大腦灰質與功能網絡在自覺認知衰退個體的改變

Abstract

研究背景 阿茲海默症目前仍然被認為是一種不可逆的神經退化疾病，近年來因生物標記的發展，我們對於它的研究也從失智症時期漸漸往前推展到臨床前期。除此之外，近年發現有一群人即使認知功能表現為正常，但卻自我感覺認知或記憶功能比起以往有下降的情形，這些人往後發展成為阿茲海默失智症或輕度認知障礙的比例較高。目前研究發現部分自覺認知衰退情形的確是阿滋海默症臨床前期的表現之一。阿茲海默症是一種不正常蛋白質堆積所導致的細胞凋亡過程：神經纖維纏結以及類澱粉蛋白為主要病理特性。本實驗目的在以研究自覺認知衰退個案，利用這兩種不正常蛋白質在腦中分佈的區域不同，探討其大腦皮質厚度，結構以及功能性連結的極早其變化，以及細微記憶成份的改變。另希望藉由大腦網絡的觀點找出自覺記憶衰退記性退化的解釋。 研究方法 本研究分做兩大部分：第一部分為大腦結構性（包含皮質厚度以及結構性連結）在自覺認知衰退的個案的變化，包含了34個正常受試者，43個來自門診的自主認知下降個案，以及44個輕度認知障礙的個案。第二部分為大腦功能性連結以及大腦網絡的探討，包含了25個正常受試者，27個來自社區的自覺認知衰退的個案，12個來自門診的自覺認知衰退的個案，以及32個輕度認知障礙的個案。在神經心理測驗方面，我們分別利用魏氏記憶量表第三版中家庭圖片改良版以及邏輯記憶，兩個子測驗和腦部結構及功能性連結的相關性，來探討自覺認知衰退個案的極早期記憶缺損特徵。因此其他研究工具即包含了高解析度T1-weighted腦部核磁造影以及靜息態功能性核磁造影。 研究結果 在我們的第一個研究發現，自覺認知衰退的個案在兩側顳葉內側包含：parahippocampal cortex、 perirhinal、entorhinal cortex 的皮質厚度已顯著減少；另外，大腦白質的神經纖維束則在雙側鉤束(uncinate fasciculi)的非等向性指標(fraction anisotropy, FA)下降。在第二個功能性連結的研究部分，結果顯示自主認知下降個案的大腦預設模式(default mode network)網絡以及警覺網絡(salience network)的網絡內功能性連結皆下降，但位於警覺網絡的雙側腦島(insula)與大腦預設模式網絡的功能性連結則顯著增強，且此現象和腦島在警覺網絡內的連結呈負相關; 另外，旁海馬迴系統的網絡內功能性連結也有中度增強的情形。最後，我們發現自覺認知衰退個案的大腦結構性改變大多與情境相關記憶有關; 而功能性連結的網絡變化在本階段並未看到與記憶表現相關。 結論 自覺認知衰退個案在雙側顳葉內側皮質厚度減少和早期神經纖維纏結出現的位置一致，而在此區功能性連結相對增強，或可視為代償機制。另外，大腦預設模式網絡：即為早期類澱粉蛋白沈積位置，其功能性連結下降。腦島為大腦警覺網絡的重要腦區，其和大腦預設模式的連結增強，我們推測和「自覺認知衰退」的「警訊」相關。藉由這些影像變化，我們推論神經纖維纏結直接造成大腦皮質神經元的凋亡，而類澱粉蛋白主要造成神經突觸的功能下降。

Background Alzheimer’s disease (AD) is considered a continuity that progresses from the pre-clinical stage to dementia. While people with subjective cognitive decline (SCD) have normal cognitive performance, some may be in the pre-clinical stage of AD. Neurofibrillary tangles (NFT) appear first in the transentorhinal cortex, followed by the entorhinal cortex in the clinically silent stage of AD. Our research rationale was that subtle but measurable structural as well as functional connectivity (FC) changes are present in the vulnerable brain areas subjects to AD pathology in individuals with SCD. Methods In cohort A, we recruited 43 subjects with spontaneous SCD (sSCD), 44 subjects with amnesic mild cognitive impairment (aMCI), and 34 normal controls (NC) without memory complaints from neurology and memory clinics; in this cohort, we perform structural analysis. In cohort B, there were 27 subjects with SCD on request (rSCD) and 25 NC from community, 12 sSCD from neurology and memory clinic, and 32 aMCI from both community and clinic, to investigate functional connectivity. Magnetic T1 weighted resonance images were used to assess cortical thickness and subcortical gray matter volume, diffusion tensor images were used to assess white matter tract integrity and resting state functional images were used to analyze FC. In cohort A we used the modified Family Picture subtest of the Wechsler Memory Scale-III, examining the performance of episodic memory subcomponents to assess neural correlates of structure and structural connectivity. In cohort B we used Logical Memory to assess neural correlates of functional connectivity. Results Our results demonstrated that subjects with sSCD showed significant cortical thinning in their medial temporal subfields, including the bilateral parahippocampal, perirhinal and entorhinal cortices, but not in their hippocampal regions. sSCD subjects also exhibited significantly decreased mean fractional anisotropy in their bilateral uncinate fasciculi. However, the functional connectivity of sSCD within the ventral default mode network (vDMN) and salience network (SAL) were both decreased whereas the FC between bilateral anterior insula (AI) and DMN were increased. Lastly, the FC intra-PHC was slightly increased. Conclusion The diminution of cortical thickness as well as hyper-connectivity in PHC corresponding to brain areas with early NFT deposition may represent a cognitive reserve in the clinically silent SCD stage. For the structures showing early diminution: parahippocampal and perirhinal cortices contribute to visual context association memory. On the other hand, brain regions with early amyloid deposition overlapping vDMN shows hypo-connectivity change. In addition, the interplay between bilateral AI to DMN is closely related to its intra-SAL FC, which, we assume may contribute to neural mechanism underpinning enhanced subjective feeling of cognitive deficit. Lastly, we propose a possible pathological attribute that neurofibrillary tangles result in direct neuronal loss while the amyloid beta mediate synaptic dysfunction