微量營養素和認知功能~轉載 @ 黑藕士(Health)

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微量營養素和認知功能

摘要

大腦需要源源不斷的能量代謝的微量營養素的神經元和神經膠質細胞，神經遞質的合成和行動，神經衝動傳遞，和同型半胱氨酸的代謝。（更多信息）
各種微量營養素的不足，尤其是B族維生素，有不良影響的認識。（更多信息）
發育中的大腦可能特別容易受到缺陷膽鹼和必需脂肪酸。（更多信息）
由於衝突的研究，在需要更多的研究來確定是否補充微量元素影響注意力相關的認知功能。（更多信息）
目前，很少有證據表明，補充與B族維生素，抗氧化維生素，膽鹼，或ω- 3脂肪酸會提高內存性能。（更多信息）
需要更多的研究，以確定是否有任何補充微量營養素對執行功能（即高層次認知過程）（更多信息）
有的，但並不是所有的研究報告說，補充微量元素改善整體的情緒和心理健康。（更多信息）
目前尚不清楚是否與補充B族維生素，抗氧化劑，或ω- 3脂肪酸可以防止與年齡有關的認知能力下降。（更多信息）
有幾個方法問題（如，測試用來評估認知，選擇研究人群，自然的補充，學習時間等）可能導致衝突的干預研究中觀察到的結果。（更多信息）

良好的營養狀況是非常重要的正確的大腦發育和維持正常的認知功能（1）。通過獨特的生物學功能，各種微量元素影響大腦功能。本文討論的角色主要微量營養素，包括B 族維生素，抗氧化維生素和某些重要礦產，認知功能。在適當的時候，研究其他化合物的作用，如必需脂肪酸和膽鹼，也提出了。認知影響微量營養素缺乏症進行了討論，並補充微量營養素的影響在廣泛領域的注意力，記憶力，執行功能，情緒，以及與年齡有關的認知衰退都包括在內。

