JP5496989B2 - Measurement calculation method to evaluate cognitive function - Google Patents
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Description
本発明は高精度で簡便かつ再現性のよい認知機能の評価方法に関する。 The present invention relates to a method for evaluating a cognitive function with high accuracy, simplicity and good reproducibility.
従来、認知症の診断で最も用いられるものは、アメリカの精神医学会が提唱しているＤＳＭ−ＩＶ（精神障害の診断と統計の手引き）である。これは、アルツハイマーや脳血管認知症など種々認知症に共通する診断基準で、多彩な認知障害の発現として、記憶障害以外に、失語、失行、失認、実行機能障害のいずれかがあり、それらが原因で社会生活に支障をきたすこと、さらに認知欠損はせん妄の経過中にのみ観察されるものではないこと、上記状態が、脳などの身体的な原因があるか、あると推測されること、としている。また、認知症の診断にはＳＰＥＣ（単一光子放射断層撮影）やＰＥＴ（ポジトロン断層法）の脳画像による解析も推奨されている。 Conventionally, the most used diagnosis of dementia is DSM-IV (Guide for diagnosis and statistics of mental disorders) proposed by the American Psychiatric Association. This is a diagnostic standard common to various dementias such as Alzheimer and cerebrovascular dementia. In addition to memory impairment, there are any of aphasia, aphasia, agnosia, and executive dysfunction, It is presumed that they cause problems in social life, and that cognitive deficits are not observed only during the course of delirium, and that the above condition may have a physical cause such as the brain It is said that. For diagnosis of dementia, analysis based on brain images of SPEC (single photon emission tomography) and PET (positron tomography) is also recommended.
その他最近では、患者の代謝産物マーカーの定量化から認知症を診断する「認知症及び神経障害の診断方法（特許文献１）」、標本細胞、組織または体液からミトコンドリア制御領域の存在やその程度の判定から「アルツハイマー病および他の神経変性疾患の発症前または発症後診断の方法および組成物（特許文献２）」の提案、さらに無症候患者のアミロイド沈着を伴う疾患への進行や病因が疑わしい認知症傾向障害を呈している患者におけるアミロイド沈着疾患を同定するための「アミロイド沈着を伴う疾患の前駆形態の診断方法（特許文献３）」、特定のアミロイドβペプチドの比の決定に基いた「アルツハイマー病の予測、診断および鑑別診断のための方法（特許文献４）」、糖鎖を付加したトランスフェリンに着目した「アルツハイマーの診断キット、診断マーカー及び病態指標の検出方法（特許文献５）」などが開示されている。 Other recently, "Diagnosis method for dementia and neuropathy (patent document 1)" for diagnosing dementia by quantifying patient metabolite markers, presence of mitochondrial control region and its extent from specimen cells, tissues or body fluids From the judgment, proposal of “method and composition for pre- or post-onset diagnosis of Alzheimer's disease and other neurodegenerative diseases (Patent Document 2)”, and further progression of asymptomatic patients with amyloid deposition and cognition with suspected etiology "Diagnosis method of precursor form of disease with amyloid deposition (patent document 3)" for identifying amyloid deposition disease in patients presenting with symptomatic disorder, "Alzheimer's" based on determination of ratio of specific amyloid β peptide "Method for Predicting, Diagnosing and Differential Diagnosis of Disease (Patent Document 4)", "Alzha Focusing on Transferrin with Added Sugar Chain" Mer diagnostic kit, such as the detection method of diagnostic markers and conditions indices (Patent Document 5) "is disclosed.
さらに近年、非侵襲的に脳血流を評価するNIRS（近赤外分光法）による認知症の評価が検証され、感度がよく簡便でコストも低いことからも、認知症を評価する装置として有用である可能性が示唆されている。また、認知症患者の脳や血中でカテコールアミンや脳神経由来神経栄養因子（ＢＤＮＦ）が低下するため、認知症診断の指標として有用である。特に、ノルアドレナリン及びアドレナリンの代謝産物である尿中ＭＨＰＧ（3-メトキシ-4-ヒドロキシフェニルグリコール）は、主に中枢由来で脳の精神活動を反映し、認知機能の低下で尿中ＭＨＰＧが低下することが知られており、脳の神経活動を把握する指標とされている。 In recent years, NIRS (Near Infrared Spectroscopy), which evaluates cerebral blood flow in a non-invasive manner, has been validated and is useful as a device for evaluating dementia because of its sensitivity, simplicity, and low cost. The possibility that it is is suggested. In addition, since catecholamine and cranial nerve-derived neurotrophic factor (BDNF) are reduced in the brain and blood of patients with dementia, it is useful as an index for dementia diagnosis. In particular, urinary MHPG (3-methoxy-4-hydroxyphenylglycol), which is a metabolite of noradrenaline and adrenaline, is mainly derived from the center and reflects brain mental activity, and urinary MHPG decreases due to a decline in cognitive function. It is known that it is an index for grasping the neural activity of the brain.
しかしながら、上記ＤＳＭ−ＩＶ診断基準を満たした場合、認知症の程度は大幅に進行していることが考えられ、早期発見、早期治療を開始することは困難である。また、脳画像による解析や、組織、体液の評価では、患者の身体的負担、時間、費用及び測定者の熟練した技術が必要であることが課題である。
本発明の目的は、精度が高く、簡便かつ再現性のよい認知機能の評価法を提供することにある。
However, when the above DSM-IV diagnostic criteria are satisfied, the degree of dementia is considered to have progressed significantly, and it is difficult to start early detection and early treatment. In addition, analysis by brain images and evaluation of tissues and body fluids require the patient's physical burden, time, cost, and skill of the measurer.
