Lecture 8 Brain and nervous system

Thiamine lackWernicke's encephalopathy

Lack of niacin 　Pellagra

Uremic coma

Diabetic coma

DehydrationNaKCa

Electrolyte imbalance

Poisoning

Poison

Cerebrovascular accident

low CBF

Orthostatic fainting

Shock

D I C

Adams-Stokes syndrome

Cardiac infarction

Low O ２

Anemia

Lungdisease

Excessive injectionof Insulin

Inslinoma Low blood of sugar

Hepatic coma High ammonia

prostaglandin D ２ Sleep center

（ medial preoptic area ）

prostaglandin E ２Arousal center（ A back hypothalamus ）

Pituitary gland

Mesencephalic reticular formation

Medullary reticular formation

ThalamusHypothalamus

Cerebral cortex

Metabolic acidosis

日 本 アメリカ

Frequency difference of Japan-U.S. of serotonin transportation body gene multi type

ＳＳ type 68.2Obedience

Depolarization

ＳＳ type 　 18.8

ＬＳ type30.1

ＬＳ type 48.9AggressiveIndependent

ＬＬ type 32.3Too aggressive

ＬＬ type 1.7

100

80

60

40

20

0

％Fre

qu

en

cy o

f ge

ne

mu

lti typ

e

（％）

The Japanese educates kindly and severely to the group and the individual because the character to which it is the same as mild others and relieves it

The education, the resource, and the target of composure are given and it teaches to an independent, independent student of the United States freely.

Teacher, please shut up!

5-HTT

0.0

50.0

100.0

L/ L L/ S S/ S

Frequency of gene polymorphism of character 　（ Number of investigations=264）

Independent type.Strong against stress

Uneasiness and the stress are sensitive

DRD4

0.0

50.0

100.0

R ２～４ のみ 5 7R ～ 有

Seeking a new thingStrong against stress

Multi type of serotonin transporter

S/S type

Tendency as which as many as four dopamine receptor multi types are the same

Caucasian type

Japanese type

Japanese type

Yamakawa, M. et al. “Serotonin transporter polymorphisms affect human blood glucose control” Biochem Biophys Res Commun. 334(4), 2005, 1165-71

only

More objective than the psychological test.

When the fearful expression is seen, the amygdaloid nucleus (right picture red) that shows feelings of likes and dislikes acts. It reacts to the Japanese and the amygdaloid nucleus reacts to a lot of S/S types that are sensitively

Inherited difference of emotion by functional, magnetic resonance image method

Serotonin transporter

　　 S type 　　　　　　　　　　　　　　　　　　 L type

○ ○

Hariri AR, Weinberger DR. “Imaging genomics” Br Med Bull. 65, 2003, 259-70

DRD4(Dopamine D4 　 receptor)

State of excitation

always

Stabilityorientation

5-HTTLPR

ReceptorSerotonin

Aggressive, Independent

Sensitive, Nervous

L is transcript revitalization ten times S

By 「 The mind has been understood here 」Kosuke oki

The mad cow disease is discovered from cannibals' Kuru disease

Sheep

The cow was made to eat sheep's

scrap meat

Cow

Eating the hamburg steak with which the nerve mixes

Kuru disease Scrape. Spongiform encephalopathyCroitsfeld Creutzfeldt-Jakob disease. Mad cow disease

Croitsfeld Creutzfeldt-

Jakob disease

Cannibals in New Guinea

The Kuru disease to the chimpanzee

Milk

is

safe

Yasuo KAGAWA, “Dr. Stanley B. Prusiner, Advocator of Prion theory 1997 Nobel Prize in Medicine”, 『 The Japanese journal of nutrition 』 , 322, 1998.1 p.26-31

Nobel Prize in Medicine in 1997

Cannibals

The agents responsible for mad cow disease is a protein of not the microorganism but Prion. It acts on the Prion in normal

person's brain and it changes it into no To Prion

Higher-order, structural

change and proliferation

of Prion

Nobel Prize inMedicine in 1997 and

Yasuo KAGAWA, “Dr. Stanley B. Prusiner, Advocator of Prion theory 1997 Nobel Prize in Medicine”, 『 The Japanese journal of nutrition 』 , 322, 1998.1 p.26-31