基本需求的認知能力

能量代謝的神經元和神經膠質細胞

人腦是一個高度組織的代謝活性依賴於源源不斷的葡萄糖，以滿足其能源需求。事實上，大腦約佔總數

的25％葡萄糖的利用身體在休息，儘管僅佔2％的成年人體重（2，3）。血糖水平必須保持在任何

時候，以避免低血糖，並提供大腦燃料，其優惠。在最初階段的空腹血糖水平維持不變，通過細分

肝臟糖原，然後通過過程的糖異生，生產的葡萄糖從非糖前體，如氨基酸。而B 維生素生物素是必需的關

鍵酶在gluconeogenic通路（4）。雖然葡萄糖是強制性的燃料，酮體也可用於由大腦葡萄糖供應不足

時，如在長時間禁食或飢餓。然而，酮體是酸性的，和非常高的水平，這些化合物在血液中的毒

性，並可能導致酮症酸中毒（5）。因此，葡萄糖是首選的和正常的能量底物的大腦。

葡萄糖氧化在大腦需要一定的微量元素作為輔助因子。例如，表格的幾種B族維生素，包括硫胺素，核

黃素，菸酸和泛酸，以及複合硫辛酸，是利用在反應，完全代謝葡萄糖為二氧化碳和水（3）。此外，

營養必不可少的礦物質，鎂，鐵，和錳都需要完整的代謝葡萄糖，這些微量元素是用來作為輔助因子，

基板或組件的酶在糖酵解和檸檬酸循環（6,7）。此外，代細胞能量的形式對ATP的電子傳遞鏈需要的

維生素，核黃素和菸酸，鐵中的鐵硫簇;和內源性合成的化合物，輔酶Q ₁₀ （8）。

腦供血

在休息時，大腦接收到大約15％的心輸出量（9）。適當的腦供血要輸送氧氣，葡萄糖等營養素和微

量營養素的需要進行適當的認知功能。具有營養作用，保持最佳的血液供應到大腦。例如，不足數膳食

成分的發展增加了風險中風，病理狀況的結果，從受損的腦供血，見病情指數為例子。

神經遞質的合成

一個神經遞質釋放的化學物質是從一個神經細胞的傳遞衝動到另一個神經細胞或效應細胞，如肌肉細

胞。神經遞質要么興奮或抑制的影響;類型的效果是依賴於受體的接收單元（10）。神經遞質大致可分

為兩大類：小的氨基酸（如伽馬氨基丁酸[GABA]，谷氨酸，天門冬氨酸，甘氨酸）和生物胺類（如多

巴胺，腎上腺素，去甲腎上腺素，五羥色胺，組織胺，乙酰膽鹼和）（ 11）。

除了各種氨基酸，多種乙族維生素，包括硫胺素，核黃素，菸酸，維生素B ₆，葉酸和維生素B ₁₂，需

要作為輔助因子的合成神經遞質。此外，維生素C是需要合成去甲腎上腺素（3）和礦物質鋅是重要的

功能是否正常的GABA，天門冬氨酸，和去甲腎上腺素（12）。另外，膽鹼是一種前體的神經遞質乙酰

膽鹼（13）。

神經遞質與受體的結合

神經遞質功能通過結合到受體的細胞膜的神經元釋放神經遞質（即突觸前神經元）或受體細胞膜上的接

收單元（即突觸後神經元）。受體結合可以介導的開放，離子通道或導致細胞內的代謝變化（3，

14）。具體來說，直接行動上離子通道的結果從神經遞質受體的結合點上的神經元突觸後膜。這種結

合使柵狀離子通道打開，允許離子流入細胞（10）。潮帶正電荷的離子進入突觸後神經元有興奮作用

的去極化膜;膜去極化可引起神經衝動或行動的潛力，如果達到一定的閾值內的神經元。這就是通常所說

的“神經元放電。”相比之下，潮帶負電荷的離子可以抑制效果由超極化膜，從而防止神經元放電

（15）。除了直接對離子通道，神經遞質可能結合到G -蛋白偶聯受體，從而引出細胞信號的影響，可

能導致代謝的變化（例如，改建活動中的各種酶）在突觸後細胞（14）。

維生素可以結合可能影響到突觸後神經遞質受體。例如，一個在體外研究表明，兩種形式的維生素

B ₆，吡哆醛和磷酸吡哆醛，抑制了綁定到突觸後GABA受體（16）。此外，老鼠研究相關維生素B ₆缺

乏胎兒發育和哺乳期間與變化的數量和多巴胺受體的結合（17）。

神經衝動的傳播

的速度，神經衝動（動作電位）傳播是受了髓鞘的神經（18）。髓鞘是指的過程中獲得的神經髓鞘護

套，絕緣層的組織由脂類和蛋白質，周圍神經纖維。這作為一個導管鞘在電力系統，使快速，高效傳遞

神經衝動（10）。

某些微量元素可影響傳播神經衝動。特別是，攝入足夠的兩個葉酸和維生素B ₁₂是非常重要的保持完整

的髓鞘和硫胺是需要維護的神經的膜電位和神經傳導正確（3）。此外，鐵具有重要作用，在發展的少

突膠質細胞，這些細胞在大腦中產生髓磷脂（19）。

同型半胱氨酸代謝

同型半胱氨酸是一種含硫氨基酸是一個中間的代謝另一含硫氨基酸，蛋氨酸。同型半胱氨酸水平升高血

液中的（即同型半胱氨酸血症）可能是一個危險因素心血管疾病，也可與老年癡呆症和阿爾茨海默氏症

（20，21）。量的血液中同型半胱氨酸是受至少有三個維生素：葉酸，維生素B ₆和維生素B ₁₂（見

圖表）。此外，營養膽鹼也參與了同型半胱氨酸的代謝。膽鹼代謝物，甜菜鹼，也可以提供一個甲基組

的同型半胱氨酸轉化為蛋氨酸。

選擇微量營養素缺乏症的後果

硫胺素

硫胺素（維生素乙₁）缺乏症，如在一些缺陷的B族維生素，有負面的認知的影響。攝入足夠的維生素B1

是很重要的反應在大腦中代謝碳水化合物，脂類和氨基酸。例如，磷酸化形式的硫胺素，包括二磷酸硫

胺素（TDP）和焦磷酸硫胺素（TPP），都需要輔助因子的酶的糖酵解，在檸檬酸循環和磷酸戊糖途徑

（22）。此外，三磷酸硫胺素（TTP）可能參與神經細胞膜的功能和神經衝動（動作電位）的產生，

但具體的生化作用TTP仍不能很好地理解（22，23）。嚴重硫胺素缺乏症，這是罕見的工業化國家，

除慢性酒精中毒患者，艾滋病毒和艾滋病，或胃腸道條件影響維生素的吸收（23），結果在這種情況

稱為腳氣病，其中有許多形式，涉及神經系統症狀。幹，濕腳氣形式包括周圍神經病變，而腦腳氣病可

導致神經細胞死亡和臨床條件韋尼克腦病和柯薩可夫的精神，尤其是在那些誰長期酗酒（22，24）。

如需有關的各種形式的硫胺素不足，看到另一篇文章的硫胺素。

菸酸

而菸酸（維生素乙₃）輔酶，NAD和NADP，是需要一些氧化還原等反應在體內（見另一篇文章的菸

酸）。嚴重菸酸缺乏症，被稱為糙皮病，在歷史上與貧窮和消費的飲食主要是以玉米，這是低生物利用

菸酸（25，26）。今天，情況並不常見，但它可以發生在例慢性酒精中毒和個人與吸收不良綜合

徵（27）。在其他症狀，糙皮病的特點是老年癡呆症，神經系統症狀的糙皮病，包括頭痛，疲勞，冷

漠，抑鬱，運動失調，注意力不集中，妄想和幻覺，這可能會導致混亂，記憶力減退，精神異常，並最

終死亡（27）。

泛酸

泛酸（維生素乙₅）必須作為一個組件的輔酶 A（COA），輔酶需要的氧化代謝的葡萄糖和脂肪酸及生

物合成的脂肪酸，膽固醇，類固醇激素，褪黑激素，而神經遞質乙酰膽鹼。一種形式的維生素（4' -

phosphopantetheine）也是必需的活性的酰基載體蛋白，這是需要合成的脂肪酸（28），包括磷脂

和鞘脂。磷脂是重要的結構成分的細胞膜和鞘脂，鞘磷脂，是一個組件的髓磷脂鞘，可提高神經傳遞

（29）。自然產生的泛酸缺乏症在人類身上是非常罕見的，並已觀察到只有在案件嚴重營養不良

（30）。因此，對於大多數信息來自於維生素缺乏引起的實驗動物在實驗室狀態。這些研究發現，選

擇在泛酸缺乏導致脫髓鞘（破壞或損失的髓鞘）和外週神經損傷（13）。在人類中，泛酸缺乏症已引

起實驗由共同管理一個泛酸拮抗劑和泛酸缺乏飲食。參加本實驗抱怨頭痛，乏力，失眠，腸紊亂和麻木

和刺痛他們的手和腳（31）。在另一項研究中，參與者誰是美聯儲只有泛酸免費飲食的發展並不缺乏

臨床體徵，雖然有些出現無精打采，抱怨疲勞（32）。

維生素B ₆

表單的維生素B ₆，吡哆醛-5' -磷酸（PLP），是一個必需的輔酶為生物合成的幾種神經遞質，包括

GABA，多巴胺，去甲腎上腺素和血清素（3）。而維生素有一些其他生物功能（見另一篇文章對維生

素B ₆）。維生素B ₆的濃度在大腦中大約100倍的水平在血液中，因此，這並不奇怪，維生素B ₆缺乏

有神經系統的影響（13）。嚴重缺乏維生素B ₆，是罕見的，但酗酒者被認為是最危險，由於低膳食攝

入量和代謝障礙的維生素。在50年代初，癲癇發作，觀察嬰兒，結果嚴重的維生素B ₆缺乏引起的錯

誤，在生產嬰幼兒奶粉。此外，異常腦電圖（EEG）模式已注意到在一些研究中的維生素B ₆缺乏症。

其他神經系統症狀，嚴重注意維生素B ₆缺乏症包括煩躁，抑鬱和困惑（33）。

生物素

生物素（維生素乙₇）必須作為輔助因子的羧酶是重要的代謝的脂肪酸和氨基酸。顯性生物素缺乏症是

相當罕見的，但已被記錄在病人長期靜脈營養（腸外營養）無生物素的補充，在個人消費量高的生雞蛋

白含有抗生物素蛋白，它結合生物素，防止其吸收;並在這些遺傳性紊亂，生物素酶缺乏症（34）。在

成人中，神經生物素缺乏症的症狀包括抑鬱，嗜睡，幻覺和麻木和刺痛的四肢（35）。

維生素B ₁₂

維生素B ₁₂缺乏症，從而影響10-15％的成年人60歲以上，經常伴有神經系統的問題。比起年輕的個

人，這維生素缺乏症多見於老年人由於發病率較高的食品勢必維生素B ₁₂吸收不良（萎縮性胃炎）和發

病率較高的自身免疫性條件，惡性貧血（39）。血液學變化，包括血中濃度升高的同型半胱氨酸和甲

基丙二酸，是診斷的維生素B ₁₂缺乏症，但是，大約25％的病例，包括神經系統症狀臨床指標作為唯一

的維生素B ₁₂缺乏症（40，41）。這種神經系統症狀的維生素B ₁₂缺乏症包括麻木和刺痛的四肢，尤

其是腿部，行走困難，集中的問題，記憶力減退，定向障礙和老年癡呆症，可能會或可能不會伴隨著情

緒的變化（41）。在某些情況下，老年癡呆症和其他神經系統症狀引起的維生素B ₁₂缺乏症，可逆轉

維生素治療（42），但似乎是可逆性的持續時間依賴於相關的神經系統並發症（41）。雖然底層的神

經生化機制效果的維生素B ₁₂缺乏症不理解，維生素缺乏症是眾所周知的破壞髓磷脂鞘覆蓋顱骨，脊

柱，和周圍神經（42，43）。

維生素 C

維生素C積聚在中樞神經系統，與神經元的大腦具有特別高的水平（44）。除了其眾所周知的抗氧化功

能，維生素C有一個數字的非抗氧化功能。例如，維生素是必需的酶反應合成的神經遞質去甲腎上腺素

的多巴胺。另一種非抗氧化作用的維生素C在大腦中減少金屬（如鐵，銅）離子（44）。此外，維生

素C也能夠再生維生素E （45），一個重要的脂溶性抗氧化劑。維生素C缺乏引起的氧化損傷，以大分

子（脂類，蛋白質）在大腦（13）。嚴重的維生素C缺乏症，稱為壞血病，是一種潛在致命的疾病。然

而，在壞血病，維生素C是由大腦保留神經功能，並最終死於這種疾病更可能因缺乏維生素C的膠原蛋白

合成（44）。膠原蛋白是一種重要的結構組成部分的血管，肌腱，韌帶和骨骼。

維生素 D

而維生素D 受體在腦組織中的表達（46），而維生素D是已知的重要的正常腦發育和功能（47）。因

此，維生素D缺乏可能損害認知能力。維生素D缺乏症是一個世界範圍內的重大問題，估計有十億人沒有

足夠水平的循環或不足25 -羥基維生素D （48）。老齡化是伴隨著減少合成維生素D的能力，在陽光照

射皮膚後（49）。因此，老年人可能更容易受到維生素D缺乏和任何不良反應的認知。一些研究老年人

要么與較低的25 -羥基維生素D水平與認知能力差的措施（50-53）或更高的25 -羥基維生素D水平與

措施，更好地認知表現（54，55）。然而，最近系統回顧五年的觀察研究得出結論，該協會在25 -羥

基維生素D濃度和認知能力尚不清楚（56）。更多的研究，特別是隨機對照試驗，以確定是否需要維生

素D缺乏症有不良影響的認識。

維生素 E

α-生育酚形式維生素E是一種重要的脂質水溶性抗氧化劑。在大腦和其他組織，α-生育酚具有關鍵的作

用，防止氧化引起的脂質的破壞，因此至關重要的保持完整的細胞膜。因此，維生素E缺乏會導致脂質

過氧化反應在腦組織（57）。嚴重缺乏維生素E的效果主要表現在神經系統症狀，包括受損的平衡和協

調（共濟失調），傷害的感覺神經（周圍神經病），肌肉無力（肌病），和破壞視網膜的眼睛（視網膜

色素）。出於這個原因，人們誰開發周圍神經病，共濟失調或色素性視網膜炎應進行篩選，維生素E缺

乏症（58）。發育中的神經系統似乎特別容易受到維生素E缺乏症。例如，孩子誰也嚴重缺乏維生素E

從出生，不與維生素E治療神經系統症狀迅速發展。相比之下，個人誰開發吸收不良的維生素E在成年神

經系統症狀可能不會發展為10到20年。應當指出，然而，維生素E缺乏症症狀的健康人誰消耗低的飲食

中的維生素E從未報告（58 59）。

鈣

鈣離子是重要的細胞內信號調節數字的生理過程，包括神經元的基因表達，神經元分泌神經遞質到突

觸和突觸可塑性（回顧60）。正常血液中的鈣是保持甚至當膳食攝入鈣不足，因為骨架提供了大量儲備

的礦產。因此，影響膳食中鈣不足會造成負面影響主要是對骨骼健康。有趣的是，鈣穩態變化在大腦可

能有助於認知功能下降與正常老化，並可能發展為神經退行性疾病（61 62）。

碘

碘是必需的合成的甲狀腺激素，調節數字的生理過程，包括生長，發育，代謝和繁殖（63，64）。此

外，甲狀腺激素是重要的髓鞘的中樞神經系統，其中大多發生在出生後不久（64，65）。由於碘是至

關重要的大腦正常發育的，缺乏這種礦物質在關鍵時期，如在胎兒發育或在幼兒期，可以有有害影響的

認識。最極端的認知發展的影響是不可逆的碘缺乏智力低下;輕度認知的影響，包括各種神經發育缺陷，

包括智力障礙（66 67）。欲了解更多信息，缺碘，這是目前公認的最常見的原因可預防腦損傷的世

界，看到的另一篇文章的碘。

鐵