An object of the present invention is to provide a method for evaluating a cognitive function that is highly accurate, simple and reproducible.
本発明は、額部皮下水分の電解質濃度を指標とする認知機能の評価方法である。
更に詳しくは、安静時の額部皮下水分の電解質濃度、及び／又は精神作業時の額部皮下水分の電解質濃度を指標とする認知機能の評価方法である。
The present invention is a method for evaluating cognitive function using the electrolyte concentration of forehead subcutaneous moisture as an index.
More specifically, it is a method for evaluating cognitive function using as an index the electrolyte concentration of the forehead subcutaneous water at rest and / or the electrolyte concentration of the forehead subcutaneous water during mental work.
本発明者らは、精神作業時では脳温維持のために額部から発汗する冷却機構が存在すること、さらに、神経伝達には細胞内外の電解質の濃度比が重要な役割を担うことに着目し、額部皮下水分の電解質濃度を測定することにより、認知症の診断及び認知機能の低下を評価することが出来ることを見出し、本発明を完成した。 The present inventors focus on the fact that there is a cooling mechanism that sweats from the forehead to maintain brain temperature during mental work, and that the concentration ratio of the electrolyte inside and outside the cell plays an important role in neurotransmission. Then, by measuring the electrolyte concentration of the forehead subcutaneous water, it was found that the diagnosis of dementia and the reduction of cognitive function can be evaluated, and the present invention was completed.
本来、認知症や認知機能が低下した状態では、脳の神経細胞の脱落が観察され、その脱落は記憶力の低下として反映される。
記憶の形成は、神経細胞の脱分極により細胞内外の電位差が小さくなり、ナトリウム、カルシウムイオンが濃度勾配に従い一気に流入する細胞の興奮で起動する種々メカニズムに由来する。脳の神経細胞における従来の研究は、脱分極以降に起こる生体反応に焦点を当てたものが主であった。
そこで本発明者らは、脱分極に影響を及ぼす細胞外のイオン濃度に着目し、これらの作用・機序の解明及びその利用について鋭意研究を進めた。
Originally, in the state where dementia and cognitive function are reduced, detachment of neurons in the brain is observed, and this detachment is reflected as a decrease in memory.
The formation of memory originates from various mechanisms that are triggered by the excitement of cells in which sodium and calcium ions flow in a single step according to a concentration gradient because the potential difference inside and outside the cell decreases due to depolarization of nerve cells. Previous studies on brain neurons have focused primarily on biological responses that occur after depolarization.
Accordingly, the present inventors paid attention to the extracellular ion concentration that affects depolarization, and advanced researches on the elucidation of these actions and mechanisms and their use.
通常、神経細胞において、カリウムは圧倒的に細胞内に多く存在し、反対にナトリウム、塩素、カルシウムはその殆どが細胞外に存在する。これら細胞内外に存在するイオンの分布差が細胞膜を隔てて電位差、即ち静止膜電位を生じ、その電位は細胞内外のイオン濃度とそのイオンの膜透過性から算出することができる（ゴールドマン・ホジキン・カッツの式）。
静止膜電位は、細胞外に存在するカリウム濃度に大きく依存し、それは漏洩カリウムチャネルによるカリウムの高い膜浸透性と、細胞外で希薄なカリウム濃度が細胞内からのわずかなカリウムの流出で濃度比が大きく変化することに起因する。
Usually, in nerve cells, potassium is predominantly present in the cell, whereas sodium, chlorine and calcium are mostly present outside the cell. The difference in the distribution of ions existing inside and outside the cell produces a potential difference across the cell membrane, that is, a resting membrane potential, which can be calculated from the ion concentration inside and outside the cell and the membrane permeability of the ion (Goldman Hodgkin). -Cuts formula).
The resting membrane potential is highly dependent on the extracellular potassium concentration, which is a high ratio of potassium permeation through leaky potassium channels, and the ratio of the concentration of extracellular dilute potassium to the slight potassium efflux from the cell. This is due to the large change in
心筋では、細胞外にカリウムが貯留することで細胞内外の電位差が小さくなり、脱分極による電位の変化量が小さくなる。そのため、高カリウム血症では心筋の信号伝達が通常通りに働かず心機能が低下、心拍が減少することが知られている。 In the myocardium, potassium is stored outside the cell, so that the potential difference between the inside and outside of the cell is reduced, and the amount of change in potential due to depolarization is reduced. Therefore, it is known that in hyperkalemia, myocardial signal transmission does not work as usual, cardiac function is reduced, and heart rate is reduced.
脱分極による膜電位の変化量は、安静時の細胞外カリウム濃度を低いまま維持し静止膜電位を低く保つことで、興奮による電位変化量を見かけ上大きくすることができる。脳の微小環境を保つ機能があるアストロサイトは、細胞外カリウムイオン濃度の調節を担うことが古くから提唱されている。 The amount of change in membrane potential due to depolarization can be apparently increased by keeping the extracellular potassium concentration at rest low and keeping the resting membrane potential low. It has long been proposed that astrocytes, which have the function of maintaining the brain microenvironment, are responsible for regulating extracellular potassium ion concentration.
