodegenerative disease with transthyretin asthe major molecular aggregates. In Taiwan, amyloid neuropathy serves as the most important etiology ofidiopathic peripheral nerve degenerative disorder. Despite extensive descriptions of clinical presentationsincluding motor, sensory, and autonomic involvement, a critical issue is the identification of signaturesreflecting degeneration-related phenotypes. Among the clinical manifestations, small fiber pathologyresulting in sensory symptoms is the predominant neurologic deficit at the early stage and through theentire natural course.Nerve injury induces neuroinflammtion, such as infiltration of macrophages. Cytokines produced byinflammatory cells serve as molecular mediators of nerve injury and consequent neuropathic pain. Theseissues are usually studied in experimental animal systems of mechanical injury. Only limited studies haveimplied the existence of inflammation at the neuronal cell body level of amyloid neuropathy. Amyloids oftransthyretin aggregates were detected in the brain of amyloid neuropathy patients from meningealvasculature to superficial cortical parenchyma. Focal neurological deficits were detected in ~31% ofamyloid neuropathy patients receiving liver transplantation, much higher than the general population.Furthermore, we have demonstrated that the patterns of brain activations were altered after peripheral nervedegeneration in diabetic neuropathy. Taken together, these observations provide foundations to ask whetherthere will be alterations of brain structures and functional imaging in patients with amyloid neuropathy, adisease traditionally considered to be a peripheral nerve disorder. We hypothesize that both peripheral nerveinflammation and plastic changes in the brain may underlie the manifestations of neuropathic pain but theseissues have not yet systematically examined. This 2-year proposal will investigated these topics from thedimensions of peripheral nerves and brain to formulate an integrated view of small fiber pathology inamyloid neuropathy. During the first year, we will examine the infiltration of inflammatory cells inperipheral nerves and heat-activated functional MRI of the brain. In Year 2, this proposal will examine theexpression of proinflammtory molecules in peripheral nerves and resting-state functional MRI of the brainto build up signatures of nerve degeneration and neuropathic pain in peripheral nerves and the brain in theneural axis. The results of this proposal should provide new insights for assessing degeneration-inducedneuropathic pain and designing new therapeutic strategies in amyloid neuropathy.
Keyword(s)
類澱粉神經病變
甲狀腺素轉運蛋白
神經退化
發炎
磁振造影
amyloid neuropathy
transthyretin
nerve degeneration
neuroinflammation
magnetic resonance
imaging