鐵是一個重要的組成部分，數百蛋白質和酶的參與各方面的細胞代謝，包括那些參與氧的運輸和儲存，

電子傳遞和能量的產生，DNA 合成（見另一篇文章的鐵）。鐵是需要適當發展的少突膠質細胞（腦細胞

產生髓磷脂）（19）和礦物也是必需的輔助因子的酶合成幾個神經遞質（68）。因此，缺鐵在不同階

段的大腦發育有不利的後果。孕婦在增加風險缺鐵因為鐵的要求顯著增加在懷孕期間，由於增加鐵的利

用率由發育中的胎兒和胎盤和血液由於體積膨脹（69）。孕婦缺鐵的嚴重後果，女人和胎兒（70）。

動物研究表明，產婦缺鐵導致降低大腦中的鐵濃度和永久性變化的認知和行為表現在後代（71）。在

人類中，缺鐵在圍產期階段，結果在持續的赤字在學習和記憶（回顧60）。此外，缺鐵在以後的發展階

段，如在兒童時期，可能與受損的認知能力的發展（見另一篇文章的鐵）。而鐵是必不可少的腦功能，

它是有毒的神經元在高濃度（60）。

鎂

鎂是需要300多在體內的代謝反應，不少是重要的，正常的腦功能（見另一篇文章對鎂）。鎂缺乏症在

健康人誰是消費均衡的飲食是罕見的，因為礦產豐富的植物和動物性食品和因為腎臟能夠限制尿鎂的攝

入量低的時候。然而，鎂缺乏已引起實驗和結果在神經系統和肌肉症狀包括震顫，肌肉痙攣和抽

搐（72）。事實上，酶參與神經肌肉的活動（即ATP酶的酶，交通鈉，鉀和鈣離子），顯然是最敏感

的鎂缺乏症（69）。

硒

硒是穀胱甘肽過氧化物酶需要（GPX）重要的抗氧化酶在大腦和其他組織。穀胱甘肽過氧化物減少可能

造成損害的活性氧（ROS），如過氧化氫和脂質過氧化物，為無害的水和醇產品，如通過耦合的減少與

氧化穀胱甘肽（見圖表中的另一篇文章對硒）（73，74 ）。硒缺乏症已與GPx活性降低大腦中的實驗

動物（75），因此，硒缺乏症可能與抗氧化能力降低大腦中的。

鋅

鋅是目前在高水平的腦裡有催化，結構和監管作用在細胞代謝（見另一篇文章對鋅）。在大腦中，大部

分的鋅離子緊密結合的蛋白質，但自由鋅存在於突觸小泡，具有介導的神經傳遞作用，谷氨酸和

GABA （76）。實驗性缺鋅在人類已被證明損害措施的精神和神經系統功能（77）。虛寒的礦產在關

鍵時期的認知發展可以更具破壞性。例如，在缺鋅可導致胎兒大腦發育的先天性畸形，缺鋅和在後期的

腦發育已與赤字的關注，學習，記憶和神經心理行為（13，78，79）。另一方面，細胞釋放鋅在大腦

中可以調解神經元凋亡，可能是病理與阿爾茨海默氏症和肌萎縮性側索硬化症（ALS）（80）。因

此，細胞內的鋅水平在大腦的homeostatically監管。

膽鹼

膽鹼，能合成人體少量，但飲食攝入是需要保持健康。因此，膽鹼被認為是一種必需的營養素對人類

（81）。膽鹼及其代謝產物具有重要生物學功能的數量（見另一篇文章對膽鹼）（82-84）。關於認

知功能，膽鹼是需要髓鞘的神經，是前體的乙酰膽鹼的重要神經遞質參與肌肉動作，記憶等功能。膽鹼

也用於合成的磷脂，磷脂和鞘磷脂，這是結構性的組成部分細胞膜和前體的某些細胞信號分子。在實驗

室老鼠研究表明，膽鹼缺乏症在圍產期期間的業績持續性記憶和其他認知障礙（85）。

必需脂肪酸

ω- 3和ω- 6 脂肪酸是多不飽和脂肪酸（PUFA），這意味著它們含有多個順雙鍵（86）。而必需脂肪

酸包括α-亞麻酸（ALA），一個ω- 3脂肪酸和亞油酸（LA），一個ω- 6脂肪酸。ALA和LA不能合成

的，因此人類必須從飲食，飲食攝取建議成立由醫學研究所是ALA和LA（見另一篇文章對必需脂肪酸）

（86）。長鏈ω- 6脂肪酸，花生四烯酸（AA），可以合成從洛杉磯。此外，兩個長鏈ω- 3脂肪酸，二

十碳五烯酸（EPA）和二十二碳六烯酸（DHA），可以合成ALA，但其合成可能不足以在一定條件下，

如在懷孕和哺乳期（87，88 ）。

剔除脂肪組織，組織的神經系統具有最集中的血脂在人體（89）。血脂在人體中發現包括脂肪酸，磷

脂，甘油三酯和膽固醇。ω- 3和ω- 6多不飽和脂肪酸被納入磷脂，在那裡他們不僅為結構中的作用細胞

膜的神經系統，也影響膜的流動性，靈活性，透氣性，以及活動的膜相關酶和受體（13，90）。通過

這些影響，ω- 3和6 PUFA發揮重要作用的一些視覺和神經系統的功能。DHA是選擇性地納入視網膜和

神經細胞膜（91 92），這表明它起著重要的作用在視覺和神經系統的功能。磷脂是大腦的灰質含有高

比例的DHA和AA，說明他們是很重要的中樞神經系統功能（93）。腦DHA含量可能特別重要，因為動

物研究表明，枯竭的DHA在大腦中會導致學習赤字。目前還不清楚如何影響大腦功能的DHA，DHA含

量的變化，但神經細胞膜的功能可能會改變離子通道或膜結合受體，以及有無神經遞質（94）。

在一般情況下，必需脂肪酸缺乏症（即兩虛證ALA和LA）已觀察到只有在患者的慢性脂肪吸收不良，囊

性纖維化，或那些在腸外營養不飽和脂肪酸（86，95）（請參閱文章上必需脂肪酸酸）。臨床表現缺

乏必需脂肪酸主要包括皮膚的影響（即，皮炎），但負面血液和免疫功能低下的影響也已經出現在人類

（96）。減少身體發育的嬰幼兒和兒童還與必需脂肪酸缺乏症。發育中的大腦可能特別容易受到影響

的缺陷必需脂肪酸（97）。由於腦磷脂的某些地區富含DHA和AA，ω- 3或Ω- 6多不飽和脂肪酸缺乏

腦發育過程中可能有持久的影響視覺和認知功能（13）。例如，在實驗室老鼠研究發現，飲食中ω- 3

多不飽和脂肪酸缺乏症的認知能力受損的措施，通過影響多巴胺神經遞質系統在額葉皮質區的腦

（98）。ω- 3 PUFA缺乏胎兒發育過程中也被證明有不良反應對視功能（審查99，100）。

補充微量營養素的影響

相對於後果微量營養素缺乏，大大減少被稱為關於認知影響微量營養素補充。許多的干預試驗迄今開展

補充研究是否與B 族維生素可能削弱認知下降與正常老化。其他試驗看著是否改善微量營養素補充的認

知能力的具體措施，包括注意力，記憶力，以及各種行政職能。這些和其他認知功能是相互關聯的，例

如，記憶新的信息是依賴於適當的關注（101）。此外，認知能力會受到其他因素，包括一個人的整體

情緒（101）。一個簡易的隨機對照試驗（RCTs）對這些認知參數介紹如下。

注意

注意是心理過程的信息，同時有選擇地集中在排除多餘的信息。需要注意的是正確的高階認知能力，因

此，赤字的關注可以深刻地影響學習和行為（102）。雖然有不同類型的注意力（即選擇性，分，持

續）（101），神經心理測試測量注意無論是視覺或聽覺刺激（102）。

一些試驗評估其效果多種維生素/礦物質補充劑的關注，大多數正在進行的學齡兒童。然而，1年期安慰

劑對照，雙盲試驗，提供十倍的建議九維生素進行了127個健康的年輕成人（年齡17-27歲）

（103）。相對於基線測量，補充多種維生素是與改善上兩次評估的重視，婦女，但沒有男人，但是，

差異的維生素和安慰劑組沒有統計學差異在任何時間點的測量（3個月，6或9個月，12個月）

（103）。在14個月的隨機，雙盲，安慰劑對照試驗，日常管理的微量營養素，強化飲料（細節缺乏）

或安慰劑，以608名兒童（年齡6-15歲）在印度，補充微量元素，以提高成績是有聯繫的一小節的重視

和濃度（諾克斯立方測試），但不另一項評估（信取消測試）（104）。另一項試驗管理的微量營養素

強化（維生素A，B ₆，B₁₂，C和葉酸和礦物質，鐵和鋅）喝，喝強化了十二碳六烯酸（DHA）和二十

碳五烯酸（EPA），喝一杯強化與微量營養素和ω- 3脂肪酸，或安慰劑，每週六天12個月為644學齡兒

童在澳大利亞和印度尼西亞（105）。這項試驗報告說，各種治療都沒有效果的關注與安慰劑相比，儘

管有一些改善營養狀況（105）。最近，一項隨機，雙盲，安慰劑對照試驗中的81名兒童（8-14歲）

居住在英國發現，每天使用的多種維生素/礦物質補充劑，含維生素以及最鐵，銅，鋅，鈣，鎂，是與增

加的精確度在一個注意任務（箭頭側衛測試）在整個12週的研究（106）。因此，試驗進行了迄今為止

的矛盾和需要更多的研究來確定其效果就注意補充微量營養素對兒童或成人。

內存

記憶是指一個人的能力進行編碼，組織和新的信息存儲和調用的信息需求。其他認知功能，如學習，推

理和語言，都依賴於一個有效的內存（107）。實驗方法評估記憶功能經常測量速度和精度響應特定任

務（101）。到目前為止，很少有過臨床試驗已經研究了影響補充微量營養素對方面的記憶。大多數的

研究是觀察和關注血液中的B 族維生素或抗氧化維生素和內存性能。

有的，但不是全部，觀察研究發現，老年人的個人與地位較低的葉酸和/或維生素B ₁₂可能內存性能較

差，尤其是情節記憶（即記憶的事件，時間和地點）（108-111）。此外，一項研究發現，較高的血漿

水平的維生素B ₆均與更好的性能兩項措施的內存性能（112）。一些觀察性研究，老人還發現，降低

血液中的維生素C和維生素E是與認知測試中表現較差的內存（109，113，114）。維生素C和E是兩

個抗氧化維生素。雖然在具體的維生素明顯不足之處有認知的影響（見微量營養素缺乏的後果選擇以

上），糾正隱性的缺陷可以通過補充可能改善方面的記憶。

然而，臨床試驗的作用補充維生素B族維生素或抗氧化劑對內存性能是有限的，他們的研究結果仍未有

定論。高架同型半胱氨酸水平的血液可能與老年癡呆症和阿爾茨海默氏病（21）。維生素B ₆，葉酸和

維生素B ₁₂規範金額循環同型半胱氨酸（見圖表），以及缺乏任何這些B族維生素可導致同型半胱氨酸

血症，治療條件，通過補充維生素B。為期3年的隨機，雙盲，安慰劑對照試驗中818老年人（年齡在

50-70歲），同型半胱氨酸水平升高，但正常的血清維生素B ₁₂水平發現，補充葉酸（800微克/天）降

低同型半胱氨酸水平和改進措施的內存性能（115）。然而，1年的隨機，雙盲，安慰劑對照試驗中

253老年人（≥65歲）的成年人同型半胱氨酸水平升高發現，補充維生素B（1000微克/天的葉酸，10

毫克/天的維生素B ₆和500微克/天的維生素B ₁₂）沒有改善措施的認知功能，包括內存，儘管降低同型

半胱氨酸水平（116）。此外，隨機，雙盲，安慰劑對照試驗中162老年人（≥70歲），輕度維生素

B ₁₂缺乏發現，維生素B ₁₂補充24週，單獨或與葉酸，並沒有提高記憶力性能（117）。另一項試驗

發現，維生素B ₆的補充（20毫克/天的鹽酸吡哆醇）三個月改善記憶，尤其是長期記憶，在38名健康老

年男性（70-79歲）的男性相比，38年齡相仿誰收到了安慰劑（118）。此外，安慰劑對照試驗中211

健康成年女性不同年齡的發現，補充維生素B（750微克/天的葉酸，75毫克/天的維生素B ₆，或15微

克/天的維生素B ₁₂）僅輕微一些措施改善記憶功能（119）。因此，結果干預試驗的B族維生素的補充

是相互矛盾的。

由於正常老化會增加自由基引起的損傷在體內，並與記憶力減退，補充抗氧化劑可能減緩與年齡有關的

記憶衰退（120）。隨機對照試驗（RCTs）的抗氧化補充劑的評估記憶功能都需要評價這一假說。一

些現有的試驗研究是否維生素E補充劑可能會降低認知功能下降與某些神經退行性疾病，如帕金森氏症

或阿爾茨海默氏症，但很少有進行具體評估的內存。一項試驗研究的效果，使用維生素E補充劑（為平

均14個月）的內存性能與早期的患者，治療帕金森氏病。具體來說，表現在數字廣度和各種召回任務沒

有差異的174個病人誰給予2000 IU /天合成α-生育酚（相當於900毫克/天的RRR -α-生育酚）和174

例誰是管理安慰劑（121）。另一項試驗評估是否相同劑量的α-生育酚，當為兩年，可能可以治療中重

度老年癡呆症。相較於使用安慰劑（84例）在這項試驗中，使用α-維生素E（85例）顯著放慢發展老年

癡呆症的老年癡呆症，證明了顯著改善癡呆的祝福規模和時間，以制度化（122）。然而，α-維生素E

補充劑並沒有影響成績的阿爾茨海默病評估量表和簡易精神狀態檢查，其中部分涉及內存性能評估

（122）。欲了解更多信息的使用維生素E在治療老年癡呆症，見另一篇文章對維生素E。整體而言，目

前還沒有證據隨機對照試驗，抗氧化劑補充提高內存性能在個人與神經退行性條件。需要更多的研究來

確定影響的抗氧化劑補充內存在健康人。

膽鹼是一種必需的營養素，有一個數字的重要生物學功能（見另一篇文章對膽鹼）。增加飲食中攝取膽

鹼很早就在生活中的嚴重程度可減少老年大鼠記憶障礙。補充膽鹼的母親對胎兒老鼠，老鼠幼仔，以及

在第一個月的生活，導致更高的性能在空間記憶測試個月後補充膽鹼已經停產（123）。由麥肯的審查

等。討論了從老鼠的實驗證據方面的研究提供產前發育過程中的膽鹼和認知功能的後代（124）。目前

還不清楚是否在囓齒類動物的研究結果是否適用於人類。需要更多的研究來確定作用膽鹼在大腦發育和

膽鹼的攝入量是否是有用的預防記憶力減退或癡呆症的人類。試驗評估治療使用的膽鹼補充患者的記憶

力減退與阿爾茨海默氏症的主要報導沒有記憶有關的福利（審查125）。此外，很少有證據表明，膽鹼

改善記憶中老年癡呆症的個人無（126）。

此外，ω- 3脂肪酸補充劑可能可以幫助預防或治療神經系統疾病相關的記憶力減退如阿爾茨海默氏病。

十二碳六烯酸（DHA，22:6 n - 3的），主要的ω- 3脂肪酸在大腦中，似乎是對發展保護性阿爾茨海默

氏症和其他類型的癡呆症（127）（見另一篇文章的必需脂肪酸）。雖然研究結果在動物模型已經有前