アストロサイトは毛細血管と接し、血液と物質交換を行なっているが、毛細血管は静脈に移行し、硬膜静脈洞に注がれ、その血液の一部は導出静脈によって頭部外表の静脈に注がれる。細胞間液は、血液により運ばれた物質が毛細血管壁を介して拡散されるので、額部と脳とは密接な関連があると考えられる。
以上のことから、認知症及び認知機能の低下は、静止膜電位を形成するイオンのターンオーバー機能低下による脱分極の電位変化量低下に起因し、額部皮下水分の電解質濃度を測定することにより、認知症の有無や認知機能低下を知る手がかりになり得るものと考えられる。
Astrocytes are in contact with capillaries and exchange substances with blood, but capillaries migrate to veins and are poured into the dural sinus. Poured. In the intercellular fluid, since the substance carried by the blood is diffused through the capillary wall, it is considered that the forehead and the brain are closely related.
Based on the above, dementia and cognitive decline were caused by a decrease in potential change in depolarization due to a decrease in turnover function of ions that formed a resting membrane potential, and by measuring the electrolyte concentration of forehead subcutaneous water It can be a clue to know the presence of dementia and cognitive decline.
本発明者らは、短時間の精神作業時の額部皮下水分の電解質濃度を測定したところ、認
知機能が低値を示した人では、精神作業時の額部皮下の電解質濃度の変化量が小さいことを確認した。
また、安静時、及び長時間の精神作業後安静にしたときの額部皮下水分の電解質濃度を測定したところ、認知症の中核関連症状や周辺関連症状を自覚する人では、安静時の電解質濃度が低値を示し、精神作業後安静にしたときも電解質濃度が低値を示し、さらに精神作業前と比較しても低値を示したことから恒常性が保たれないことを確認した。
When the inventors measured the electrolyte concentration of the forehead subcutaneous water during a short mental work, the amount of change in the electrolyte concentration of the forehead subcutaneous during the mental work was found in those who showed a low cognitive function. I confirmed it was small.
In addition, when the electrolyte concentration of the forehead subcutaneous water was measured at rest and after resting after prolonged mental work, the electrolyte concentration at rest was found in those who were aware of the core related symptoms and peripheral related symptoms of dementia. Was low, and the electrolyte concentration was low even when resting after mental work, and even when compared to before mental work, it was confirmed that the homeostasis was not maintained.
以上のことは、細胞外にカリウムが停滞することで精神作業に必要な電解質代謝が円滑に行われなかったことに起因すると推測している。
そこで本発明者は、この作用を利用して本発明を完成した。
The above is presumed to be caused by the fact that potassium was stagnant outside the cells, and electrolyte metabolism necessary for mental work was not smoothly performed.
Therefore, the present inventor has completed the present invention using this action.
即ち、本発明は安静時の額部皮下水分の電解質濃度、及び／或いは精神作業時の額部皮下の電解質濃度変化量を指標とした認知症の診断及び認知機能の評価方法である。認知症或いは、認知機能が低下した時、正常時と比較して安静時及び／或いは精神作業時の額部皮下の電解質濃度が低値を示す。 That is, the present invention is a method for diagnosing dementia and evaluating cognitive function using the electrolyte concentration of the forehead subcutaneous water at rest and / or the amount of change in the electrolyte concentration of the forehead subcutaneous during mental work as an index. When dementia or cognitive function is reduced, the electrolyte concentration in the forehead subcutaneous area at rest and / or mental work is lower than that at normal time.
ここで、安静時額部皮下水分の電解質濃度（ＩＱ／ＢＰ）、精神作業時額部皮下水分の電解質濃度変化量（ΔＩＱ／ＢＰ）とは、皮下の電解質量（ＩＱ値、通常μＣで表される）に対する皮下の水分量（ＢＰ値、通常μＡで表される）の比を示す数値である。
Here, the electrolyte concentration (IQ / BP) of resting forehead subcutaneous fluid at rest and the amount of change in electrolyte concentration (ΔIQ / BP) of forehead subcutaneous fluid during mental work are expressed by the subcutaneous electrolytic mass (IQ value, usually μC). Is a numerical value showing the ratio of the subcutaneous water content (BP value, usually expressed in μA).
本発明により、高精度で簡便かつ再現性のよい認知症の診断及び認知機能の評価方法を提供することが可能となった。具体的には、ヒトの認知症や認知機能を医師、薬剤師はもちろんのこと、自身でも容易にセルフチェックでき、健康管理ツールとしても有用である。また抗認知症或いは抗認知機能低下に有効な薬剤や健康食品のスクリーニング手段として、或いは商品販売時における販促ツールとしても利用できる。
According to the present invention, it is possible to provide a highly accurate, simple and reproducible diagnosis of dementia and a method for evaluating cognitive function. Specifically, humans can easily check self-dementia and cognitive functions, not only for doctors and pharmacists, but also as a health management tool. It can also be used as a screening means for drugs and health foods effective for antidementia or a decline in anticognitive function, or as a sales promotion tool at the time of product sales.
本願発明を実施する形態の一例を紹介する。
まず被験者に対し、皮下水分量及び皮下電解質量を測定できる装置を額部に装着し、安静時及び一定の精神作業を負荷している最中に、額部皮下水分及び電解質量を測定する。測定終了後に、額部皮下水分の電解質濃度を算出し、安静時の電解質濃度、精神作業時の電解質濃度変化量によって認知症或いは認知機能の状態を評価する。
An example of an embodiment for carrying out the present invention will be introduced.
