臺灣博碩士論文加值系統

內頸靜脈是一條腦靜脈回流的主要通道，因此異常的內頸靜脈構造或是血流狀況皆可能影響腦部靜脈回流異常，而造成腦部病變。越來越多的研究顯示內頸靜脈逆流和某些神經疾病有相關。但是目前依然缺乏證據證明內頸靜脈逆流會回傳靜脈壓力至腦部靜脈系統並且影響腦部循環。我的研究目標如下：(一)建立一個正常台灣人的內頸靜脈血流超音波參數之資料庫；(二)證明內頸靜脈逆流可以回傳靜脈壓力至腦部靜脈系統；(三)證明內頸靜脈逆流不但可以回傳靜脈壓力至腦部靜脈系統，還會進一步影響腦血流，導致腦血流下降；(四)內頸靜脈逆流與臨床疾病的相關性，提出內頸靜脈逆流與年紀相關的腦部白質病變之間相關的證據；(五)建立一個內頸靜脈逆流的動物模式。
雖然許多研究利用超音波發現內頸靜脈血流異常和某些神經疾病有相關性，但是目前還沒有一個大型正常人的內頸靜脈血流超音波參數之資料庫可供比較或是相關性的探討研究。我第一個研究是用一擬訂的超音波檢查流程與方法，來收集349位涵蓋各個年齡層正常成人的內頸靜脈血流超音波參數。這大型的資料庫除了可供未來臨床診斷或是研究臨床相關性參考外，還發現，隨著年齡上升，內頸靜脈血流的許多超音波參數顯示出內頸靜脈下游回流阻力上升。
視網膜循環是由腦部靜脈系統負責其靜脈回流。視網膜靜脈擴張通常代表著下游的靜脈壓力上升。在我第二個研究中，我發現在Valsalva maneuver所造成的內頸靜脈壓力上升會導致視網膜靜脈擴張，此外，有內頸靜脈逆流的人其視網膜靜脈擴張的程度較沒有內頸靜脈逆流的人較大。這個實驗成功證明了我其中一個假設，即內頸靜脈逆流會經由回傳靜脈壓力至腦部靜脈系統來影響腦部靜脈回流。第三個研究則進一步利用穿顱超音波，來觀察腦血流量在Valsalva maneuver時的改變是否會因為有否內頸靜脈逆流而有所不同。結果顯示內頸靜脈逆流會影響腦血流的假設是正確的，有內頸靜脈逆流的人其在Valsalva maneuver時腦血流的確較沒有內頸靜脈逆流的人低。
與年紀相關的腦部白質病變是老年人血管性失智與失能的一主要原因，即使有臨床的重要性，其病因目前仍未明。根據前面三個研究子題的結果與許多對於與年紀相關的腦部白質病變的相關研究，我提出了內頸靜脈逆流與此腦部白質病變的機轉有關的假設，並且進行了臨床研究。結果顯示有較嚴重內頸靜脈逆流的老年人，其腦部白質病變的嚴重度較高，尤其是在後腦區域。此外，這個相關性在越高齡的病患當中越顯著。
最後，為了往後可以更清楚明白長時間內頸靜脈逆流對於腦部的影響，我建立了一個內頸靜脈逆流的動物模式，並且探討了利用3D time-of-flight 核磁共振動脈攝影方法，應用在類似頸靜脈逆流動物模型手術成功與否的測試。
相較於腦動脈系統，腦靜脈系統的發展與已知的知識是遠遠落後的。這造成了我們遺漏或是低估了與腦靜脈回流異常有關的神經疾病，甚至許多重要但是機轉未明的神經疾病都和腦靜脈回流異常有關。我的研究結果首次提出證據證明內頸靜脈逆流可以回傳靜脈壓力至腦部靜脈系統，並且進一步影響腦血流，導致腦血流下降。這些結果將有助於釐清許多已發現和腦靜脈回流異常有相關的神經疾病其病理機轉，這當中包含了我們所發現相關的與年紀相關的腦部白質病變。