It is Japan that in the world with a lot of dementias and bedridden

70

75

80

85

90

95

Life e

xpe

ctan

cy

/life ex

pe

ctan

cy w

itho

ut

de

me

ntia

（％）Remainder of one's life without 77-years old man's dementia

Eiji YANO, “The statistics tells. From average life span to Healthy life span. Its challenge and international comparison” 『 The Journal of the Japanese medical association 』 , 123(6), 2000.3 p.823-8

認知症認知症

見当識なし

Checkpoints where the dementia is doubted

Not understanding my age.

Not understanding a familiar interpersonal relationship.

Dangerous sign

Forgetting that should be noted

Forgetting that happens with aging

The name of the actor who reflects in the television cannot be recalled. It has forgotten to buy one carelessly though it went shopping. Sentences are being written, the Chinese character cannot be recalled, and it often uses a dictionary

A personal experience of the previous state is forgotten for a moment. The same thing is repeated many times in a series of conversation

How of dementia symptom to appear

Main symptom

hallucination

Delusion

Confusionperplexity

excitement

Other intellectual disabilities

emotional disorder

Impaired orientationEasy angry

Not computable

Symptom in surrounding

Defect of memory

Creation of talk

Not writing

Not perception

認知症

= 　 Dementia by cerebral infarction and 　 brain hemorrhage

Cause of Dementia

Disease can be treated Chronic subdural hematoma Normal pressure hydrocephalus Brain tumor False dementia Dementia symptom by medicine

Vascular dementia

Degenerative nervous disease (Alzheimer's disease. etc )

Relation of dangerous rate of lifestyle and cerebrovascular dementia

Non factor 　　 　　　 1１ factor 　　　＋ 　　　　－ 　－ 　　　－　　　　－ 14.4

　　　－ 　　　　＋ 　－ 　　　－　　　　　 － 2.7

　　　－　　　　　－ 　＋ 　　　－　　　　　 － 2.9　　　－　　　　　－ 　－ 　　　＋ 　　　　－

2.5　　　－　 － 　－ 　　　－　　　　　 ＋ 2.2

２ factors 　　　　　　 5.3 ～42.2３ factors 　　 　 14.5～ 115.6４ factors 42.6 ～284.9５ factors 　　　＋ ＋ 　＋ 　　　＋　　　　　 ＋ 　 613.4

not leisure active 　

Past of hypertension

notexerciseactive

Head injury loses senses

Nonparticipation to the medical examination

Risk(odds ratio)

Kiyotaro KONDO, “Lifestyle and dementia （ Featuring : lifestyle and disease-Effectiveness of preventive medicine and the actual patient guidance ）」 , 『 The journal of the Japanese medical association 』 , 119(7), 1998.4 p.935-41

To prevent the acknowledgment syndrome, the simple calculation is read aloud early

Red

is a b

rain activity

Red

is a b

rain activity

Left brain

Left brain

Left brain

Right brainRight brain

Right brain

Brain when easy calculation problem is solved fast

Brain when complicated calculation is solved

Brain when book is read aloud

Working of the brain when an easy calculation problem is solved as soon as possible is shown. It is understood that a lot of places of a right and left brain move actively

Working of the brain when working on the complicated calculation is shown. The prefrontal region and times of a lower head of a left brain work. A right brain doesn't work

Working of the brain when the book is read aloud is shown. More much more places work than reading it silently by a right and left brain. It is understood the faster the reading speed is the prefrontal region, the more to work

Risk of folic acid intake and cerebral infarctionRisk of folic acid intake and cerebral infarction(follow-up survey of 43,732 men and 14 years)(follow-up survey of 43,732 men and 14 years)

0

0.5

1

1.5

Low High

Folic acid intake

Relative

risk

He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, Ascherio A. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men (2004) Stroke 35(1) p.169-74

相対危険度

Method of calculating diversity score of food intake

Meat, Seafood, Eggs, Milk, Soybean and processed soy product, Brightly colored vegetable, Sea weed, Potato, Fruit, Oils and fats

Each food group“Eat almost every day” １ point "Do not eat" is 0 point.*The maximum becomes ten points.