First, the subject is equipped with a device capable of measuring the subcutaneous water content and the subcutaneous electrolysis mass on the forehead, and the forehead subcutaneous moisture and the electrolysis mass are measured at rest and while loading a certain mental work. After the measurement is completed, the electrolyte concentration of the forehead subcutaneous water is calculated, and the state of dementia or cognitive function is evaluated based on the electrolyte concentration at rest and the amount of electrolyte concentration change during mental work.
精神作業は被験者の年齢や身体能力等により種々選択が可能である。例えば、内田クレペリン検査、１桁の数字の加算、減算、乗算等の繰り返しの計算課題、数字の暗唱や逆唱、特定の文字、数字や記号等の画像に指差しなどで特定の反応をする課題、鏡映描写課題、課題想起などが挙げられる。 Various mental tasks can be selected depending on the age and physical ability of the subject. For example, repeat a calculation task such as Uchida-Kraepelin test, 1-digit number addition, subtraction, multiplication, etc., recite or recite numbers, point to specific characters, numbers, symbols, etc. Issues, mirror depiction tasks, task recall, etc.
具体的には以下のような基準で、認知症或いは認知機能の低下を判断することができるが、これらによって限定されるものではない。
前述したような精神作業を健常人を対象に実施すると、精神作業中には額部皮下水分の電解質濃度（ΔＩＱ／ＢＰ）が増加し、作業後に安静することにより精神作業前のＩＱ／ＢＰに戻り、それにより恒常性が維持されていることが確認される。一方、認知症の中核或いは周辺関連症状を呈する等の認知機能が低下したヒトでは、精神作業中のΔＩＱ／ＢＰの増加が抑制され、作業後に安静することによりさらにＩＱ／ＢＰが低くなり、恒常性が維持されていないことが確認される。
Specifically, dementia or a decline in cognitive function can be determined based on the following criteria, but is not limited thereto.
When the mental work as described above is performed on a healthy person, the electrolyte concentration (ΔIQ / BP) of the forehead subcutaneous water increases during the mental work, and the IQ / BP before the mental work is reduced by resting after the work. Returning, thereby confirming that homeostasis is maintained. On the other hand, in humans with reduced cognitive functions such as the core of dementia or peripheral related symptoms, the increase in ΔIQ / BP during mental work is suppressed, and IQ / BP is further lowered by resting after work, resulting in constant It is confirmed that sex is not maintained.
例えば、精神作業として５分程度の計算課題と数字の暗唱を実施し、精神作業前安静時と精神作業中のＩＱ／ＢＰを測定し、そのΔＩＱ／ＢＰを算出する。すると、健常人ではΔＩＱ／ＢＰが０．０５〜０．７増加するが、認知機能が低下したヒトではΔＩＱ／ＢＰが−０．３〜０．０５の変化に留まる。 For example, a calculation task of about 5 minutes and recitation of a number are performed as mental work, IQ / BP is measured before and during mental work, and ΔIQ / BP is calculated. Then, ΔIQ / BP increases by 0.05 to 0.7 in healthy persons, but ΔIQ / BP remains in a change of −0.3 to 0.05 in humans with reduced cognitive function.
さらに、例えば精神作業として３０分程度の内田クレペリン検査を実施し、精神作業前安静時と作業終了５分間の安静後のＩＱ／ＢＰを測定し、そのΔＩＱ／ＢＰを算出する。すると、健常人では精神作業前後のΔＩＱ／ＢＰが−０．２〜０．２であり恒常性が維持されているが、認知機能が低下したヒトではΔＩＱ／ＢＰが−１．４〜−０．２と低値を示し、恒常性が維持されていないことが確認される。 Further, for example, the Uchida-Kraepelin test is performed for about 30 minutes as mental work, IQ / BP after resting before the mental work and after resting for 5 minutes is measured, and ΔIQ / BP is calculated. Then, in healthy individuals, ΔIQ / BP before and after mental work is −0.2 to 0.2 and homeostasis is maintained, but in humans whose cognitive function is reduced, ΔIQ / BP is −1.4 to −0. .2 shows a low value, confirming that homeostasis is not maintained.
したがって、例えば認知症や認知機能低下の有無を評価する場合には、精神作業の条件（種類と時間）を設定し、健常人における精神作業前後でのΔＩＱ／ＢＰを基準値として設定し、その基準値を満たさない場合には、認知機能が低下していると判断することができる。 Therefore, for example, when assessing the presence or absence of dementia or cognitive decline, mental work conditions (type and time) are set, and ΔIQ / BP before and after mental work in a healthy person is set as a reference value. When the reference value is not satisfied, it can be determined that the cognitive function is deteriorated.
例えば、精神作業として５分程度の計算課題と数字の暗唱を実施した場合、健常人の精神作業中のΔＩＱ／ＢＰ＝０．０５〜０．７を基準値とし、被験者のΔＩＱ／ＢＰが当該基準値よりも低値であれば認知機能が低下しているとして判断することができる。 For example, when a calculation task of about 5 minutes and recitation of numbers are performed as mental work, ΔIQ / BP = 0.05 to 0.7 during normal work of a healthy person is used as a reference value, and the subject's ΔIQ / BP is If the value is lower than the reference value, it can be determined that the cognitive function is degraded.