途（審查128），它目前還不知道是否可以補充DHA有助於治療阿爾茨海默氏病的人類。最近，一項隨

機，雙盲，安慰劑對照試驗中295例阿爾茨海默氏病發現，DHA補充劑（2克/天）18個月沒有有效地減

緩認知能力下降（129）。

行政職能

行政職能是指幾個高層次的認知過程，如推理，計劃，戰略思維，問題解決了，多任務（101，130，

131）。具體的例子行政職能包括兩種行為之間的轉移，抑制習慣性的行為，更新信息，並規劃

（131）。這些行政職能的實驗評估從業人員的認知任務，如威斯康星卡片分類測試，斯特魯普色字測

試，或言語流暢性測驗（102，132）。某些認知任務的執行功能可以測量一個評估，以及其他認知功

能（131）。

到目前為止，很少有研究探討了影響微量營養素補充對行政運作。在一個隨機，雙盲，安慰劑對照試驗

中216健康婦女（25-50歲），補充與每日維生素/礦物質九週是與一個顯著的增加速度和精度性能上的

Stroop顏色字試驗（133）。總體而言，補充微量元素在這次審判是與提高精度性能電池測試評估多任

務（133）。然而，一項隨機，雙盲，安慰劑對照試驗中的215人（35-55歲）發現，每天補充與B 族

維生素（3至13倍的電流RDA，除了葉酸，這是包括在劑量相當於RDA），維生素C（500毫克/天），

鋅（10毫克/天）和鎂（100毫克/天）33天無影響測量性能的行政職能，包括的Stroop顏色單詞測

試，聯繫匯率和球的任務，威斯康星卡片分類任務（134）。此外，1年期安慰劑對照試驗的成年人65

歲以上的發現，每天補充多種維生素與/礦物並未受益認知表現在口頭流利的測試評估中，參與者被要求

列出一個單詞開始某些字母在指定時間內（135）。此外，安慰劑對照試驗中老年人的152（年齡在

70-80歲）有輕度認知功能損害的報告說，補充維生素B（50毫克/天的維生素B ₆，5毫克/天的葉酸和

0.4毫克/天對維生素B ₁₂）一年沒有提高性能上進行類似的測試言語流利（136）。需要更多的研究，

以確定是否有任何補充微量營養素對執行功能的不同人群。

情緒和心理幸福感

缺陷在選擇營養素，主要是某些B 族維生素，都與抑鬱症（見上面）。因此，補充微量元素，尤其是在

個人或邊緣有明顯的缺陷，可能可以改善整體的情緒狀態和心理福祉。大多數研究討論本節進行了健康

人。重要的是要注意，情緒狀態通常是評估自評量表，如自我管理的問卷調查，這是不客觀的測量

（101）。

一些研究在不同年齡的人已評估是否每天服用多種維生素/礦物質補充劑是與變化的情緒狀態或心理福

祉。一個隨機，雙盲，安慰劑控制的129個年輕健康的成年人發現，服用補充含有十倍的每日允許攝入

量建議為九個不同的維生素（維生素A，硫胺素，核黃素，菸酸，維生素B ₆，葉酸，維生素乙₁₂，維生

素C，維生素E）一年提高了一個自我評估的情緒，即是“比較認同” （137）。最近進行的試驗已經

在短得多的時間，通常持續約一至三個月。例如，雙盲，安慰劑對照研究在80名健康男性，年齡18〜

42歲，發現使用多種維生素/礦物質補充劑28天，是與在主觀措施減少焦慮和壓力感受（138 ）。在這

項研究中，劑量B族維生素和維生素C為3至12倍，目前美國的RDA，鋅被控制在數額幾乎RDA和補充也

包含分數的RDA的鈣和鎂（138）。最近，一項隨機，雙盲，安慰劑對照試驗中215人，年齡介乎35

至55歲，研究了影響補充維生素B（3至13倍的電流RDA，除了葉酸這是包括在劑量相當於RDA），維

生素C（500毫克/天）和礦物質，鋅（10毫克/天），鈣（100毫克/天），鎂（100毫克/天）對情緒和

知覺壓力（ 134）。相較於安慰劑，男性誰了多種維生素，礦物質補充劑33天有明顯改善收視率在一

（活力，活動評分）的六個組成部分的文件的情緒狀態（POMS）規模，顯著減少主觀應力測量感知壓

力量表，並顯著改善自我評價心理疲勞之前和之後電池的認知艱鉅的任務（134）。此外，在30天的

安慰劑對照試驗中300成人（年齡18-65歲），與B族維生素補充（在劑量約3至13倍的RDA，不包括葉

酸），維生素C（1000毫克/天），鈣（100毫克/天），鎂（100毫克/天）是與顯著改善，各項分數的

心理壓力比安慰劑（139）。然而，試驗216健康婦女（25-50歲）發現沒有什麼好處的多種維生素/礦

物質補充劑;微量營養素補充劑九週無影響情緒的幾個措施，包括健康調查，疲勞調查，在POMS評估，

但伴隨著減少自覺身體疲勞是電腦化評估多任務（133）。此外，一項隨機，雙盲，安慰劑對照試驗在

81名健康兒童，8歲至14歲，報告說，補充與每日維生素/礦物質12週沒有對各種措施的心情

（106）。有趣的是，在30小試絕經前婦女發現，每天補充多種維生素十週沒有改善整體的情緒，但是

當補充也包含7毫克/天的鋅（RDA = 8毫克/天），作者指出顯著改善兩個組成部分POMS：憤怒，敵

意和抑鬱，沮喪的分數（140）。

除了鋅，與其他單一營養補充可能會影響情緒。在一項研究中127個年輕，平均年齡20.3歲）的婦女，

補充了高劑量維生素B1（50毫克/天，45倍的電流RDA）兩個月是有聯繫的改進，自我報告的情緒，包

括感覺被越來越清醒（141）。兩項試驗在急性住院患者表明，短期（約7天）補充維生素C濃度增加的

抗壞血酸在血漿和白細胞，並導致34-35％的改善情緒狀態，作為衡量POMS （142，143）。

其它營養素的不足之處，包括維生素B ₆，維生素B ₁₂，和ω- 3脂肪酸，都與抑鬱症（見病情指數）和

維生素D缺乏還與對情緒的負面影響（51，144 ）。但是，它不知道是否與這些營養素補充提高整體情

緒或抑鬱症狀的抑鬱症。

大部分的上述研究，進行個人推測是健康的。鑑於這一事實，一個重要的比例一般人群不消耗足夠的膳

食水平幾個微量元素（145），每日多種維生素/礦物質補充劑可以幫助改善微量營養素狀況，並可能

有一定的認知和其它健康益處。然而，需要更多的研究來確定是否多種維生素/礦物質營養補充品或單改

善情緒狀態，心理壓力大，心理和整體功能。

年齡有關的認知衰退

正常老化與輕度認知功能障礙是由多種神經解剖的改變，包括改變在大腦受體，髓鞘營養不良，失去樹

突棘，並改變神經傳遞（146）。良好的營養狀態是已知的重要的，正常的認知功能，但飲食中的作

用，預防與年齡有關的認知衰退還不是很清楚。充足的膳食攝入量的B族維生素，抗氧化維生素，必需

礦物質和ω- 3脂肪酸可能有助於防止認知功能下降與正常老化（1）。但是，它不知道是否補充攝入這

些營養物質會導致額外的好處。干預試驗是有限的，而現有的試驗結果是不一致的。總體而言，小利已

被觀察到與微量營養素或ω- 3脂肪酸補充劑。認知影響可能可能取決於基線營養狀況，即任何好處的微

量營養素補充劑可能只體現在個人與微營養素缺乏症，而不是在那些有足夠的微量營養素的地位。另一

個重要因素是一個人的年齡在時間的干預，營養干預應最好開始時或之前所觀察到的認知能力下降

（146）。本節審查結果的臨床試驗中使用的B族維生素，抗氧化維生素和ω- 3脂肪酸可能的療法正常

認知老化。研究個人與老年癡呆症和其他相關病症並不包括在這篇文章。

在許多缺陷的B族維生素的結果負認知的影響（見微量營養素缺乏選擇的後果），和一個數字的研究已

發現，降低血液中的B族維生素與一些認知障礙（147-154）。維生素B ₆，葉酸和維生素B ₁₂調節血

液中同型半胱氨酸（見同型半胱氨酸代謝以上圖） -一種氨基酸來源於蛋氨酸可能與認知能力下降

（155）。然而，證據表明，維生素B補充劑降低風險的認知能力下降的不足。最近三個系統評價和薈

萃分析都認為，短期補充葉酸，有無其他B族維生素，不改善與年齡有關的認知衰退或整體的認知和試

驗需要較長的時間（21，156 -158）。

由於年齡相關的認知衰退已與自由基誘導的氧化損傷大腦中（159，160），補充抗氧化劑可能有助於

防止認知老化。前瞻性隊列研究報告說，維生素C的攝入補充劑（161，162）或維生素E的攝入量從食

物和補充劑（161）是與一些保護，防止認知能力下降。然而，隨機對照試驗，以確定是否需要補充抗

氧化劑減緩或防止與年齡有關的認知衰退。一個隨機，雙盲，安慰劑對照試驗發現沒有證據表明，每日

補充含12毫克的抗氧化劑β-胡蘿蔔素，維生素C 500毫克和400毫克的維生素E，當採取長達12個月，

改善精神表現在老年人（163）。另一種安慰劑對照試驗中老年人癡呆症的高危人群發現，補充維生素

C（200毫克/天）和維生素E（500毫克/天）12週並沒有改變任何測量的認知功能降低的水平，儘管

nonsignificantly在F ₂ - isoprostanes，生物標誌物的脂質過氧化體內。大型試驗的持續時間較長，

需要補充抗氧化劑，以了解是否可能有助於預防與年齡有關的認知衰退。欲了解更多信息，微量營養素

和植物化學物質相關的認知下降或神經退行性疾病，請參閱文章，為老年人微量元素。

認知衰退已與水平下降的十二碳六烯酸（DHA）在大腦中（164）。DHA是一種長鏈歐米加3脂肪酸存

在於魚油（見另一篇文章對必需脂肪酸）。一些觀察性研究有關聯的攝入量較高的魚類與利益相關的認

知能力（165，166）和認知能力下降（167，168），以及低風險的某些類型的癡呆症，包括阿爾茨

海默氏病（166，169-171 ）。此外，一個前瞻性隊列研究報告逆協會之間的ω- 3脂肪酸含量的紅細

胞細胞膜（指標的ω- 3脂肪酸攝入量）和認知能力下降（172）。因此，補充DHA，也許與其他長鏈

ω- 3脂肪酸可能有助於維持認知衰老過程並可能有助於防止與年齡有關的認知衰退。迄今為止，臨床試

驗的ω- 3脂肪酸補充劑已主要在患者血管性癡呆，阿爾茨海默氏症或其他腦病變（173，174）。長期

干預研究健康人或那些與輕度認知功能損害是必要的。結果是老年人和n - 3長鏈多不飽和脂肪酸

（OPAL）研究最近發表（175）。在這項試驗中，748健康老年人的認知能力，年齡70-79歲，均補

充了兩年的組合500毫克/天的DHA和200毫克/天的二十碳五烯酸或安慰劑含有橄欖油。認知功能下

降，沒有任何一組在2年期（175），表明不再干預試驗，以確定是否需要長鏈ω- 3脂肪酸有預防效

用，在與年齡有關的認知衰退。3年試驗的DHA補充劑（800毫克/天）老年癡呆症的成年人沒有目前正

在進行（見：www.clinicaltrials.gov）。

結論

雖然我們有很好的了解其後果微量營養素缺乏的認識，我們知道大大減少對認知的影響微量營養素補

充。目前，很少有證據表明，補充微量元素提供認知益處，與文獻報導的好處是大多與心情。迄今為

止，一些在隨機對照試驗（RCTs）已進行或在老年人或個人與病理條件如阿爾茨海默氏症。因此，有

必要進行精心設計，大規模，長期隨機對照試驗在健康的成年人，在個人與微量營養素缺乏，以及在兒

童，年齡組進行快速的認知和大腦發育。提供微量營養素幾年可能須遵守任何認知的影響。微量營養素

的研究，測量血液中的地位和關聯與認知功能，還需要更好地評估作用的微量營養素對心理功能。一般

情況下，補充了廣泛的微量營養素，而不是一個或幾個選定的，將包括微量營養素的需要更多的樣本，

也將給予合理的知名的各種營養素之間的相互作用方面的認知。雖然這種方法可能會產生並發症方面的

表現歸咎於任何認知的影響，評估營養狀況基線和補充後，將有助於告知大概是機械的問題。

此外，重要的是要注意，可用隨機對照試驗已利用了大量的認知測試，以研究影響補充微量元素。最近

的一項系統回顧了39項隨機對照試驗使用補充微量營養素或植物化學物質的試驗發現，利用121不同的

認知任務，從而使其難以進行比較研究和整體之間數據的解釋（131）。因此，該領域將受益於更加規

範化，系統化的方法來研究影響補充微量營養素對認知功能。許多紙張和鉛筆採用問卷，以評估認知能

力可能不敏感，可以探測微小的變化而導致的短期干預措施的補充微量營養素（101，102）。另一方

面，驗證基於計算機的測試，成為廣泛使用，這些測試確保高靈敏度的測量，無論是在計算精度和速度

的性能在各種認知領域。增加使用電腦認知評估可能援助的能力來檢測微妙的變化可能導致微量營養素

補充健康人。

雖然目前尚不清楚是否微量營養素補充有益的作用在不同的認知領域，它是行之有效的微量營養素缺

乏，尤其是B 維生素的不足，有不良影響的認識。飲食良好的飲食習慣是很重要的最佳健康和預防慢性

疾病（見健康飲食在LPI接收衛生）。美國全國性的調查表明，相當一部分美國人是不符合當前的建議

攝入量為一個數字的微量營養素，包括維生素E，鎂，維生素A和維生素C作為其處方衛生，萊納斯波林

研究所的建議在日常多種維生素/礦物質營養補充保險，以滿足作為微量營養素的需求（見補充在LPI接

收衛生）。

參考文獻

寫在2011年2月由：

維多利亞J.德雷克博士

萊納斯鮑林研究所

俄勒岡州立大學

回顧2011年2月由：

Juerg哈勒博士

樓霍夫曼-羅氏有限公司

巴塞爾，瑞士

這篇文章是包銷，部分由贈款拜耳保健消費品公司，巴塞爾，瑞士。

免責聲明

微量營養素的萊納斯鮑林研究所信息中心提供的科學信息對健康方面的微量營養素和植物化學物質為一般公眾。該信息提供與理解，作者和出版者不提供醫療，心理，營養諮詢服務或本網站上。這些信息不應該被用來代替諮詢與主管醫療保健或營養專業。

