皮質下缺血疾病與阿茲海默症患者之神經血管耦合 暨血清維生素B12及葉酸濃度關聯性

Abstract

研究背景：神經血管耦合(neurovascular coupling; NVC) 對人類大腦具有重要功能。然而，失智症患者的神經血管耦合的機轉因子仍有待探討。我們因此針對以下兩點進行本研究：(一)運用腦血流(cerebral blood flow; CBF)與白質變化(white matter hyperintensities; WMHs)做為神經血管耦合因子之於認知功能的影響；(二)檢視上述神經血管耦合是否將隨失智症病程、亞型、及營養狀態而改變。

研究材料與方法：本研究招募皮質下缺血疾病患者(subcortical ischemic vascular disease; SIVD)、阿茲海默症患者(Alzheimer's disease; AD)、及認知功能正常受試者。以上個案均接受認知功能評估暨多模式腦部磁振造影檢查(magnetic resonance imaging; MRI) (含擬連續動脈自旋標記及擴散張量造影)。病患族群額外接受血清檢驗：包含維生素B12 (cobalamin; Cbl)、葉酸、及同半胱胺酸(homocysteine; Hcy)。在實驗一，我們比較組間磁振造影測量之腦血流及白質變化指標差異，並分析這些指標預測認知分數的效力。接著，經由「腦血流―白質變化」呈現神經血管耦合指標，依照失智症病程及亞型予以拓撲特徵描述。在實驗二，腦血流及白質變化容積分別依維生素B12、葉酸、及同半胱胺酸濃度三分位數分群進行組間比較，並依淨相關分析建立腦血流/白質變化與維生素B12/葉酸/同半胱胺酸關聯性。承接上述結果，我們聚焦於「額葉―皮質下迴路」，進一步檢視維生素B12/葉酸/同半胱胺酸對於腦血流以及白質(white matter; WM)微小結構參數的關聯。

結果：在實驗一，額葉與基底核(basal ganglia ;BG)的白質變化分別對於整體認知功能及執行功能有微顯著效應。同樣區域的腦血流則對於整體認知功能、記憶力、及(某種程度的)專注力/執行功能有更顯著的影響。結合白質變化與腦血流指標可達到最佳的認知可解釋變異。失智症亞型組間比較顯示：相較於其他組別，皮質下缺血疾病組呈現額顳葉腦血流指標低下；這跟該類型患者具有較高的白質變化及較嚴重的執行功能/專注力缺損相符合。此外，皮質下缺血疾病組的神經血管耦合拓撲特徵顯示：額顳葉的白質變化與雙側視丘的腦血流在失智症初期【臨床失智症量表(Clinical Dementia Rating; CDR = 0.5)】相關：而基底核的白質變化則與額顳葉的腦血流在失智症較後期【臨床失智症量表= 1-2】相關。阿茲海默症組亦呈現類似的「皮質―皮質下」腦血流耦合，但耦合區域較皮質下缺血疾病組少。在實驗二，失智症患者整體分析顯示：維生素B12及葉酸血清濃度的上升與區域性腦血流增加有關，而同半胱胺酸血清濃度上升與白質變化容積增加有關。失智症亞型組間分析顯示：皮質下缺血疾病組比阿茲海默症組的腦血流與維生素B12/葉酸呈現出更顯著的相關性；其中維生素B12相關腦區範圍廣泛，而葉酸相關腦區範圍較侷限。值得注意的是，皮質下缺血疾病組於雙側「內側前額葉皮質―基底核」迴路呈現腦血流交互作用；無論是否考慮同半胱胺酸濃度，該「額葉―皮質下迴路」腦血流耦合均為維生素B12所調控。而葉酸/同半胱胺酸血清濃度，則與在該「額葉―皮質下迴路」內的白質纖維之軸向及徑向擴散指標分別呈現負/正相關。