また、例えば精神作業として３０分程度の内田クレペリン検査を実施した場合、健常人
の精神作業前後のΔＩＱ／ＢＰ＝−０．２〜０．２を基準値とし、被験者のΔＩＱ／ＢＰが当該基準値よりも低値であれば認知機能が低下していると判断することができる。
Further, for example, when the Uchida-Kraepelin test is performed for about 30 minutes as mental work, ΔIQ / BP = −0.2 to 0.2 before and after the mental work of a healthy person is used as a reference value, and ΔIQ / BP of the subject is the reference value. If the value is lower than the value, it can be determined that the cognitive function is reduced.
また、健常人では安静時の額部皮下水分の電解質濃度ＩＱ／ＢＰが０．５〜１．５であるが、認知機能が低下したヒトではＩＱ／ＢＰが０．２〜０．５と健常人よりも低値を示す。
したがって、例えば認知機能低下の有無の判断基準を安静時のＩＱ／ＢＰ＝０．５〜１．５とし、ＩＱ／ＢＰが０．５よりも低値を示す場合には認知機能が低下しているとして判断することできる。
In healthy individuals, the electrolyte concentration IQ / BP of the forehead subcutaneous water at rest is 0.5 to 1.5, but IQ / BP is 0.2 to 0.5 in humans with reduced cognitive function. It is lower than humans.
Therefore, for example, the criterion for the presence or absence of cognitive function deterioration is IQ / BP = 0.5 to 1.5 at rest, and when IQ / BP is lower than 0.5, the cognitive function is reduced. Can be judged as being.
なお、抗認知症若しくは抗認知機能低下物質、又は認知症若しくは認知機能改善薬のスクリーニング時に当該評価方法を用いる場合には、電解質濃度測定開始前に前もって被験物質を付与しておき、その後上記測定を行なう。安静時の電解質濃度が増加した物質や精神作業時の電解質濃度変化量が増加した物質は認知機能の改善効果等を有するものと判断できる。 In addition, when using the said evaluation method at the time of the screening of an anti-dementia or an anti-cognitive function lowering substance, or a dementia or a cognitive function improvement drug, a test substance is previously given before starting electrolyte concentration measurement, and then the above-mentioned measurement To do. It can be determined that a substance with an increased electrolyte concentration at rest or a substance with an increased amount of electrolyte concentration change during mental work has an effect of improving cognitive function.
以下、実施例を挙げて本発明をさらに詳細に説明する。実施例１では高齢者を対象とし、実施例２では健常成人を対象として健常成人でも認知機能の低下を評価できるかを検証した。 Hereinafter, the present invention will be described in more detail with reference to examples. In Example 1, the elderly was targeted, and in Example 2, it was verified whether a decrease in cognitive function could be evaluated in healthy adults.
（実施例１）
認知機能と額部皮下水分の電解質濃度との関連について、次の試験により確認した。
６４歳から９６歳の高齢者（女性２４名、男性６名）を対象に、採尿後に認知機能検査（ＭＭＳＥ）、標準注意・意欲検査（ＣＰＴ Ｘ課題）及び数字記憶の検査を実施した。機器による測定は、安静時及び精神作業として標準注意・意欲検査（ＣＰＴ Ｘ課題）と数字記憶を実施している５分間の額部皮下水分値（ＢＰ：水分量、ＩＱ：電解質量、ＩＱ／ＢＰ：電解質濃度）を分極電流計（ＡＭＩＣＡ）により測定し、さらに、精神作業時の前頭葉血流をＮＩＲＯ−２００により測定した。また、尿検査として一般検査及びＭＨＰＧ測定（クレアチニン補正、単位ｍｇ／ｇＣｒ）を行った。
Example 1
The relationship between cognitive function and electrolyte concentration of forehead subcutaneous water was confirmed by the following test.
A cognitive function test (MMSE), a standard attention / motivation test (CPT X task), and a numerical memory test were performed after urine collection for elderly people aged 64 to 96 (24 women and 6 men). The measurement by the device is the 5-minute forehead subcutaneous moisture value (BP: moisture content, IQ: electrolytic mass, IQ / BP: electrolyte concentration) was measured with a polarization ammeter (AMICA), and frontal lobe blood flow during mental work was measured with NIRO-200. Further, as a urine test, a general test and MHPG measurement (correction of creatinine, unit mg / gCr) were performed.
分極電流計は、（有）アミカ社製を使用した。分極電流計とは、皮膚にパルス電圧（ＤＣ３Ｖ、５００μsecの短形波）を印加し、１μsec単位で電極間を流れた電流量を精密に計測し、電気生理学的に皮膚の状態を測る装置である。
皮膚表面に電圧を加えると、水分の多い皮下の真皮層に電気が流れるが、最初に検出される電流（ＢＰ値、単位μＡ）は真皮層の断面積に比例することから、真皮水分量を推測することができる。一方、ＩＱ値は、基底膜に溜まった電気量（ＩＱ値：単位μＣ）を示し、電解質が多くなるとＩＱ値が高くなる。そして、ＩＱ／ＢＰ値は、電解質濃度を示すことになる。
A polarization ammeter manufactured by Amica Co., Ltd. was used. A polarization ammeter is a device that applies a pulse voltage (DC3V, 500μsec short wave) to the skin, accurately measures the amount of current flowing between the electrodes in 1μsec units, and measures the skin condition electrophysiologically. is there.