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原文：

Micronutrient Information Center

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Micronutrients and Cognitive Function

Summary

The brain requires a constant supply of micronutrients for energy metabolism of neurons and glial cells, neurotransmitter synthesis and action, nerve impulse propagation, and homocysteine metabolism.(More Information)
Deficiencies in various micronutrients, especially the B vitamins, have adverse effects on cognition.
The developing brain may be particularly vulnerable to deficiencies in choline and essential fatty acids. (More Information)
Due to conflicting studies, more research in needed to determine whether micronutrient supplementation affects attention-related cognitive functions. (More Information)
Presently, there is little evidence that supplementation with B vitamins, antioxidant vitamins, choline, or omega-3 fatty acids will improve memory performance. (More Information)
More research is needed to determine whether micronutrient supplementation has any effects on executive functioning (i.e., higher-order cognitive processes). (More Information)
Some, but not all, studies have reported that micronutrient supplementation improves overall mood and psychological well-being.(More Information)
It is not yet clear whether supplementation with B vitamins, antioxidants, or omega-3 fatty acids protects against age-related cognitive decline. (More Information)
Several methodological issues (e.g., tests used to assess cognition, choice of study population, nature of the supplementation, study duration, etc.) may have contributed to the conflicting results observed in intervention studies. (More Information)

Good nutritional status is important for proper brain development and maintenance of normal cognitive function (1). Through unique biological functions, various micronutrients affect brain function. This article discusses the roles of key micronutrients, including the B vitamins, antioxidant vitamins, and certain essential minerals, in cognitive function. When appropriate, research on the role of other compounds, such as essential fatty acids andcholine, is also presented. The cognitive effects of micronutrient deficiencies are discussed, and the effects of micronutrient supplementation on the broad areas of attention, memory, executive functions, mood, as well as age-related cognitive decline are covered.

Basic Needs for Cognitive Performance

Energy Metabolism of Neurons and Glial Cells

The human brain is a highly metabolically active tissue that depends on a constant supply of glucose to meet its energy needs. In fact, the brain accounts for approximately 25% of total body glucose utilization at rest, despite representing only 2% of adult body weight (2, 3). Blood glucose levels must be maintained at all times to avoid hypoglycemia and to supply the brain with its preferential fuel. During the initial stages of fasting, blood glucose levels are maintained through the breakdown of liver glycogen and then through the process of gluconeogenesis—the production of glucose from non-carbohydrate precursors, such as amino acids. The B vitamin biotin is required for a key enzyme in the gluconeogenic pathway (4). While glucose is the obligatory fuel, ketone bodies can also be used by the brain when glucose supply is inadequate, such as during prolonged fasting or starvation. However, ketone bodies are acidic, and very high levels of these compounds in the blood are toxic and may result in ketoacidosis (5). Thus, glucose is the preferred and normal energy substrate of the brain.

Glucose oxidation in the brain requires certain micronutrients as cofactors. For instance, forms of several B vitamins, including thiamin, riboflavin, niacin, and pantothenic acid, as well as the compound lipoic acid, are utilized in reactions that completely metabolize glucose to carbon dioxide and water(3). Additionally, the nutritionally essential minerals, magnesium, iron, andmanganese are required for the complete metabolism of glucose; these micronutrients are utilized as cofactors, substrates, or components of enzymes in glycolysis and the citric acid cycle (6, 7). Moreover, generation of cellular energy in the form of ATP by the electron transport chain requires the vitamins, riboflavin and niacin; iron contained in iron-sulfur clusters; and theendogenously synthesized compound, coenzyme Q₁₀ (8).

Cerebral Blood Supply

At rest, the brain receives approximately 15% of cardiac output (9). Propercerebral blood supply is necessary to deliver oxygen, glucose and othermacronutrients, and the required micronutrients for proper cognitive function. Nutrition has a role in maintaining optimal blood supply to the brain. For instance, insufficiency of several dietary components increases the risk of developing stroke, a pathological condition that results from impaired cerebral blood supply; see the Disease Index for examples.

Neurotransmitter Synthesis

A neurotransmitter is a chemical released from a nerve cell that transmits an impulse to another nerve cell or an effector cell, such as a muscle cell. Neurotransmitters have either excitatory or inhibitory effects; the type of effect is dependent on the receptor on the receiving cell (10). Neurotransmitters can be broadly divided into two main classes: small amino acids (e.g., gamma aminobutyric acid [GABA], glutamate, aspartate, and glycine) and biogenic amines (e.g., dopamine, epinephrine, norepinephrine,serotonin, histamine, and acetylcholine) (11).

In addition to various amino acids, several B vitamins, including thiamin,riboflavin, niacin, vitamin B₆, folate, and vitamin B₁₂, are needed as cofactorsfor the synthesis of neurotransmitters. Moreover, vitamin C is required for synthesis of norepinephrine (3), and the mineral zinc is important for proper function of GABA, aspartate, and norepinephrine (12). Further, choline is aprecursor for the neurotransmitter acetylcholine (13).

Neurotransmitter Binding to Receptors

Neurotransmitters function by binding to receptors on the cell membrane of the neuron releasing the neurotransmitter (i.e., presynaptic neuron) or to receptors on the cell membrane of the receiving cell (i.e., the postsynaptic neuron). Receptor binding can either mediate the opening of ion channels or cause metabolic changes within the cell (3, 14). Specifically, direct action on ion channels results from neurotransmitter binding to receptor sites on the membrane of postsynaptic neurons. This binding causes the gate-like ion channels to open, which allows ions to flow into the cell (10). Influx of positively charged ions into the postsynaptic neuron can have excitatory effects by depolarizing the membrane; membrane depolarization can cause anerve impulse or action potential if a certain threshold is reached within the neuron. This is commonly referred to as “neuronal firing.” In contrast, influx of negatively charged ions can have inhibitory effects by hyperpolarizing the membrane and thus preventing neuronal firing (15). In addition to direct effects on ion channels, neurotransmitters may bind to G-protein coupled receptors, thereby eliciting cell-signaling effects that could result in metabolic changes (e.g., alterations in activity of various enzymes) within a postsynaptic cell (14).

Vitamins could possibly influence binding of neurotransmitters to postsynaptic receptors. For instance, an in vitro study showed that two forms of vitamin B₆, pyridoxal and pyridoxal phosphate, inhibited the binding of GABA to postsynaptic receptors (16). Also, a rat study associated vitamin B₆ deficiency during fetal development and lactation with changes in the number and binding of dopamine receptors (17).

Nerve Impulse Propagation

The speed at which nerve impulses (action potentials) are propagated is influenced by the myelination of the nerve (18). Myelination refers to the process in which nerves acquire a myelin sheath—the insulating layer of tissue made up of lipids and proteins that surrounds nerve fibers. This sheath acts as a conduit in an electrical system, allowing rapid and efficient transmission of nerve impulses (10).

Certain micronutrients can affect the propagation of nerve impulses. In particular, adequate intake of both folate and vitamin B₁₂ is important in maintaining the integrity of the myelin sheath, and thiamin is needed for maintenance of the nerve’s membrane potential and for proper nerve conductance (3). Additionally, iron has an important role in the development of oligodendrocytes, the cells in the brain that produce myelin (19).

Homocysteine Metabolism

Homocysteine is a sulfur-containing amino acid that is an intermediate in themetabolism of another sulfur-containing amino acid, methionine. Elevated homocysteine levels in the blood (i.e., hyperhomocysteinemia) may be a risk factor for cardiovascular diseases and could also be linked to dementia and Alzheimer’s disease (20, 21). The amount of homocysteine in the blood is regulated by at least three vitamins: folate, vitamin B₆, and vitamin B₁₂ (seediagram). Additionally, the nutrient choline is also involved in homocysteine metabolism. The choline metabolite, betaine, can also provide a methyl group for the conversion of homocysteine to methionine.

Consequences of Select Micronutrient Deficiencies

Thiamin

Thiamin (vitamin B₁) deficiency, like deficiencies in several of the B vitamins, has negative cognitive effects. Adequate intake of thiamin is important for reactions in the brain that metabolize carbohydrates, lipids, and amino acids. For instance, phosphorylated forms of thiamin, including thiamin diphosphate (TDP) and thiamin pyrophosphate (TPP), are required cofactors for enzymesof glycolysis, the citric acid cycle, and the pentose phosphate pathway (22). Additionally, thiamin triphosphate (TTP) may be involved in neuronal membrane functions and nerve impulse (action potential) generation, but the exact biochemical role of TTP is still not well understood (22, 23). Severe thiamin deficiency, which is rare in industrialized nations, except in patients with chronic alcoholism, HIV-AIDS, or gastrointestinal conditions that impair vitamin absorption (23), results in the condition called beriberi, of which there are many forms that involve neurological symptoms. The dry and wet forms of beriberi involve peripheral neuropathy, whereas cerebral beriberi can lead to neuronal cell death and the clinical conditions of Wernicke's encephalopathy and Korsakoff's psychosis, especially in those who chronically abuse alcohol(22, 24). For more information about the various forms of thiamin deficiency, see the separate article on Thiamin.

Niacin

The niacin (vitamin B₃) coenzymes, NAD and NADP, are needed for severalredox and other reactions in the body (see the separate article on Niacin). Severe niacin deficiency, known as pellagra, has been historically associated with poverty and consumption of a diet predominantly based on corn, which is low in bioavailable niacin (25, 26). Today, the condition is uncommon, but it can occur in cases of chronic alcoholism and in individuals with malabsorption syndromes (27). Among other symptoms, pellagra is characterized bydementia. Neurologic symptoms of pellagra include headache, fatigue, apathy, depression, ataxia, poor concentration, delusions, and hallucinations, which can lead to confusion, memory loss, psychosis, and eventual death(27).

Pantothenic Acid

Pantothenic acid (vitamin B₅) is required as a component of coenzyme A (CoA), a coenzyme needed for the oxidative metabolism of glucose and fatty acids and for the biosynthesis of fatty acids, cholesterol, steroid hormones, the hormone melatonin, and the neurotransmitter acetylcholine. A form of the vitamin (4'-phosphopantetheine) is also required for the activity of acyl carrierprotein, which is needed for the synthesis of fatty acids (28), includingphospholipids and sphingolipids. Phospholipids are important structural components of cell membranes, and the sphingolipid, sphingomyelin, is a component of the myelin sheath that enhances nerve transmission (29). Naturally occurring pantothenic acid deficiency in humans is very rare and has been observed only in cases of severe malnutrition (30). Therefore, most information regarding the vitamin deficiency comes from experimentally induced states in laboratory animals. Such studies have found that select deficiency in pantothenic acid causes demyelination (destruction or loss of the myelin sheath) and peripheral nerve damage (13). In humans, pantothenic acid deficiency has been induced experimentally by co-administering a pantothenic acid antagonist and a pantothenic acid-deficient diet. Participants in this experiment complained of headache, fatigue, insomnia, intestinal disturbances, and numbness and tingling of their hands and feet(31). In another study, participants who were fed only a pantothenic acid-free diet did not develop clinical signs of deficiency, although some appeared listless and complained of fatigue (32).

