建立以非侵入性神經影像技術為基礎之大腦血流循環指標

Abstract

腦循環系統是維持大腦正常功能重要的機制，其機制涉及到血氧與營養代謝運送以及廢物清除。腦循環系統中，血管自我調節與血管反應的兩大特性，在維持腦血流之穩定供應扮演重要的角色。先前研究指出為了滿足大腦神經活化時的能量需求，調控血管擴張及局部腦血流增加以輸送氧氣與葡萄糖，此一連串反應機制稱之為神經血管耦合。當神經血管耦合機制出現問題，可導致腦循環末梢小血管血流不足，可能會造成局部腦神經的損傷，進而造成認知功能衰退、微小血管疾病、甚至中風。因此，如何透過非侵入性神經影樣技術，去建立可靠的腦血流相關生物指標，以提供個體大腦神經血管健康資訊，對於探討大腦老化機制及高齡相關神經疾病之早期偵測與介入至為重要。因此，本論文著重於發展兩種量測分析技術以觀察個體大腦神經血流變化，內容包含：1) 運用具有高時間解析度特性的近紅外光譜儀量測，探討高齡長者於執行認知測驗時之大腦局部動態血氧濃度變化; 2) 透過具有高空間解析度特性的功能性磁振造影儀，從中萃取動靜脈血流傳輸時間等相關參數，探討微小血管異常族群之血流變化及其與疾病嚴重度之相關性。 目標一，為了探究在執行認知功能任務時，年齡相關因素是否造成個體神經血流變化，我們運用近紅外光譜儀於個體前額葉區域，分別針對年輕族群與高齡族群，進行血氧相依濃度訊號量測。此研究在認知測驗結果顯示，年輕族群相較於高齡族群，在測驗完成度與反應速度表現上顯著較好，測驗錯誤率較低。在近紅外光譜儀量測結果顯示，進行認知測驗時高齡族群的血氧濃度相對於年輕族群較低，血氧濃度趨勢呈現較緩慢且平穩上升。 目標二，為了探究微小血管病變與腦血流變化之潛在關係，我們運用靜息態功能性磁振造影影像，萃取系統性低頻振幅訊號，搭配時間序列交錯分析演算法，建立健康高齡族群與微小血管異常族群之動靜脈血液穿流時間等指標。此研究證實血液穿流時間指標會隨著年齡增長而增加，並在控制年齡效應後，與白質損傷體積存在顯著正相關之關係。此外，我們發現相較於健康高齡族群，微小血管異常族群其血液穿流時間較長，並且會隨著疾病嚴重程度，呈現了劑量效應的上升趨勢。 總結而論，本論文運用近紅外光譜儀與功能性磁振造影儀，兩種在時間空間維度具有互補資訊的非侵入性神經影像量測技術，所建立的血氧濃度及血流變化訊號，來反應個體大腦老化中的認知表現以及透過於微小血管疾病之應用驗證其臨床可行性。因此，透過此系列研究成果，提供多元的量測技術，以反應個體大腦神經血管健康程度，並作為未來神經及血管相關疾病之血流生物標誌。

Cerebral circulation involves the transport of blood oxygen and nutrients, waste removal, and nutrient metabolism. Maintaining a stable supply of cerebral blood flow depends on vascular autoregulation and vasoreactivity in the cerebral circulatory system. Past studies have indicated that neurovascular coupling occurs to assemble the energy demands of brain nerve activation, regulate blood vessel dilation, and increase cerebral blood flow to transport oxygen and glucose. Earlier studies have indicated that in order to meet the energy needs of the brain during neural activation, the regulation of blood vessel expansion and local brain blood flow increase to transport oxygen and glucose is called the neural vascular coupling mechanism. When the neural vascular coupling mechanism is impaired, it can lead to insufficient blood flow in the terminal small blood vessels of the brain circulation, which may cause damage to local brain nerves, leading to cognitive decline, small vessel disease, and even stroke. Therefore, for exploring the mechanism of brain aging and early detection and intervention of age-related neurological diseases, how to develop reliable brain blood flow-related biomarkers using non-invasive neuroimaging techniques to provide individual brain neurovascular health information is crucial. The purpose of this dissertation was to develop techniques for observing the blood flow changes of individual brain regions, including (1) using a near-infrared spectrometer with high time resolution to measure and explore the brain's hemodynamics dynamic change when elderly individuals perform cognitive tests; (2) using functional magnetic resonance imaging with a high spatial resolution to extract the relevant parameters of arterial and venous transit time, to examine changes in blood flow of cerebral small vessel disease and its relationship with disease severity. In Aim 1, to investigate whether age caused individual neurovascular changes, we used near-infrared spectroscopy to measure the concentration change of hemoglobin in the frontal lobe region of young and elderly populations. According to the results of this study, the younger group performed significantly better than the elderly group on the cognitive test in terms of test completion and reaction speed. In addition, the younger group had a lower error rate during the trial. During the cognitive test, the blood oxygen concentration of the elderly group was lower than that of the younger group. The trend of oxyhemoglobin concentrations was slowly and steadily rising. In Aim 2, for examining the potential association between microvascular lesions and cerebral blood flow changes, we used resting-state functional magnetic resonance imaging to extract systematic low-frequency oscillation signals and further applied cross-correlation analysis to estimate the individual vascular relevant parameters (arterial and venous transit time) in healthy aging and cerebral small vessel disease populations. The result revealed that the transit time increased with age. In addition, after controlling this age effect, there still was a significant positive correlation between the transit time and white matter lesions volume. Furthermore, compared to the healthy elderly group, the transit time was longer in the cerebral small vessel disease group, and the alteration showed the dose-effect increasing tread with the disease severity. In summary, this dissertation utilized near-infrared spectroscopy and functional magnetic resonance imaging, two non-invasive neuroimaging measurement techniques with complementary information in temporal and spatial dimensions, to establish oxygen concentration and cerebral brain flow indices that reflected individual cognitive performance in the aging process and validated the clinical feasibility in cerebral small vessel disease. Therefore, based on these study results, we provided multiple measurement techniques that reflected individual neurovascular healthy and might serve as potential biomarkers for neurological and vascular-related diseases in the future.