When voltage is applied to the skin surface, electricity flows through the subcutaneous dermis layer with a lot of water, but the current (BP value, unit μA) detected first is proportional to the cross-sectional area of the dermis layer, so Can be guessed. On the other hand, the IQ value indicates the amount of electricity accumulated in the basement membrane (IQ value: unit μC), and the IQ value increases as the electrolyte increases. The IQ / BP value indicates the electrolyte concentration.
精神作業時の前頭葉血流は、光トポグラフィ法（ＮＩＲＳ）による脳酸素代謝と脳血液循環を指標とした。このＮＩＲＳは頭蓋骨外から近赤外光を照射・受光し、無侵襲で局所脳血流動態を計測する方法で、例えば、赤外線酸素モニタ装置（浜松ホトニクス社製ＮＩＲＯ２００）を用いることできる。
この装置により、脳血流の指標として、酸素化ヘモグロビン濃度（Ｏ2Ｈｂ）、脱酸素化ヘモグロビン濃度（ＨＨｂ）、ヘモグロビン酸素飽和度（ＴＯＩ）、組織中総ヘモグロビン相対値（ｎＴＨＩ）の各測定値が得られる。
The frontal lobe blood flow during mental work was indexed by cerebral oxygen metabolism and cerebral blood circulation by optical topography (NIRS). This NIRS is a method of irradiating and receiving near-infrared light from outside the skull and measuring local cerebral blood flow dynamics non-invasively. For example, an infrared oxygen monitor device (NIRO200 manufactured by Hamamatsu Photonics) can be used.
With this device, as an index of cerebral blood flow, measurement of oxygenated hemoglobin concentration (O 2 Hb), deoxygenated hemoglobin concentration (HHb), hemoglobin oxygen saturation (TOI), and total hemoglobin relative value (nTHI) in tissue A value is obtained.
そして「酸素化ヘモグロビン濃度変化量（ΔＯ2Ｈｂ）」とは、酸素と結合したヘモグロビンの濃度の経時的変化量を示す数値で、通常μｍｏＬ／Ｌで表示される。
「脱酸素化ヘモグロビン濃度変化量（ΔＨＨｂ）」とは、酸素が外れたヘモグロビンの濃度の経時的変化量を示す数値で、通常μｍｏＬ／Ｌで表示される。
このΔＯ2ＨｂとΔＨＨｂの変化量により、精神作業による酸素供給量の変動を測ることができる。
「ヘモグロビン酸素飽和度（ＴＯＩ）」とは、血液中のヘモグロビンの何％が酸素と結合しているかを示す数値で、酸素化ヘモグロビンと総ヘモグロビンの濃度比であり、通常％で表示される。
また、「組織中総ヘモグロビン相対値（ｎＴＨＩ）」とは、組織ヘモグロビン指標で、血流量を示す数値であり、ａ．ｕ．（任意単位）で表される。
The “oxygenated hemoglobin concentration change amount (ΔO 2 Hb)” is a numerical value indicating the change over time in the concentration of hemoglobin combined with oxygen, and is usually expressed in μmoL / L.
The “deoxygenated hemoglobin concentration change amount (ΔHHb)” is a numerical value indicating the change over time in the concentration of hemoglobin from which oxygen has been removed, and is usually expressed in μmoL / L.
The variation in the oxygen supply amount due to mental work can be measured from the amount of change in ΔO 2 Hb and ΔHHb.
“Hemoglobin oxygen saturation (TOI)” is a numerical value indicating what percentage of hemoglobin in blood is bound to oxygen, and is a concentration ratio between oxygenated hemoglobin and total hemoglobin, and is usually expressed in%.
“Tissue total hemoglobin relative value (nTHI)” is a tissue hemoglobin index, which is a numerical value indicating blood flow, and a. u. (Arbitrary unit).
酸素化ヘモグロビンの変化は「局所脳血流の変化」と高い相関を示していること（Hoshi,et.al., Journal of Applied Physilogy, 90, 1657, 2001）、神経活動に必要な大量の酸素と栄養を運ぶ「局所脳血流の増加」は、その部位の神経活動の増加を反映したものであると報告されている（Jueptner M & Weller C. (Neuroimage, 2, 148(1995)）おり、「ＴＯＩ」を前頭葉血流の指標とした。 Changes in oxygenated hemoglobin are highly correlated with "changes in local cerebral blood flow" (Hoshi, et.al., Journal of Applied Physilogy, 90, 1657, 2001), and large amounts of oxygen required for neuronal activity "Increased regional cerebral blood flow" that carries nutrients and nutrients has been reported to reflect an increase in neural activity at the site (Jueptner M & Weller C. (Neuroimage, 2, 148 (1995)) “TOI” was used as an index of frontal blood flow.
中核症状の認知機能（ＭＭＳＥ）と精神作業中の皮下水分電解質濃度（ΔＩＱ/ＢＰ）、及びヘモグロビン酸素飽和度（ＴＯＩ）との間の相関関係を解析した（スピアマンの順位相関係数の検定）。
ＭＭＳＥスコアとΔＩＱ/ＢＰとの間には、図１に示すように有意な正の相関が認められ、認知症の疑いがあると判定されるＭＭＳＥ２３点以下では、ΔＩＱ/ＢＰの顕著な増加は全く認められなかった。
一方、ＭＭＳＥとＴＯＩとの間には、図２に示すように顕著な相関は認められなかった。
We analyzed the correlation between cognitive function of core symptoms (MMSE), subcutaneous water electrolyte concentration during mental work (ΔIQ / BP), and hemoglobin oxygen saturation (TOI) (Spearman rank correlation coefficient test) .