Vitamin B₆

A form of vitamin B₆, pyridoxal 5'-phosphate (PLP), is a required coenzyme for the biosynthesis of several neurotransmitters, including GABA, dopamine, norepinephrine, and serotonin (3). The vitamin has a number of other biological functions (see the separate article on Vitamin B₆). Vitamin B₆concentrations in the brain are about 100 times higher than levels in the blood; thus, it is not surprising that vitamin B₆ deficiency has neurologiceffects (13). Severe deficiency of vitamin B₆ is uncommon, but alcoholics are thought to be most at risk due to low dietary intakes and impaired metabolism of the vitamin. In the early 1950s, seizures were observed in infants as a result of severe vitamin B₆ deficiency caused by an error in the manufacture of infant formula. Additionally, abnormal electroencephalogram (EEG) patterns have been noted in some studies of vitamin B₆ deficiency. Other neurologic symptoms noted in severe vitamin B₆ deficiency include irritability, depression, and confusion (33).

Biotin

Biotin (vitamin B₇) is required as a cofactor for carboxylase enzymes that are important in the metabolism of fatty acids and amino acids. Overt biotin deficiency is quite rare but has been documented in patients on prolonged intravenous feeding (parenteral nutrition) without biotin supplementation; in individuals consuming high amounts of raw egg white that contains avidin, which binds biotin and prevents its absorption; and in those with hereditary disorder, biotinidase deficiency (34). In adults, neurologic symptoms of biotin deficiency include depression, lethargy, hallucinations, and numbness and tingling of the extremities (35).

Vitamin B₁₂

Vitamin B₁₂ deficiency, which affects 10-15% of adults over the age of 60, is frequently associated with neurological problems. Compared to younger individuals, this vitamin deficiency is more common in older adults because of the higher prevalence of food-bound vitamin B₁₂ malabsorption (atrophic gastritis) and the higher incidence of the autoimmune condition, pernicious anemia (39). Hematological changes, including elevated blood levels ofhomocysteine and methylmalonic acid, are diagnostic of vitamin B₁₂deficiency; however, approximately 25% of cases include neurological symptoms as the only clinical indicator of vitamin B₁₂ deficiency (40, 41). Such neurologic symptoms of vitamin B₁₂ deficiency include numbness and tingling of the extremities, especially the legs; difficulty walking; concentration problems; memory loss; disorientation; and dementia that may or may not be accompanied by mood changes (41). In some cases, the dementia and other neurologic symptoms caused by vitamin B₁₂ deficiency can be reversed by vitamin treatment (42), but reversibility seems to be dependent upon the duration of the associated neurologic complications (41). While the biochemical mechanisms underlying the neurological effects of vitamin B₁₂deficiency are not understood, the vitamin deficiency is known to damage themyelin sheath covering cranial, spinal, and peripheral nerves (42, 43).

Vitamin C

Vitamin C accumulates in the central nervous system, with neurons of the brain having especially high levels (44). In addition to its well-knownantioxidant functions, vitamin C has a number of non-antioxidant functions. For instance, the vitamin is required for enzymatic reaction that synthesizesthe neurotransmitter norepinephrine from dopamine. Another non-antioxidant action of vitamin C in the brain is in the reduction of metal (e.g.,iron, copper) ions (44). Further, vitamin C may also be able to regeneratevitamin E (45), an important lipid-soluble antioxidant. Vitamin C deficiency causes oxidative damage to macromolecules (lipids, proteins) in the brain(13). Severe vitamin C deficiency, called scurvy, is a potentially fatal disease. However, in scurvy, vitamin C is retained by the brain for neuronal function, and eventual death from the disease is more likely due to lack of vitamin C forcollagen synthesis (44). Collagen is an important structural component of blood vessels, tendons, ligaments, and bone.

Vitamin D

The vitamin D receptor is expressed in brain tissue (46), and vitamin D is known to be important for normal brain development and function (47). Accordingly, vitamin D deficiency may impair cognitive abilities. Vitamin D deficiency is a major problem worldwide, with an estimated one billion people having insufficient or deficient levels of circulating 25-hydroxyvitamin D (48). Aging is associated with a reduced capacity to synthesize vitamin D in the skin upon sun exposure (49). Thus, older adults may be more vulnerable to vitamin D deficiency and any untoward effects on cognition. Some studies in older adults have either linked lower 25-hydroxyvitamin D levels with measures of poor cognitive performance (50-53) or higher 25-hydroxyvitamin D levels with measures of better cognitive performance (54, 55). However, a recent systematic review of five observational studies concluded that the association between 25-hydroxyvitamin D concentrations and cognitive performance is not yet clear (56). More research, especially from randomized controlled trials, is needed to determine whether vitamin D deficiency has adverse effects on cognition.

Vitamin E

The alpha-tocopherol form of vitamin E is an important lipid-solubleantioxidant. In the brain and other tissues, alpha-tocopherol has a key role in preventing oxidant-induced lipid destruction and is therefore vital in maintaining the integrity of cell membranes. Accordingly, vitamin E deficiency causes lipid peroxidation in brain tissues (57). Severe vitamin E deficiency results mainly in neurological symptoms, including impaired balance and coordination (ataxia), injury to the sensory nerves (peripheral neuropathy), muscle weakness (myopathy), and damage to the retina of the eye (pigmented retinopathy). For this reason, people who develop peripheral neuropathy, ataxia, or retinitis pigmentosa should be screened for vitamin E deficiency (58). The developing nervous system appears to be especially vulnerable to vitamin E deficiency. For instance, children who have with severe vitamin E deficiency from birth and are not treated with vitamin E rapidly develop neurological symptoms. In contrast, individuals who develop malabsorption of vitamin E in adulthood may not develop neurological symptoms for ten to 20 years. It should be noted, however, that symptomatic vitamin E deficiency in healthy individuals who consume diets low in vitamin E has never been reported (58, 59).

Calcium

Calcium ions are important intracellular signals that regulate a number of physiological processes, including neuronal gene expression, neuronal secretion of neurotransmitters into synapses, and synaptic plasticity(reviewed in 60). Normal blood levels of calcium are maintained even when dietary intake of calcium is inadequate because the skeleton provides a large reserve of the mineral. Thus, effects of dietary calcium inadequacy would primarily result in negative effects to bone health. Interestingly, changes in calcium homeostasis in the brain may contribute to the cognitive decline associated with normal aging and possibly to the development of neurodegenerative disorders (61, 62).

Iodine

Iodine is required for the synthesis of thyroid hormones that regulate a number of physiological processes, including growth, development, metabolism, and reproduction (63, 64). In addition, thyroid hormones are important for myelination of the central nervous system, which mostly occurs before and shortly after birth (64, 65). Because iodine is critical for normal development of the brain, deficiency of this mineral during critical periods, such as during fetal development or during early childhood, can have deleterious effects on cognition. The most extreme cognitive effect of developmental iodine deficiency is irreversible mental retardation; milder cognitive effects include various neurodevelopmental deficits, including intellectual impairment (66, 67). For more information on iodine deficiency, which is now accepted as the most common cause of preventable brain damage in the world, see the separate article on Iodine.

Iron

Iron is an essential component of hundreds of proteins and enzymes involved in various aspects of cellular metabolism, including those involved in oxygen transport and storage, electron transport and energy generation, and DNA synthesis (see the separate article on Iron). Iron is needed for proper development of oligodendrocytes (the brain cells that produce myelin) (19), and the mineral is also a required cofactor for several enzymes that synthesize neurotransmitters (68). Accordingly, iron deficiency during various stages of brain development has detrimental consequences. Pregnant women are at increased risk of iron deficiency because iron requirements are significantly increased during pregnancy due to increased iron utilization by the developing fetus and placenta and because of blood volume expansion(69). Maternal iron deficiency has serious consequences for the woman and the fetus (70). Animal studies have shown that maternal iron deficiency results in decreased iron concentrations in the brain and permanent changes in cognitive performance and behavior in the offspring (71). In humans, iron deficiency during perinatal stages results in persistent deficits in learning and memory (reviewed in 60). Moreover, iron deficiency in later stages of development, such as during childhood, may be associated with impaired cognitive development (see the separate article on Iron). While iron is essential for brain function, it is toxic to neurons at high concentrations (60).

Magnesium

Magnesium is required for more than 300 metabolic reactions in the body, many being important for normal brain function (see the separate article onMagnesium). Magnesium deficiency in healthy individuals who are consuming a balanced diet is uncommon because the mineral is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. However, magnesium deficiency has been induced experimentally and results in neurologic and muscular symptoms that include tremor, muscle spasms, and tetany (72). In fact, enzymes involved in neuromuscular activity (i.e., the ATPase enzymes that transport of sodium, potassium, and calcium ions) are apparently most sensitive to magnesium deficiency (69).

Selenium

Selenium is required for glutathione peroxidases (GPx)—importantantioxidant enzymes in the brain and other tissues. GPx reduce potentially damaging reactive oxygen species (ROS), such as hydrogen peroxide and lipid hydroperoxides, to harmless products like water and alcohols by coupling their reduction with the oxidation of glutathione (see the diagram in the separate article on selenium) (73, 74). Selenium deficiency has been associated with decreased GPx activity in the brain of laboratory animals(75); thus, selenium deficiency may be linked to a reduced antioxidant capacity in the brain.

Zinc

Zinc is present at high levels in the brain where it has catalytic, structural, and regulatory roles in cellular metabolism (see the separate article on Zinc). In the brain, most of the zinc ion is tightly bound to proteins, but free zinc is present in synaptic vesicles and has a role in neurotransmission mediated by glutamate and GABA (76). Experimentally induced zinc deficiency in humans has been shown to impair measures of mental and neurologic function (77). Deficiency of the mineral during critical periods of cognitive development can be more devastating. For instance, zinc deficiency during fetal brain development can cause congenital malformations, and zinc deficiency during later stages of brain development have been associated with deficits in attention, learning, memory, and neuropsychological behavior (13, 78, 79). On the other hand, cellular release of zinc in the brain can mediate neuronal apoptosis and may be pathologically associated with Alzheimer’s disease andamyotrophic lateral sclerosis (ALS) (80). Thus, intracellular zinc levels in the brain are homeostatically regulated.

Choline

Choline can be synthesized by the body in small amounts, but dietary intake is needed to maintain health. Thus, choline is considered to be an essential nutrient for humans (81). Choline and its metabolites have a number of vital biological functions (see the separate article on Choline) (82-84). With respect to cognitive function, choline is needed for myelination of nerves and is a precursor for acetylcholine—an important neurotransmitter involved in muscle action, memory, and other functions. Choline is also used in the synthesis of the phospholipids, phosphatidylcholine and sphingomyelin, which are structural components of cell membranes and precursors for certain cell-signaling molecules. Studies in laboratory rats have shown that choline deficiency during the perinatal period results in persistent memory and other cognitive deficits (85).

Essential Fatty Acids

Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids (PUFA), meaning they contain more than one cis double bond (86). The essential fatty acids include alpha-linolenic acid (ALA), an omega-3 fatty acid, and linoleic acid (LA), an omega-6 fatty acid. ALA and LA cannot be synthesized by humans and thus must be obtained from the diet; dietary intake recommendations set by the Institute of Medicine are for ALA and LA (see the separate article on Essential Fatty Acids) (86). The long-chain omega-6 fatty acid, arachidonic acid (AA), can be synthesized from LA. Additionally, two long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can be synthesized from ALA, but their synthesis may be insufficient under certain conditions, such as during pregnancy and lactation (87, 88).

Excluding adipose tissue, tissue of the nervous system has the greatest concentration of lipids in the human body (89). Lipids found in the human body include fatty acids, phospholipids, triglycerides, and cholesterol. Omega-3 and omega-6 PUFA are incorporated into phospholipids, where they not only serve structural roles in cell membranes of the nervous system, but also affect membrane fluidity, flexibility, permeability, as well as the activities of membrane-associated enzymes and receptors (13, 90). Through these effects, omega-3 and 6 PUFA play several important roles in vision and nervous system function. DHA is selectively incorporated into retinal andneuronal cell membranes (91, 92), suggesting it plays important roles in vision and nervous system function. The phospholipids of the brain's gray matter contain high proportions of DHA and AA, indicating they are important to central nervous system function (93). Brain DHA content may be particularly important, since animal studies have shown that depletion of DHA in the brain can result in learning deficits. It is not clear how DHA affects brain function, but changes in DHA content of neuronal cell membranes could alter the function of ion channels or membrane-associated receptors, as well as the availability of neurotransmitters (94).