討論：在實驗一，我們呈現統合腦血流與白質變化指標做為神經血管耦合的適當性：腦血流與白質變化對於認知功能各有獨特貢獻。我們詳細記載了隨失智症病程而變化的腦血流。皮質下缺血疾病組及阿茲海默症組均呈現右側額顳葉腦血流低下(即腦血流偏側化現象)：其中，皮質下缺血疾病組右側額葉腦血流下降現象比阿茲海默症組更早期發生。統合「腦血流―白質變化」反應之「皮質―皮質下」神經血管耦合觀察顯示：皮質下缺血疾病組比阿茲海默症組有更寬廣的腦區影響。這呼應了皮質下缺血疾病患者的「皮質―皮質下」迴路存在著重要的致病機轉。在實驗二，我們藉由區分失智症患者維生素B12/葉酸/同半胱胺酸相關之神經血管耦合，進一步延伸了解這些維生素暨代謝物的神經生化效應。維生素B12/葉酸主要與腦血流有關，而同半胱胺酸只跟白質變化有關。神經血管耦合關聯性因失智症亞型而改變：「維生素B12―腦血流」的神經滋養效應以及「同半胱胺酸―白質完整性」的神經毒害效應主要存在於皮質下缺血疾病組，「葉酸―白質完整性」的神經滋養效應以及「葉酸―腦血流」的矛盾效應則存在於皮質下缺血疾病組及阿茲海默症組。藉由神經血管耦合的概念，維生素B12於皮質下缺血疾病組「額葉―皮質下迴路」的調節作用以及「葉酸/同半胱胺酸―白質完整性」的關聯分析延伸了該研究領域既有發現。葉酸/同半胱胺酸與擴散指標的關聯性代表著軸突與髓鞘的微小結構改變。

結論：統合腦血流與白質變化指標做為神經血管耦合是一個具有潛力的生物標記；相關臨床運用包含其認知功能關聯性及鑑別診斷。雖然皮質下缺血疾病及阿茲海默症患者均呈現「皮質―皮質下」神經血管耦合特徵(其中「皮質白質變化―皮質下腦血流」耦合將早於「皮質下白質變化―皮質腦血流」耦合)。但是相較於阿茲海默症，失智症早期右側額葉腦血流下降以及隨失智症病程呈現較廣泛的「皮質―皮質下」神經血管耦合皆暗示皮質下缺血疾病的可能性。。另外，維生素B12/葉酸/同半胱胺酸各自對應之神經血管耦合關聯因子會隨失智症亞型有所變化。本研究結果可協助評估維生素B12/葉酸於失智症患者相關治療效益、劑量、及追蹤。

Background: Neurovascular coupling (NVC) plays a critical role in human brain functioning. However, the mechanistic determinants of NCV among dementia patients remain largely unknown. The current research therefore aimed to (i) investigate the effect of factors related to NCV including cerebral blood flow (CBF) and white matter hyperintensities (WMHs) on cognition, and (ii) test the hypothesis that NCV varies by dementia stage, dementia subtype, and nutritional status.

Materials and Methods: This study recruited patients with subcortical ischemic vascular disease (SIVD), patients with Alzheimer's disease (AD), and cognitively normal subjects. All participants underwent cognitive assessments and multimodal brain magnetic resonance imaging (MRI) including pseudo-continuous arterial spin-labelling and diffusion tensor imaging. Serum samples were obtained from the patient groups to measure the values of cobalamin (Cbl), folate, and homocysteine (Hcy). In Experiment I, the MRI-based CBF and WMH metrics were compared by groups and then analyzed as predictors of cognitive scores. The NVC reflected by CBF-WMH coupling was topologically characterized by the dementia stage and subtype. In Experiment II, CBF and WMH volumes were compared among the tertile groups separately defined by Cbl, folate, and Hcy. Partial correlations were analyzed between CBF/WMHs and Cbl/folate/Hcy. Within the frontal-subcortical circuits, the moderation effects of Cbl/folate/Hcy on CBF and their correlations with white matter (WM) microstructural indices were examined.