There is a significant positive correlation between the MMSE score and ΔIQ / BP, as shown in FIG. 1, and a significant increase in ΔIQ / BP is below 23 MMSE, which is determined to be suspected of dementia. It was not recognized at all.
On the other hand, no significant correlation was observed between MMSE and TOI as shown in FIG.
中核症状の認知機能（ＭＭＳＥ）について、スコア高低で分割し（ＭＭＳＥ低値群：ＭＭＳＥ２７点以下、ＭＭＳＥ高値群：ＭＭＳＥ２８点以上）、精神作業中の額部皮下水分の電解質濃度（ΔＩＱ/ＢＰ）を比較した（ｔ-検定）。
ＭＭＳＥ低値群はＭＭＳＥ高値群と比較して、図３に示すようにΔＩＱ／ＢＰが有意に低値を示した。
一方、ＴＯＩについては、図４に示すように差が認められなかった。
The core symptom cognitive function (MMSE) was divided into high and low scores (MMSE low value group: MMSE 27 points or less, MMSE high value group:
Compared with the MMSE high value group, the MMSE low value group showed a significantly low ΔIQ / BP as shown in FIG.
On the other hand, no difference was observed for TOI as shown in FIG.
主に中枢由来のノルアドレナリン及びアドレナリンの代謝産物である尿中ＭＨＰＧと精神作業中の額部皮下水分の電解質濃度（ΔＩＱ/ＢＰ）との間の相関関係を解析した（スピアマンの順位相関係数の検定）。
尿中ＭＨＰＧとΔＩＱ/ＢＰとの間には、図５に示すように有意な正の相関が認められた。
We analyzed the correlation between urinary MHPG, which is a metabolite of noradrenaline and adrenaline mainly derived from the center, and the electrolyte concentration (ΔIQ / BP) of subcutaneous fluid in the forehead during mental work (Spearman's rank correlation coefficient) Test).
A significant positive correlation was observed between urinary MHPG and ΔIQ / BP as shown in FIG.
（実施例２）
認知症の中核症状及び周辺症状と、額部皮下水分の電解質濃度との関連について、さらに上記項目と血清中カリウムとの関連について次の試験により確認した。
健常成人（女性ｎ＝４０、男性ｎ＝１４）を対象に、安静時、及び精神作業としてクレペリン検査を実施し５分程度安静にした後の額部皮下水分の電解質濃度を分極電流計（ＡＭＩＣＡ）により測定し、精神作業時の前頭葉血流をＮＩＲＯ−２００を用いて測定した。また、気分プロフィール調査（ＰＯＭＳ）、意識調査（ＶＡＳ）、体調アンケートを実施し、さらに安静時に採血を行い、血清中のカリウム濃度を評価した。
(Example 2)
The relationship between the core and peripheral symptoms of dementia and the electrolyte concentration of subcutaneous water in the forehead was further confirmed by the following test on the relationship between the above items and serum potassium.
For healthy adults (female n = 40, male n = 14), the electrolyte concentration of the subcutaneous fluid in the forehead after resting and resting for about 5 minutes as a mental work, and the resting water for about 5 minutes ), And frontal lobe blood flow during mental work was measured using NIRO-200. In addition, a mood profile survey (POMS), a consciousness survey (VAS), and a physical condition questionnaire were conducted, blood was collected at rest, and the potassium concentration in serum was evaluated.
ＰＯＭＳの質問項目のスコア（５段階）、意識調査として自覚的な活動意識のＶＡＳ度数（ＶＡＳスコア（Visual Analogue Scale）法による評価で１０ｃｍスケールの自覚的な意識値（ｃｍ）を度数とした）、その他の体調アンケートにおいて認知症の中核症状又は周辺症状に関連する自覚症状の程度と、皮下水分の電解質濃度ＩＱ／ＢＰ（安静時或い
はクレペリン検査後の変化量）との関連を解析した（単回帰分析及び対応のないｔ-検定）。
POMS question item score (5 levels), VAS frequency of subjective activity awareness as a consciousness survey (10cm scale subjective consciousness value (cm) as a frequency measured by VAS score (Visual Analogue Scale) method)) In other physical condition questionnaires, we analyzed the relationship between the degree of subjective symptoms related to core symptoms or peripheral symptoms of dementia and the electrolyte concentration IQ / BP (changes after resting or after the Kraepelin test) of subcutaneous water (single Regression analysis and unpaired t-test).
安静時皮下水分の電解質濃度の高低、或いは血清中カリウム濃度高低で分割し、
中核症状の計画性について比較した（ｔ-検定）。また、周辺関連に関連する自覚症状の程度や自覚的な活動意識のＶＡＳ度数と、血清中カリウムとの関連を解析した（対応のないｔ−検定）。
Divide according to the electrolyte concentration of resting subcutaneous water, or serum potassium concentration
The planning of core symptoms was compared (t-test). In addition, the relationship between the degree of subjective symptoms related to peripheral associations and the VAS frequency of subjective activity awareness and serum potassium was analyzed (unpaired t-test).