In general, essential fatty acid deficiency (i.e., deficiency of both ALA and LA) has been observed only in patients with chronic fat malabsorption, cystic fibrosis, or those on parenteral nutrition without PUFA (86, 95) (see the article on Essential Fatty Acids). Clinical manifestations of essential fatty acid deficiency primarily include skin effects (i.e., dermatitis), but negativehematologic effects and impaired immunity have also been seen in humans(96). Decreased physical growth in infants and children is also associated with essential fatty acid deficiency. The developing brain may be especially vulnerable to the effects of deficiencies in essential fatty acids (97). Since phospholipids of certain brain regions are enriched with DHA and AA, omega-3 or omega-6 PUFA deficiency during brain development could have lasting effects on visual and cognitive function (13). For instance, studies in laboratory rodents have found that dietary omega-3 PUFA deficiency impaired measures of cognitive performance through influencing the dopamine neurotransmitter system in the frontal cortex region of the brain (98). Omega-3 PUFA deficiency during fetal development has also been shown to have untoward effects on visual function (reviewed in 99, 100).

Effects of Micronutrient Supplementation

Compared to the consequences of micronutrient deficiencies, considerably less is known regarding the cognitive effects of micronutrient supplementation. Many of the intervention trials conducted to date have examined whether supplementation with B vitamins might attenuate the cognitive decline associated with normal aging. Other trials have looked at whether micronutrient supplementation improves specific measures of cognitive performance, including attention, memory, and various executive functions. These and other cognitive functions are interrelated; for example, memory of new information is dependent on proper attention (101). Additionally, cognitive performance can be affected by other factors, including one’s overall mood (101). A summary of randomized controlled trials (RCTs)on these cognitive parameters is presented below.

Attention

Attention is the mental process of selectively concentrating on information while excluding extraneous information. Proper attention is needed for higher-order cognitive abilities; thus, deficits in attention can profoundly affect learning and behavior (102). While there are different types of attention (i.e., selective, divided, sustained) (101), neuropsychological tests measure attention to either visual or auditory stimuli (102).

A few trials have assessed the effect of multivitamin/mineral supplementation on attention, with most being conducted in school-aged children. Yet, a 1-year placebo-controlled, double-blind trial that provided ten times the recommendation of nine vitamins was carried out in 127 healthy young adults (aged 17-27 years) (103). Compared to baseline measurements, the multiple vitamin supplementation was associated with improvements on two assessments of attention in women but not in men; however, the differences between the vitamin and placebo groups were not statistically different at any of the measured timepoints (3 months, 6 or 9 months, and 12 months)(103). In a 14-month randomized, double-blind, placebo-controlled trial that administered a daily micronutrient-fortified beverage (details lacking) or placebo to 608 children (aged 6-15 years) in India, micronutrient supplementation was linked to improved scores on one measure of attention and concentration (Knox Cube test) but not on another assessment (Letter Cancellation test) (104). Another trial administered a micronutrient-fortified (vitamins A, B₆, B₁₂, C, and folate and the minerals, iron and zinc) drink, a drink fortified with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), a drink fortified with the micronutrients and omega-3 fatty acids, or placebo for six days a week for 12 months to 644 school-aged children in Australia and Indonesia (105). This trial reported that the various treatments had no effect on attention compared to placebo, despite some improvements in nutrient status (105). Most recently, a randomized, double-blind, placebo-controlled trial in 81 children (8-14 years) residing in the UK found that use of a daily multivitamin/mineral supplement, containing most vitamins as well as iron, copper, zinc, calcium, and magnesium, was associated with an increase in accuracy on one attention task (Arrows Flankers test) throughout the 12-week study (106). Thus, trials conducted to date are conflicting and more research is needed to determine the effect of micronutrient supplementation on attention in children or adults.

Memory

Memory refers to one’s ability to encode, organize, and store new information and recall the information on demand. Other cognitive functions, such as learning, reasoning, and language, are dependent on a functioning memory(107). Experimental methods that assess memory functions often measure the speed or accuracy of response to a certain task (101). To date, there have been few clinical trials that have examined the effects of supplemental micronutrients on aspects of memory. Most of the research is observationaland concerns blood levels of B vitamins or antioxidant vitamins and memory performance.

Some, but not all, observational studies have found that elderly individuals with lower status of folate and/or vitamin B₁₂ may have poorer memory performance, especially episodic memory (i.e., memory of events, times, and places) (108-111). In addition, one study found that higher plasma levels ofvitamin B₆ were associated with better performance on two measures of memory performance (112). Some observational studies in elderly people have also found that lower blood levels of vitamin C or vitamin E to be associated with poorer performance on cognitive tests of memory (109, 113, 114). Vitamins C and E are the two antioxidant vitamins. While overt deficiencies in specific vitamins have cognitive effects (see Consequences of Select Micronutrient Deficiencies above), correcting subclinical deficiencies through supplementation could possibly improve aspects of memory.

However, clinical trials on the effect of supplemental B vitamins or antioxidant vitamins on memory performance are limited and their findings are inconclusive. Elevated homocysteine levels in the blood may be linked todementia and Alzheimer’s disease (21). Vitamin B₆, folate, and vitamin B₁₂regulate the amount of circulating homocysteine (see diagram), and a deficiency of any of these B vitamins can lead to hyperhomocysteinemia, a condition treated through B vitamin supplementation. A 3-year randomized,double-blind, placebo-controlled trial in 818 older adults (aged 50-70 years) with elevated homocysteine levels but normal serum vitamin B₁₂ levels found that folic acid supplementation (800 mcg/day) lowered homocysteine levels and improved measures of memory performance (115). However, a 1-year randomized, double-blind, placebo-controlled trial in 253 elderly (≥ 65 years) adults with elevated homocysteine levels found that B vitamin supplementation (1,000 mcg/day of folate, 10 mg/day of vitamin B₆, and 500 mcg/day of vitamin B₁₂) did not improve measures of cognitive function, including memory, despite lowering homocysteine levels (116). Additionally, a randomized, double-blind, placebo-controlled trial in 162 elderly people (≥ 70 years) with mild vitamin B₁₂ deficiency found that vitamin B₁₂supplementation for 24 weeks, alone or in combination with folic acid, did not improve memory performance (117). Another trial found that vitamin B₆supplementation (20 mg/day of pyridoxine hydrochloride) for three months improved memory, especially long-term memory, in 38 healthy elderly men (70-79 years) compared to 38 men of similar age who received a placebo(118). Further, a placebo-controlled trial in 211 healthy adult women of varying ages found that B vitamin supplementation (750 mcg/day of folic acid, 75 mg/day of vitamin B₆, or 15 mcg/day of vitamin B₁₂) only slightly improved some measures of memory function (119). Thus, results of intervention trialsof B vitamin supplementation are conflicting.

Because normal aging is associated with increased free radical-induced damage in the body and also with memory loss, antioxidant supplementation might slow age-related memory declines (120). Randomized controlled trials (RCTs) of antioxidant supplementation that evaluate memory functions are needed to evaluate this hypothesis. Some of the existing trials have examined whether vitamin E supplements might slow the cognitive decline associated with certain neurodegenerative diseases, such as Parkinson’s disease or Alzheimer’s disease, although few have conducted specific assessments of memory. One trial examined the effect of using vitamin E supplements (for a mean of 14 months) on memory performance in patients with early, untreated Parkinson’s disease. Specifically, performance on digit span and various recall tasks did not differ between the 174 patients who were given 2,000 IU/day of synthetic alpha-tocopherol (equivalent to 900 mg/day of RRR-alpha-tocopherol) and the 174 patients who were administered a placebo (121). Another trial evaluated whether the same dose of alpha-tocopherol, when provided for two years, could possibly treat moderately severe Alzheimer’s disease. Compared to use of a placebo (84 patients) in this trial, use of alpha-tocopherol (85 patients) significantly slowed progression of Alzheimer's dementia, evidenced by significant improvements on the Blessed Dementia Scale and time to institutionalization(122). However, alpha-tocopherol supplementation did not affect scores on the Alzheimer’s Disease Assessment Scale and the Mini-Mental State Examination, which in part involve assessment of memory performance (122). For more information on the use of vitamin E in the treatment of Alzheimer’s disease, see the separate article on Vitamin E. Overall, there is currently little evidence from RCTs that antioxidant supplementation improves memory performance in individuals with neurodegenerative conditions. More research is needed to determine the effects of antioxidant supplements on memory in healthy individuals.

Choline is an essential nutrient that has a number of vital biological functions (see the separate article on Choline). Increased dietary intake of choline very early in life can diminish the severity of memory deficits in aged rats. Choline supplementation of the mothers of unborn rats, as well as rat pups during the first month of life, leads to improved performance in spatial memory tests months after choline supplementation has been discontinued (123). A review by McCann et al. discusses the experimental evidence from rodent studies regarding the availability of choline during prenatal development and cognitive function in the offspring (124). It is not clear whether findings in rodent studies are applicable to humans. More research is needed to determine the role of choline in the developing brain and whether choline intake is useful in the prevention of memory loss or dementia in humans. Trials evaluating the therapeutic use of choline supplementation for memory loss in patients with Alzheimer’s disease have mainly reported no memory-related benefits (reviewed in 125). Additionally, there is little evidence that choline improves memory in elderly individuals without dementia (126).

Further, omega-3 fatty acid supplementation could possibly help prevent or treat neurological disorders associated with memory loss like Alzheimer’s disease. Docosahexaenoic acid (DHA; 22:6n-3), the major omega-3 fatty acid in the brain, appears to be protective against the development of Alzheimer's disease and other types of dementia (127) (see the separate article onEssential Fatty Acids). Although results of studies in animal models have been promising (reviewed in 128), it is not yet known whether DHA supplementation can help treat Alzheimer's disease in humans. Recently, a randomized, double-blind, placebo-controlled trial in 295 patients with Alzheimer’s disease found that DHA supplementation (2 grams/day) for 18 months was not effective in slowing cognitive decline (129).

Executive Functions

Executive functions refer to several higher-order cognitive processes, such as reasoning, planning, strategic thinking, problem solving, and multitasking(101, 130, 131). Specific examples of executive functions include shifting between two behaviors, inhibiting habitual behaviors, updating information, and planning (131). Such executive functions are experimentally assessed by employing cognitive tasks like the Wisconsin card-sorting test, the Stroop color-word test, or verbal fluency tests (102, 132). Certain cognitive tasks measuring one executive function may assess other cognitive functions as well (131).

To date, few studies have examined the effects of micronutrientsupplementation on executive functioning. In a randomized, double-blind,placebo-controlled trial in 216 healthy women (25-50 years old), supplementation with a daily multivitamin/mineral for nine weeks was associated with a significant increase in speed and accuracy of performance on the Stroop color-word test (133). Overall, micronutrient supplementation in this trial was associated with increased accuracy of performance on a battery of tests assessing multitasking (133). Yet, a randomized, double-blind, placebo-controlled trial in 215 men (35-55 years old) found that daily supplementation with B vitamins (at 3 to 13 times the current RDA, except forfolic acid, which was included at a dose equivalent to the RDA), vitamin C(500 mg/day), zinc (10 mg/day), and magnesium (100 mg/day) for 33 days had no effect on measured performance of executive functions, including the Stroop color-word test, the peg-and-ball task, and the Wisconsin card-sorting task (134). Additionally, a 1-year placebo-controlled trial in adults aged 65 years and older found that daily supplementation with a multivitamin/mineral did not benefit cognitive performance on a verbal fluency test—an assessment in which participants were asked to list words starting with a certain letter in a designated time period (135). Further, a placebo-controlled trial in 152 elderly adults (aged 70-80 years) with mild cognitive impairment reported that B vitamin supplementation (50 mg/day of vitamin B₆, 5 mg/day of folic acid, and 0.4 mg/day of vitamin B₁₂) for one year did not improve performance on a similar test of verbal fluency (136). More research is needed to determine whether micronutrient supplementation has any effects on executive functioning in various populations.