Results: In Experiment I, WMHs within the frontal and basal ganglia (BG) regions had marginal effects on global cognition and executive function, respectively. CBF within the same regions had a more noticeable effect on global cognition, memory, and attention/executive function to a certain degree. Combining WMH and CBF metrics yielded the best explanatory variance for cognition. CBF metrics by dementia subtype revealed a picture showing decreased CBF within the frontotemporal regions in the SIVD group, which was consistent with the greater WMHs and executive/attention deficits compared to the other two groups. The topological evolution of NVC in the SIVD group showed that WMHs in frontotemporal areas were correlated with CBF in bilateral thalami at an earlier stage (Clinical Dementia Rating; CDR = 0.5), followed by the correlations between WMHs in BG areas and CBF in frontotemporal areas at a later stage (CDR = 1 or 2). Similar corticosubcortical coupling was observed in the AD group, however, the coupling involved fewer areas. In Experiment II, increased serum levels of Cbl and folate were associated with higher CBF, while an increased serum level of Hcy was associated with greater WMH volumes in both the SIVD and AD groups. When dementia subtypes were considered, more noticeable CBF correlations (spatially pervasive with Cbl and focal with folate) were noted in the SIVD group than in the AD group. Of note, bilateral CBF interactions were found between the medial prefrontal cortex and ipsilateral BG in the SIVD group, and this frontal-subcortical CBF coupling was moderated by Cbl before and after controlling for Hcy. Within the frontal-subcortical WM tracts, serum levels of folate and Hcy were correlated with axial/radial diffusivity in an inverse and positive direction, respectively.

Discussion: In Experiment I, preferable NVC was demonstrated according to its cognitive effect, in which distinct contributions from WMH and CBF metrics were shown. Stage-dependent CBF changes were delineated. Shared CBF lateralization was noted in both the SIVD and AD groups as evidenced by hypoperfusion within the right frontotemporal regions, while right hypofrontality presented earlier in the SIVD group than in the AD group. Using the CBF-WMH association as the corticosubcortical NVC, the SIVD group showed greater changes in CBF by the dementia stage compared to the AD group, underpinning that cortico-subcortical circuits appeared to be critical for the pathogenesis of SIVD.

In Experiment II, we extended the neurobiological knowledge of Cbl/folate/Hcy by parceling NCV correlates among dementia patients. Cbl and folate were mainly associated with CBF, while Hcy was exclusively associated with WMHs. The NVC correlations differed by dementia subtype. The neurotrophic effect of Cbl on CBF and the neurotoxic effect of Hcy on WM integrity were mainly found in the SIVD group, while the neurotrophic effect of folate on WM integrity and paradoxical effect of folate on CBF were found in both the SIVD and AD groups. Within the frontal-subcortical circuits in the SIVD group, the significant moderation effect of Cbl on CBF in line with the significant correlations between folate/Hcy and WM integrity provided an NCV-centered reference under the known pathogenesis. The associations between folate/Hcy and diffusivity parameters were further related to axon and myelin sheath damage as the corresponding microstructural changes.

Conclusions: NVC involving WMHs and CBF is a potential biomarker that may be able to provide cognitively relevant information and could be useful in differential diagnostics. A stage-dependent yet reciprocal cortico-subcortical NVC pattern was characterized in both the SIVD and AD groups, where the extent of “cortical WMH-subcortical CBF” coupling predated “subcortical WMH-cortical CBF” coupling. Right hypofrontality during the early stage of dementia indicated the possibility of SIVD. The greater topological evolution of NVC, along with the dementia stage, also favored SIVD more than AD. In addition, the dissociable NCV correlates of serum Cbl/folate/Hcy varied by dementia subtype. Our results may help resolve the inconsistent findings of the efficacy of Cbl/folate treatment for dementia and optimize the adjuvant Cbl/folate supplementation.