0

0.5

1

1.5

１～３ ４～８ ５～１０

Relative risk of decrease in higher-order life function of diversity score each crowd of food intake

point

When various foods are taken, it is not easy to become Dementia

point point

Osamu KUMAGAI, “Relation of Variety of food intake in regional home senior person and higher-order life depression”, 『 The journal of Japanese public health 』 , 50(12), 2003.12 p.1117-24

Protective efficacy by fishBordeaux, FRANCE

1,674 of 68 years old or more is pursued seven years later. 170 people became dementias. 135 people became Alzheimer sooner or later

Eat fish 1 time or more everyday (stndard)

1 time a week

Someties

Not at all

1 time a week

Someties

Not at all

Eat meat 1 time or more everyday

Rate of appearance

It is the effect none even if it takes it as supplement

The vegetable and the fruit prevent Alzheimer

Chicago : 1993-2000. 815 of 65 years old or more is pursued average 3.9 years later

Rotterdam : 1993-2000. 5395 of 55 years old or more is pursued average 6 years later

Intakes of vitamin E under the meal are 70% low from few crowds of a lot of crowds that are

Intakes of vitamin C & E under the meal are 43% low from few crowds of a lot of crowds that are

-20

-10

0

10

20

Food that prevents Dementia 　（１９９５→２００２）

Brightly colored vegetables

Beans Seafood

Am

ou

nt o

f inc

reas

e

an

d d

ecre

as

e

Potato

（％）

Healthy Japan 21,”Tentative nearest results value in healthy Japan 21 to target value (2005)”, Available from <http://ml-www.kenkounippon21.gr.jp/kenkounippon21/ugoki/houkoku/pdf/0410mokuhyou_zanteiti.pdf>, (accessed 2007-11-4)

As for the content of the folic acid, in the analysis table, availability is different

Structure of folic acids

PteridineAminobenzoic aci

d

Mono-glutamic acid type folic acid

Polyglutamic acid type folic acid

Folic acid in multivitamin and enriched food

Folic acid in natural food

Polyglutamic acid type folic acid

Mono-glutamic acid type folic acid or

Folic acid (Pteroylpolyglutamic acid)

(Monoglutamic folic acid: polyglutamic folic acid = 1:2)

The number of homo cysteines increases due to folic acid shortage

AdenosylHomo cysteine

アデノシルメチオニン

メチオニン

Homocysteine

Tetrahydrofolic acid

Dihydrofolic acid

5 、 10-methyleneTetrahydrofolic

acid5-MethylicTetrahydrofolic

acid

Shistationin

Cysteine

CBS

B ６

　 CLB ６

MTHFR　 B ２　

BHMTMS 　

B １２ベタイン

N,N-Gemetilgrishin

　 痴呆Infarction DementiaExamining TT type

Folicacid

Methionine

Adenosyl

methionine

Betaine

From the folic acid to the reaction of DNA methylation

• ① 　 Transportation body small intestines and → Folmiltetorahidoro folic acid → Metenil tet rahydrofolic acid → Metirentetorahidoro folic acid of folic acid

• ② 　 Metirentetorahidoro folic acid + NADH→ methylenetetrahydrofolate reductase → Metilt 　 etorahidoro folic acid + NAD

• ③ homo cysteine + Metiltetorahidoro folic acid → methionine 　　synthetase → methionine + tetrahydrofolic acid

• ④ 　 Methylate + of C methionine + ATP→ S adenosylmethionine → DNACpG island S adenosyl homo cysteine.The activity leaf acid lack after DNA methyl transferase (five kinds) generates the egg is measured due to 14C methylic radical uniting decrease to DNA.

