你知道，在長時間躺下后，你站起來有點太快會感到頭暈目眩嗎？

這種感覺是由大腦血流量突然減少引起的，減少了約30％。現在想象一下每天每分鐘生活的血流量都會減少。

患有阿爾茨海默病的人不必想象它。阿爾茨海默病患者腦血流減少的存在已有數十年的歷史，但與認知功能受損的確切相關性卻鮮為人知。

康奈爾大學生物醫學工程副教授Chris Schaffer說：“人們可能會適應血流減少，因此他們不會一直感到頭暈，但有明顯的證據表明它會影響認知功能。”

來自Schaffer聯合實驗室和Nizimura西村副教授的一項新研究為這種急劇減少的血流提供了解釋：白細胞粘附在毛細血管內部，是大腦中最小的血管。雖然只有一小部分毛細血管經歷了這種阻塞，但每個停滯的血管導致多個下游血管中的血流減少，從而放大了對整個腦血流的影響。

他們的論文“腦毛細血管中的中性粒細胞粘附減少皮質血流并損害阿爾茨海默病小鼠模型中的記憶功能”，發表在Nature Neuroscience上。

該論文的共同主要作者是現任哈佛醫學院博士后研究員的Jean Cruz-Hernandez博士和Schaffer-Nishimura實驗室的研究員Oliver Bracko。

Schaffer說，這篇論文是大約十年研究，數據收集和分析的結晶。它開始于一項研究，其中西村試圖將凝塊放入阿爾茨海默氏癥小鼠大腦的血管中以觀察其效果。

“事實證明......我們試圖引發的阻塞已經存在，”她說。“這有點改變了研究 - 這是一種已經發生的現象。”

最近的研究表明，腦血流不足是癡呆癥最早可檢測的癥狀之一。

“我們所做的是確定導致阿爾茨海默病模型中腦血流量減少的細胞機制，即中性粒細胞[白細胞]粘在毛細血管中，”Schaffer說。“我們已經證明，當我們阻斷導致失速的細胞機制時，我們可以獲得改善的血流量，并且與改善的血流相關聯可以立即恢復空間和工作記憶任務的認知表現。”

“現在我們已經了解細胞機制，”他說，“鑒別藥物或治療它的治療方法是一條更為狹窄的道路。”

該團隊已經確定了大約20種藥物，其中許多已經獲得FDA批準供人類使用，這些藥物具有癡呆治療的潛力，現在正在阿爾茨海默氏癥小鼠中篩查這些藥物。

Schaffer表示他“非常樂觀”，如果人類和老鼠一樣，毛細血管阻斷機制起著相同作用，這一系列研究“可能會成為阿爾茨海默病患者完全改變游戲規則的因素”。

該研究由美國國立衛生研究院，阿爾茨海默氏癥藥物發現基金會，阿爾茨海默氏癥藝術被子計劃和Brightfocus基金會資助。

New Alzheimer's therapy with brain blood flow discovery?

By discovering the culprit behind decreased blood flow in the brain of people with Alzheimer's, biomedical engineers at Cornell University have made possible promising new therapies for the disease.

You know that dizzy feeling you get when, after lying down for an extended period, you stand up a little too quickly?

That feeling is caused by a sudden reduction of blood flow to the brain, a reduction of around 30 percent. Now imagine living every minute of every day with that level of decreased blood flow.

People with Alzheimer's disease don't have to imagine it. The existence of cerebral blood flow reduction in Alzheimer's patients has been known for decades, but the exact correlation to impaired cognitive function is less understood.

"People probably adapt to the decreased blood flow, so that they don't feel dizzy all of the time, but there's clear evidence that it impacts cognitive function," said Chris Schaffer, associate professor of biomedical engineering at Cornell University.

A new study from the joint lab of Schaffer and associate professor Nozomi Nishimura, offers an explanation for this dramatic blood flow decrease: white blood cells stuck to the inside of capillaries, the smallest blood vessels in the brain. And while only a small percentage of capillaries experience this blockage, each stalled vessel leads to decreased blood flow in multiple downstream vessels, magnifying the impact on overall brain blood flow.

Their paper, "Neutrophil Adhesion in Brain Capillaries Reduces Cortical Blood Flow and Impairs Memory Function in Alzheimer's Disease Mouse Models," published in Nature Neuroscience.

The paper's co-lead authors are Jean Cruz-Hernandez, Ph.D., now a postdoctoral researcher at Harvard Medical School, and Oliver Bracko, a research associate in the Schaffer-Nishimura Lab.

The paper, Schaffer said, is the culmination of approximately a decade of study, data gathering and analysis. It began with a study in which Nishimura was attempting to put clots into the vasculatures of Alzheimer's mouse brains to see their effect.

"It turns out that ... the blockages we were trying to induce were already in there," she said. "It sort of turned the research around -- this is a phenomenon that was already happening."

Recent studies suggest that brain blood flow deficits are one of the earliest detectable symptoms of dementia.

"What we've done is identify the cellular mechanism that causes reduced brain blood flow in Alzheimer's disease models, which is neutrophils [white blood cells] sticking in capillaries," Schaffer said. "We've shown that when we block the cellular mechanism [that causes the stalls], we get an improved blood flow, and associated with that improved blood flow is immediate restoration of cognitive performance of spatial- and working-memory tasks."

"Now that we know the cellular mechanism," he said, "it's a much narrower path to identify the drug or the therapeutic approach to treat it."

The team has identified approximately 20 drugs, many of them already FDA approved for human use, that have potential in dementia therapy and are screening these drugs in Alzheimer's mice now.

Schaffer said he's "super-optimistic" that, if the same capillary-blocking mechanism is at play in humans as it is in mice, this line of research "could be a complete game-changer for people with Alzheimer's disease."

This research was funded by the National Institutes of Health, the Alzheimer's Drug Discovery Foundation, the Alzheimer's Art Quilt Initiative, and the Brightfocus Foundation.

Story Source:
Materials provided by Cornell University. Note: Content may be edited for style and length.

Journal Reference:
Jean C. Cruz Hernández, Oliver Bracko, Calvin J. Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay K. Vinarcsik, Iryna Ivasyk, Daniel A. Rivera, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey D. Beverly, Elizabeth Davenport, Yohan Davit, Charles P. Lin, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris B. Schaffer. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nature Neuroscience, 2019; DOI: 10.1038/s41593-018-0329-4