Internal jugular vein (IJV) is a main cerebral venous outflow tract, which abnormalities in structures and hemodynamics are presumed to impair cerebral venous drainage. More and more researches have found significant associations between jugular venous reflux (JVR) and neurological disorders. However, there still lacks evidences that JVR could influence cerebral circulation. The aims of my research are to: (1) elucidate the hemodynamics of IJV in Taiwan population; (2) proof that the retrogradely-transmitted venous pressure of JVR could reach cerebral venous system; (3) provide evidences that JVR has an influence in cerebral blood flow; (4) proof one of our hypotheses of a relationship between JVR and age-related white matter changes; and (5) establish an animal model which mimics the JVR phenomenon in human.
The first study has provided a normal reference set of IJV hemodynamic parameters derived from a large, healthy population over a wide range of age which, until now, has been lacking. Color-coded duplex ultrasonography was performed on the IJVs of 349 subjects. With increasing age, I have found increased lumen area, decreased flow velocities, and increased frequency of JVR in bilateral IJV of our population, which suggests increased IJV outflow impedance with aging.
Retinal circulation is drained by cerebral venous system. A dilated retinal venule usually indicates an elevated downstream venous pressure. In the second study, I have shown that elevated venous pressure in IJV during Valsalva maneuver would result in dilated retinal venules, and in individuals with JVR, the extent of retinal venules dilatation is more significant. These results provide the evidence that elevated venous pressure in IJV and JVR respectively could retrogradely transmit venous pressure into cerebral venous system. The third study used transcranial Doppler study to examine the cerebral blood flow changes during Valsalva maneuver in people with JVR. The results have shown that there was a more decrease in cerebral blood flow during Valsalva maneuver in people with JVR than people without JVR, which proof the hypothesis that JVR has an impact on cerebral blood flow.
Age-related white matter changes are one major cause of vascular dementia and disable in the elderly people, however, the etiology is still unclear. Based on my above findings of JVR and previous research results of age-related white matter changes, I proposed that JVR plays a role in the pathogenesis of age-related white matter changes. The clinical study showed people with severe JVR exhibit more severe age-related white matter changes, especially in caudal brain regions. I also demonstrate age-dependent JVR effects on the severity of age-related white matter changes.
Finally, I established an animal model which mimics JVR phenomenon in human. A resourceful validating method using 3D time-of-flight MRA for animal model with JVR has also been conferred in the present work. This animal model could be used to future studies on the effects of long-term JVR on cerebral parenchyma.
Compared with cerebral arterial system, the knowledge about the pathophysiology of cerebral venous system disorders is far falling behind. This might lead to an underestimation of neurological disorders caused by cerebral venous drainage insufficiency. My present researches could be contributive to elucidate the effects of JVR in cerebral circulation and its clinical implications. These results could shed lights on the pathophysiology of several unknown-etiology neurological disorders which have been found to be associated with cerebral venous drainage insufficiency.

1. Introduction
1.1. Background
1.1.1. Cerebral venous system
1.1.2. Cerebral venous blood drainage
1.1.3. Extracranial venous drainage pathway
1.1.4. Internal jugular vein
1.1.5. Jugular venous reflux
1.2. Jugular Venous Blood Flow Patterns in Taiwan Population
1.3. The Impacts of Jugular Venous Reflux on Cerebral Circulation
1.3.1. Cerebral venous hypertension in arteriovenous malformation and cerebral sinus-venous thrombosis
1.3.2. Would the retrograde-transmitted venous pressure by jugular venous reflux affect cerebral venous drainage?
1.3.3. Would jugular venous reflux decrease cerebral blood flow?
1.4. Hypothesis: Jugular Venous Reflux Plays a Role in the Pathogenesis of Age-related White Matter Changes
1.4.1. Age-related white matter changes
1.4.2. Pathology of venous ischemia and age-related white matter changes
1.4.3. Age and hypertension: predictors of age-related white matter changes
1.4.4. White matter abnormality and dementia in cerebral venous hypertension
1.4.5. Impaired cerebral endothelial function in age-related white matter changes and cerebral venous hypertension
1.4.6. Periventricular venule collagenosis: a reactive change to long-term cerebral venule hypertension
1.4.7. Summary
1.5. Animal Model of Jugular Venous Reflux

2. Materials and Methods
2.1. Jugular Venous Blood Flow Patterns in Taiwan Population
2.2. Jugular Venous Reflux and Cerebral Venous Drainage
2.3. Jugular Venous Reflux and Cerebral Blood Flow Changes
2.4. Jugular Venous Reflux and Age-related White Matter Changes
2.5. Animal Model of Jugular Venous Reflux

3. Results
3.1. Jugular Venous Blood Flow Patterns in Taiwan Population
3.2. Jugular Venous Reflux and Cerebral Venous Drainage
3.3. Jugular Venous Reflux and Cerebral Blood Flow Changes
3.4. Jugular Venous Reflux and Age-related White Matter Changes
3.5. Animal Model of Jugular Venous Reflux

4. Discussion
4.1. Increased Jugular Venous Drainage Impedance with Aging
4.2. Jugular Venous Reflux could Retrogradely Transmit Venous Pressure into Cerebral Circulation and Affect Cerebral Venous Drainage
4.3. Jugular Venous Reflux could Influence Cerebral Blood Flow
4.4. Elderly People with Severe Jugular Venous Reflux have More Severe Age-related White Matter Changes
4.5. Establishment of an Animal Model of Jugular Venous Reflux and the Validation Method

5. Conclusion and Perspectives

6. References

7. Figures

8. Tables

9. Appendix

10. Publications

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