RFC-1 ： 1 reduction folic acid transportation body multi type

Digestion, absorption of folic acid, Digestion, absorption of folic acid,

and resolution of Porigltamil radicaland resolution of Porigltamil radical

amylase

Protease

Conjugase

Blood

Folic acids

Mono-glutamic acid type folic acid

Mono-glutamic acid type folic acid

Mono-glutamic acid type folic acid

Protein Folic acid

Starch, Protein, Folic acid

Polyglutamic folic acid

Small intestines epithelial cell

methylenetetrahydrofolate

100g当たり140mg

This folic acid reinforced plan and eating folic acid amounts in the This folic acid reinforced plan and eating folic acid amounts in the United States (DFEs)United States (DFEs)

I Obligated synthetic folic acids of the grain processed foods such as bread and cereals (every 100g) to be strengthened in the United States in 1998

The correction coefficient of this 1.7 originates in the ratio in which the presumption availability of a synthetic folic acid in food is divided by the presumption average availability of eating sericulture

Eating folic acid this amount Folic acid under mealAmount of synthetic

folic acid

Folic acid in food that exists naturally

Synthetic folic acid in enriched food

Absorption factor of 50%

Absorption factor of 85%

When the folic acid is insufficient, it becomes an acknowledgment syndrome

Rise of homo cysteine in blood

Cardiac infarction

DementiaCerebral infarction

Do

n’t like

vegetab

les

Co

ns

titutio

n(g

en

e

）

It is not worrying if it notes it for a moment because this gene polymorphism is a small difference of the gene between normal people.

*p < 0.05, **p<0.01

(n)0

5

10

15

(82) (129) (39)

****

CC CT TT

Even if the folic acid, VB6, and the VB12 intake are fulfilled, the density of

the person of the TT type of the serum total homocysteine is high

The entire object person

(74) (113) (36)

****

Those who fulfill folic acid Recommendation amount

(54) (81) (28)

**

Folic acid ・B6 ・ B12 those fulfill recommendation amount

(mol/l)

As for the diabetic, folic acid shortage becomes the patient of a As for the diabetic, folic acid shortage becomes the patient of a multi type with the risk in the limitation food with a lot of multi type with the risk in the limitation food with a lot of

acknowledgment syndromes (Alzheimer's disease and apoplexy).acknowledgment syndromes (Alzheimer's disease and apoplexy).

0

50

100

150

200

Comparison Diabetic

Ris

k o

f A

lzh

eim

er

100

165

Arvanitakis Z. et al. “Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function” Arch Neurol. 61(5), 2004, 661-6

0

1

2

3

4

5

6

0

1

2

3

4

5

6

7

8

Unnoticed Cerebral infarction

Homocysteine (nmol/ml) Homocysteine (nmol/ml)

**

Cerebral infarction that notices symptoms

The cerebral infarction increases by a factor of 5.5-7.5 when the homo cysteine is high

*

*** ***

<6.8 　 6.9-8.1 8.2-10.2 ≥10.3

<6.8 　 6.9-8.1 8.2-10.2 ≥10.3

Amount of homocysteineAmount of

homocysteine

Disco

very frequ

ency o

f cerebral in

farction Araki A. et al. “Association between plasma homocysteine concentrations and asympt

omatic cerebral infarction or leukoaraiosis in elderly diabetic patients” Geriatrics and Gerontology International. 3(1), 2003, 15-23

Disco

very frequ

ency o

f cerebral in

farction

22

23

24

25

26

27

20

25

30

35Achievement test１　MMSE

Achievement test 2

few middle lot few middle lot

Amount of homocysteine (nmol/ml) Amount of homocysteine (nmol/ml)

* **

The intelligence decrease begins before the syndrome of acknowledgment when the homo cysteine is high

Score Score

Araki A. et al. “Plasma homocysteine and cognitive function in elderly patients with diabetes mellitus” Geriatrics and Gerontology International. 3(2), 2003, 86-92

Density of serum folic acid according to acknowledgment syndrome senior citizen‘ MTHFR C677T gene polymorphism and the total density of serum ho

mocysteine （ Dementia senior perwon at Yokufu-Kai ）

Folic acidFolic acid Total homocysteine Total homocysteine

* *

(mol/l)

0

10

20

30

40

*

(nmol/l)

* p<0.005 (vs. TT)CC CT TT

0

10

20

30

40

50

Seniordementia

Young women

Middle and advance women

Young women

Middle and advance women

Such high!