Mood and Psychological Well-Being

Deficiencies in select micronutrients, mainly certain B vitamins, have been linked to depression (see above). Thus, micronutrient supplementation, especially in individuals with overt or marginal deficiencies, could possibly improve overall mood state and psychological well-being. Most studies discussed in this section were conducted in healthy individuals. It is important to note that mood state is commonly assessed by self-rating scales, such as self-administered questionnaires, which are not objective measurements(101).

Several studies in people of varying ages have evaluated whether taking a daily multivitamin/mineral supplement is associated with changes in mood state or psychological well-being. A randomized, double-blind, placebo-controlled in 129 young healthy adults found that taking a supplement that contained ten times the daily intake recommendations for nine different vitamins (vitamin A, thiamin, riboflavin, niacin, vitamin B₆, folic acid, vitamin B₁₂, vitamin C, vitamin E) for one year improved one self-assessment of mood, i.e., being “more agreeable” (137). Trials conducted more recently have been of much shorter duration, typically lasting about one to three months. For instance, a double-blind, placebo-controlled study in 80 healthy men, aged 18 to 42 years, found that use of a multivitamin/mineral supplement for 28 days was associated with reductions in the subjective measures of anxiety and perceived stress (138). In this study, the dosage of B vitamins and vitamin C was 3 to 12 times the current U.S. RDA, zinc was contained at an amount almost the RDA, and the supplement also contained fractions of the RDA for calcium and magnesium (138). More recently, a randomized, double-blind, placebo-controlled trial in 215 men, aged 35 to 55 years, examined the effects of supplemental B vitamins (at 3 to 13 times the current RDA, except for folic acid which was included at a dose equivalent to the RDA), vitamin C (500 mg/day), and the minerals, zinc (10 mg/day), calcium (100 mg/day), and magnesium (100 mg/day) on mood and perceived stress(134). Compared to placebo, men who took the multiple vitamin-mineral supplement for 33 days had significantly improved ratings on one (vigor-activity score) of the six components of the Profile of Mood States (POMS) scale, significantly reduced subjective stress as measured by the Perceived Stress Scale, and significantly improved self-ratings of mental tiredness prior to and following a battery of cognitively demanding tasks (134). Additionally, in a 30-day placebo-controlled trial in 300 adults (aged 18-65 years), supplementation with the B vitamins (at doses of about 3 to 13 times the RDA, excluding folic acid), vitamin C (1,000 mg/day), calcium (100 mg/day), and magnesium (100 mg/day) was associated with significant improvements in various scores of psychological stress compared to a placebo (139). However, a trial in 216 healthy women (25-50 years old) found little benefit of a multivitamin/mineral supplement; micronutrient supplement use for nine weeks had no effect on several measures of mood, including a health survey, a fatigue survey, and the POMS assessment, but was associated with a reduction in perceived physical tiredness on a computerized assessment of multi-tasking (133). Further, a randomized, double-blind, placebo-controlled trial in 81 healthy children, aged 8 to 14 years, reported that supplementation with a daily multivitamin/mineral for 12 weeks had no effect on various measures of mood (106). Interestingly, a small trial in 30 premenopausal women found that daily multivitamin supplementation for ten weeks did not improve overall mood, but when the supplement also contained 7 mg/day of zinc (RDA=8 mg/day), the authors noted significant improvements in two components of POMS: the anger-hostility and the depression-dejection scores (140).

In addition to zinc, supplementation with other single nutrients may impact mood. In one study of 127 young mean age, 20.3 years) women, supplementation with a high dose of thiamin (50 mg/day; 45 times the current RDA) for two months was linked to improvements in self-reported mood, including the feeling of being more clear-headed (141). Two trials in acutely hospitalized patients have shown that short-term (around 7 days) vitamin C supplementation increased concentrations of ascorbic acid inplasma and leukocytes and led to 34-35% improvements in mood state, as measured by POMS (142, 143).

Deficiencies in other micronutrients, including vitamin B₆, vitamin B₁₂, andomega-3 fatty acids, have been linked to depression (see the Disease Index), and vitamin D deficiency has also been associated with negative effects on mood (51, 144). However, it is not known whether supplementation with these nutrients improves overall mood or depressive symptoms in those with depression.

Most of the abovementioned studies were conducted in individuals presumed to be healthy. Given that fact that a significant percentage of the general population does not consume adequate dietary levels for several micronutrients (145), a daily multivitamin/mineral supplement could help improve micronutrient status and possibly have some cognitive and other health benefits. However, more research is needed to determine whether multivitamin/mineral or single nutrient supplements improve mood state, psychological stress, and overall mental function.

Age-Related Cognitive Decline

Normal aging is associated with mild cognitive impairments that are caused by various neuroanatomical changes, including alterations in brain receptors,myelin dystrophy, loss of dendritic spines, and changes in nerve transmission(146). Good nutritional status is known to be important for normal cognitive functioning, but the role of diet in the prevention of age-related cognitive decline is not well understood. Adequate dietary intake of B vitamins,antioxidant vitamins, essential minerals, and omega-3 fatty acids may help protect against the cognitive decline associated with normal aging (1). However, it is not known whether supplemental intake of these nutrients would result in additional benefits. Intervention trials are limited, and the findings of available trials are inconsistent. Overall, little benefit has been observed with micronutrient or omega-3 fatty acid supplementation. Cognitive effects could possibly depend on baseline nutritional status, i.e., any benefits of micronutrient supplementation might only be realized in individuals with micronutrient deficiencies and not in those with adequate micronutrient status. Another important factor is a person’s age at time of intervention, as nutritional interventions should ideally start at or before the observed cognitive decline (146). This section reviews the findings of clinical trials using B vitamins, antioxidant vitamins, and omega-3 fatty acids as possible therapeutics for normal cognitive aging. Studies in individuals withdementia and other related pathologies are not covered in this article.

Deficiencies in many of the B vitamins results in negative cognitive effects (see Consequences of Select Micronutrient Deficiencies), and a number of studies have linked lower blood levels of B vitamins with some cognitive impairments (147-154). Vitamin B₆, folate, and vitamin B₁₂ regulate blood levels of homocysteine (see Homocysteine Metabolism above and diagram)—an amino acid derived from methionine that may be associated with cognitive decline (155). However, evidence that B vitamin supplementation lowers the risk of cognitive decline is lacking. Three recent systematic reviews and ameta-analysis all concluded that short-term supplementation with folic acid, with or without other B vitamins, does not improve age-related cognitive decline or overall cognition and that trials of longer duration are needed (21,156-158).

Because age-related cognitive decline has been linked to free radical-inducedoxidative damage in the brain (159, 160), antioxidant supplements might help protect against cognitive aging. Prospective cohort studies have reported that vitamin C intake from supplements (161, 162) or vitamin Eintake from food and supplements (161) was associated with some protection against cognitive decline. However, randomized controlled trialsare needed to determine whether antioxidant supplements slow or prevent age-related cognitive decline. One randomized, double-blind, placebo-controlled trial found no evidence that a daily antioxidant supplement containing 12 mg of beta-carotene, 500 mg of vitamin C, and 400 mg of vitamin E, when taken for up to 12 months, improved mental performance in elderly people (163). Another placebo-controlled trial in older adults at high risk of dementia found that supplementation with vitamin C (200 mg/day) and vitamin E (500 mg/day) for 12 weeks did not alter any of the measured cognitive functions despite nonsignificantly lowering levels of
F₂-isoprostanes—biomarkers of lipid peroxidation in vivo. Large-scale trials of longer duration are needed to understand whether antioxidant supplementation might help prevent age-related cognitive decline. For more information on micronutrients and phytochemicals related to cognitive decline or neurodegenerative diseases, see the article, Micronutrients for Older Adults.

Cognitive decline has been linked to decreased levels of docosahexaenoic acid (DHA) in the brain (164). DHA is a long-chain omega 3-fatty acid found in oily fish (see the separate article on Essential Fatty Acids). Severalobservational studies have associated higher intakes of fish with benefits related to cognitive performance (165, 166) and cognitive decline (167, 168), as well as with lower risks of some types of dementia, including Alzheimer’s disease (166, 169-171). Additionally, one prospective cohort study reported an inverse association between omega-3 fatty acid content of red blood cell membranes (an indicator of omega-3 fatty acid intake) and cognitive decline(172). Thus, supplementation with DHA and perhaps other long-chain omega-3 fatty acids may help maintain cognition during aging and could possibly help protect against age-related cognitive decline. To date, clinical trials of omega-3 fatty acid supplementation have been mainly conducted in patients with vascular dementia, Alzheimer’s disease, or other brain pathologies (173, 174). Long-term intervention studies in healthy individuals or in those with mild cognitive impairment are needed. Results of the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study were recently published(175). In this trial, 748 cognitively healthy elderly adults, aged 70-79 years, were supplemented for two years with a combination of 500 mg/day of DHA and 200 mg/day of eicosapentaenoic acid or with a placebo containing olive oil. Cognitive function did not decline in either group over the 2-year period(175), suggesting that longer intervention trials are needed to determine whether long-chain omega-3 fatty acids have utility in the prevention of age-related cognitive decline. A 3-year trial of DHA supplementation (800 mg/day) in elderly adults without dementia is currently underway (see:www.clinicaltrials.gov).

Conclusion

While we have a good understanding of the consequences of micronutrientdeficiencies on cognition, we know considerably less about the cognitiveeffects of micronutrient supplementation. At present, there is little evidence that micronutrient supplementation provides cognitive benefits, with the reported benefits being mostly related to mood. To date, several of therandomized controlled trials (RCTs) have been conducted either in the elderly or in individuals with pathological conditions like Alzheimer’s disease. Therefore, there is a need for well-designed, large-scale, long-term RCTs in healthy adults, in individuals with micronutrient deficiencies, as well as in children—an age group undergoing rapid cognitive and brain development. Provision of micronutrients for several years may be required to observe any cognitive effects. Studies that measure micronutrient status in blood and correlate that with cognitive function are also needed to better assess the role of micronutrients on mental function. In general, supplementation with a broad range of micronutrients, rather than one or a selected few, would cover the micronutrient needs of more of the sample and would also be sensible given the well-known interactions among the various micronutrients with respect to cognition. While this approach may create complications in terms of attributing any demonstrated cognitive effects, assessment of the nutritional status at baseline and after supplementation will presumably help inform mechanistic questions.

Additionally, it is important to note that the available RCTs have utilized a plethora of cognitive tests to study the effects of micronutrient supplementation. A recent systematic review of 39 RCTs using supplemental micronutrients or phytochemicals found that the trials utilized 121 different cognitive tasks, thereby making it difficult for comparison among studies and for overall data interpretation (131). Thus, the field would benefit from more standardized and systematic approaches to study the effect of micronutrient supplementation on cognitive functions. Many of the paper and pencil questionnaires employed to assess cognitive abilities may not be sensitive enough to detect small changes that result from short-term interventions of micronutrient supplementation (101, 102). On the other hand, validated computer-based tests are becoming widely available; such tests ensure high sensitivity of measurement, both in terms of accuracy and speed of performance across various cognitive domains. Increased use of computerized cognitive assessments may aid in the ability to detect subtle changes that might result from micronutrient supplementation in healthy individuals.

Although it is not yet clear whether micronutrient supplementation has beneficial effects on various cognitive domains, it is well-established that micronutrient deficiencies, especially B vitamin deficiencies, have adverse effects on cognition. Eating a good diet is important for optimum health and prevention of chronic disease (see Healthy Eating in the LPI Rx for Health). U.S. national surveys indicate that a significant proportion of Americans are not meeting the current recommended intakes for a number of micronutrients, including vitamin E, magnesium, vitamin A, and vitamin C. As part of its Prescription for Health, the Linus Pauling Institute recommends a daily multivitamin/mineral supplement as nutritional insurance to meet micronutrient needs (see Supplements in the LPI Rx for Health).

References

Written in February 2011 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in February 2011 by:
Juerg Haller, Ph.D.
F. Hoffman-La Roche Ltd
Basel, Switzerland

This article was underwritten, in part, by a grant from
Bayer Consumer Care AG, Basel, Switzerland.

Disclaimer

The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.

The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.

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