摘要:腦中的類澱粉斑塊沉積和神經纖維纏結是阿滋海默型失智症的病理特徵,會進一步造成神經細胞的過氧化壓力和細胞凋亡。研究發現在某些輕度知能障礙的病人,早期即可由正子攝影發現腦中的類澱粉開始不正常堆積的情形。然而,近年發現有一群人雖然藉由死後病理解剖發現腦中類澱粉的堆積,但終生並發生智能退化的情形。另一方面,神經纖維纏結被認為主要從顳葉內側開始出現並往新大腦皮質擴散堆積,類似普里昂蛋白質的表現,部分研究者認為神經纖維纏結病變與認知缺損更為息息相關。近年來,藉由功能性核磁造影技術的演進,科學家發現許多不同的大腦網絡在不同認知運作或外界刺激的環境下有著不同的活性與相互動態變化。其中,預設模式網絡被認為在阿滋海默症病人已發現網內連結的減退,但在輕度認知障礙的病人卻結果不一。然而,前顳葉網絡由早期神經纖維纏結堆積的腦區所構成,其連結強度與認知功能的關聯性並不清楚。研究目的本實驗預計評估功能性核磁造影下的兩種靜止態大腦網絡連結:預設模式網絡與前顳葉網絡,其兩者與記憶功能的相關性。並觀察在腦中有類澱粉蛋白沈積的主觀記憶衰退受試者的大腦網絡變化,是否具有代償作用?以及大腦神經纖維破壞是否會造成大腦網絡模式功能的降低和認知功能惡化。研究方法預計收集主觀記憶衰退與輕度知能障礙的個案個各20 名,再依照類澱粉造影的有無分成四組,並進行ApoE 基因定序。受試者預計進行人為神經心理測驗及電腦化評測、功能性核磁造影和彌散張量成像。而後,對於兩種靜止態大腦網絡連結及神經纖維結構強度進行組間比較,並分析兩種網絡連結強度與非情境脈絡記憶的相關性,構成預設模式網絡的神經纖維結構強度與功能強度的相關性。並在第三年度對受試者再進行認知評估,比較疾病進展組和非進展組在收案時的兩種大腦網絡功能強度與神經纖維結構強度的不同。並進行第二次功能性核磁造影,比較在疾病發生後的兩種大腦網絡變化。預期結果我們預期在腦中有類澱粉蛋白沈積的主觀記憶衰退受試者的預設模式網絡會有代償性的連結增強,前顳葉網絡及部分神經纖維結構的連結強度在輕度知能障礙的個案可能減退,疾病進展組在未發病前的預設模式網絡及其構成的神經纖維結構強度比起非進展組較弱,但在這群人裡,認知功能的減退與前顳葉網絡的連結強度衰退較為相關。
Abstract: BackgroundAmyloid plaque deposition precedes neurodegeneration in Alzheimer’s disease. However, the presence ofamyloid deposition does not definite mean further cognitive deterioration in the future. In opposite point ofview, cognitive performance is more related to the development of neurofibrillary tangles (NFT) in AD brainas well the atrophic pattern. Alternations of large, scale, resting state network (RSN) have been investigatedwidely in neurodegeneration disease. One of them is the default mode network (DMN), brain hubsunderlying DMN showed earliest amyloid brain deposition. The DMN activity in amnesic mild cognitiveimpairment (aMCI) is controversial. In opposite, NFT is initially developed in subregions of mesial temporallobe, mainly peri/entorhinal cortex, uncus, and head of hippocampal formation, composing anterior temporalnetwork (ATN). The relationship of ATN functional study and earliest as well as long-term cognitive changesare not well clarified.ObjectTherefore, we want to explore which surrogate marker (ATN or DMN) is related to clinical performance andfurther cognitive decline accurately. In addition, whether there is compensated effect of which functionalconnectivity at preclinical stage (brain with amyloid deposition), acting as a protecting effect. Last, we wantto know whether brain white matter microstructural change (neuron synapse damage) finally leads tofunctional decompensate, warning for clinical cognitive decline.MethodWe will include subjects of aMCI, and subjective cognitive decline (SCD), matched with education, sex andage. Participants will further divided in to subgroups on the basis of PiB positivity. They will receive ApoE4genotyping, and complete neuropsychology batteries including: Word Sequence Learning test, family picturenaming and computerized cognition assessment and so on. Then, subject will undergo brain MRI studies forfunctional network connectivity of DMN and ATN; diffuse tensor image (DTI) for structural connectivity offocused association fibers connecting hubs of DMN. First, we will conduct statistical analysis to performgroup comparison and correlation study between 1. functional connectivity (FC) and NPT performance, 2. FCand structural connectivity (SC). After a 2 years follow-up, we will compare the baseline FC and SC of clinicalconverter (ex: SCD to aMCI or aMCI to AD) versus non-converters and which most surrogate markers (DMN,ATN) change shows most contribution in cognition decline.Expected outcomeWe expect that increased FC of DMN will be shown in SCD with brain amyloid deposition. In MCI subject,the ATN connectivity as well as structural connectivity is decreased comparing to SCD at baseline. Afterfollow-up, we expect converters would show less DMN connectivity strength and more disrupted whitematter microstructure at baseline. But it’s the temporally decreased ATN connectivity contributing to inclinical status conversion.