表１に示すように、中核症状として「計画性がある（ＶＡＳ度数）」と安静時皮下水分の電解質濃度との間には、有意な正の相関が認められた。
また表２に示すように、周辺症状として「日中覚醒（ＶＡＳ度数）」と安静時皮下水分の電解質濃度との間にも、有意な正の相関が認められた。
As shown in Table 1, a significant positive correlation was observed between “there is planability (VAS frequency)” as the core symptom and the electrolyte concentration of resting subcutaneous water.
Further, as shown in Table 2, a significant positive correlation was also observed between “daytime awakening (VAS frequency)” and the electrolyte concentration of resting subcutaneous water as peripheral symptoms.
中核症状として「計画性がある（ＶＡＳ度数）」「集中力低下（体調アンケート）」についてネガティブな症状の自覚を有するほど、図６及び図８に示すように安静時額部皮下水分の電解質濃度が有意に低かった。
一方、このときのＴＯＩには、図７及び図９に示すように差が認められなかった。
また、「頭がすっきりする（ＰＯＭＳの度数）」の度数が低いほど、図１０に示すように精神作業時の額部水分の電解質濃度が有意に低く、このときのＴＯＩも図１１に示すように有意に低かった。
As shown in FIG. 6 and FIG. 8, the electrolyte concentration of the subcutaneous fluid in the forehead at rest, as the symptom is negative about “there is planability (VAS frequency)” and “concentration reduction (physical condition questionnaire)” as core symptoms Was significantly lower.
On the other hand, no difference was recognized in the TOI at this time as shown in FIGS.
Further, as the frequency of “head refreshed (POMS frequency)” is lower, the electrolyte concentration of the forehead moisture during mental work is significantly lower as shown in FIG. 10, and the TOI at this time is also as shown in FIG. Was significantly lower.
周辺症状として「やる気が出ない（体調アンケート）」「日中眠たくなる」について、ネガティブな症状の自覚を有するほど、図１２及び図１４に示すように安静時額部皮下水分の電解質濃度が有意に低かった。
一方、この時のＴＯＩには、図１３及び図１５に示すように差が認められなかった。
また、「心の中で憤慨する（ＰＯＭＳの度数）」が高いほど、図１６に示すように安静時の額部水分の電解質濃度が有意に低く、このときのＴＯＩも図１７に示すように有意に低かった。
As the peripheral symptoms are “not motivated (physical condition questionnaire)” and “getting to sleep during the day”, the more negative the symptoms are, the more significant the electrolyte concentration of the forehead subcutaneous fluid at rest as shown in FIG. 12 and FIG. It was low.
On the other hand, no difference was observed in the TOI at this time as shown in FIGS.
Further, the higher the “in the heart (POMS frequency)”, the lower the electrolyte concentration of the forehead moisture at rest as shown in FIG. 16, and the TOI at this time is also as shown in FIG. Significantly lower.
また、周辺症状として「物事に気乗りがしない（ＰＯＭＳの度数）」「憂うつだ（ＰＯＭＳの度数）」について度数が高いほど、図１８及び図２０に示すように精神作業時の額部水分の電解質濃度が有意に低く、このときのＴＯＩも図１９及び図２１に示すように有意に低かった。 In addition, as the peripheral symptom is “I don't care about things (POMS frequency)” or “Depressed (POMS frequency)”, the higher the frequency, the more the electrolyte of the forehead moisture during mental work as shown in FIG. 18 and FIG. The concentration was significantly low, and the TOI at this time was also significantly low as shown in FIGS.
安静時額部皮下水分の電解質濃度或いは血清中のカリウム濃度の高低で分割したとき、図２２及び図２３に示すように電解質濃度高値及び血清中カリウム低値ほど、中核症状の「計画性」度数が有意に高かった。 When divided by the electrolyte concentration of resting subcutaneous skin water or the level of potassium in serum, as shown in FIG. 22 and FIG. 23, the higher the concentration of electrolyte and the lower the level of potassium in serum, the “planning” frequency of core symptoms Was significantly higher.
また、周辺症状として「物事に気乗りがしない（ＰＯＭＳの度数）」が高いほど、「精神作業後の活動度（ＶＡＳ度数）」が低値ほど、図２４及び図２５に示すように血清中カリウム濃度が有意に高かった。 In addition, as the peripheral symptom “do not care about things (POMS frequency)” is higher, “activity after mental work (VAS frequency)” is lower, and serum potassium as shown in FIG. 24 and FIG. Concentration was significantly higher.
以上のように、額部皮下水分の電解質濃度は、認知機能や認知症の症状を反映している。これは安静時の細胞外カリウム濃度を低く保つことで、精神作業時の電解質代謝が円滑に行われるように備えているものと考えられる。 As described above, the electrolyte concentration of the forehead subcutaneous water reflects cognitive function and symptoms of dementia. This is considered to be prepared so that electrolyte metabolism during mental work is performed smoothly by keeping the extracellular potassium concentration at rest low.
以上の結果より、額部の皮下水分の電解質濃度は、電解質代謝の活動を評価することで認知症の診断及び認知機能を評価する指標にとなりうることが確認された。 From the above results, it was confirmed that the electrolyte concentration of subcutaneous water in the forehead can serve as an index for evaluating diagnosis and cognitive function of dementia by evaluating the activity of electrolyte metabolism.
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