Such low!

Seniordementia

If the person of the TT type also takes the folic acid of 400μg every day, it is safe

３１６：１２１０－１２１６　（２００４）

Gene polymorphism and folic acid blood levelFolic acid administering Folic acid administering

Den

sity of fo

lic acid

in b

loo

d

HIRAOKA,KATO,SAITO,YASUDA, KAGAWA

Of Japanese

a day a day

Preliminary examinationNumber of 300

Load examinationNumber of 100

Cerebral infarction and dementia's worries are a little if 400 νg intakes of the folic acid in case of the type as well as the CC type and the CT type

(weeks)

Acknowledgment level point after density of senior citizen of plasma folic acid and three stages and three years of folic acid intakePrevention of acknowledgment syndrome of start

-1.05

-0.9

-0.75

-0.6

-0.45

-0.3

-0.15

0

0.15

0.3

0.45

0.6

Ch

ang

e in

ackno

wled

gm

ent level

po

int

Elderly person : 321 （ 60-74 ）

<20nmol/L <339μg/d

20-30 339-523nmol/L μg/d

>30nmol/L >523μg/d

Density of plasma folic acid

Folic acid intake amount/day

******

****** P<0.0001

** P<0.01

Tucker KL. et al. “High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study” Am J Clin Nutr. 82(3), 2005, 627-35

The density of the serum folic acid falls sharply and the intelligence of the level 80 years old per four Nano mg/ml falls sharply

Tettamanti M. et al. “Low folate and the risk of cognitive and functional deficits in the very old: the Monzino 80-plus study” J Am Coll Nutr. 25(6), 2006, 502-8

Min

i men

tal test score

Serum folic acid （ ng/ml)

Lim

its are 4Nan

o

Intelligence test of 471 of 87 years old on average.The correlation of MMSE and the density of the serum folic acid is extremely significant

r=0.36(p<0.0001)

The folic acid of 140μg for every 100g is compulsorily added to bread and cereals in 1998 and it makes significant progress in the United States. A nursing necessary senior citizen decreaseGreat decrease in cardiac infarction. The deformed child of the nerve also : to 1/8. The folic acid recommendation amount has increased to about twice that of Japan,too.

Healty nourishment investigation in US. Serum folicacid

0

2

4

6

8

10

12

14

16

1988-1994 1999-2000 2001-2002

Investigation year

Ser

um fol

ic a

cid

ng/m

l

It increases the serum folic acid because of US citizen's food folic acid strengtheningGanji V. et al. : J. Nutrition 136: 153-158 (2006)

Folic acid

addition to

bread

Healty nourishment investigation in US. Homoshistin densitytransition

0

2

4

6

8

10

12

1988-1994 1999-2000 2001-2001

Investigation year

Ser

um H

omos

hist

in d

ensi

tyUS citizen's food: decreasing the homo cysteine because of the folic acid strengthening. Ganji V. et al. : J. Nutrition 136: 153-158 (2006)

Folic acid addition to bread

Role of folic acid and Food that contains a lot of folic acids

Functions of folic acids Main supply source of folic acids

Necessary amount of folic acids

Alzheimer type dementia prevention

Arteriosclerosis prevention

The risk of embryo's nerve tube hypoplasia is decreased Spinach

Roasted laverGreen tea Extracted material

Broccoli

Cabbage

Egg

(a day)

for pregnant woman

The Ministry of Health, Labour and Welfare

(5th ed Food composition table)

per

(Mami FUKUSHIMA, Yasuo KAGAWA et at all)

“Sakado” Folic acid project

１． The lack of the folic acid intake is measured with the homo cysteine

2.The constitution with the folic acid is an insufficient easily is judged by the inheritance

Meal investigation (questionnaire) and guidance

It improves it judging the lifestyle that becomes an acknowledgment syndrome easily

Gene multi type judgment applicant

October 2ed

： Individual guidance about result

September 4th

： Explanation-Agreement-Collecting blood

Cooking practice and physical exercise

After half a year, inspecting again the homocysteine

The acknowledgment syndrome and the cerebral infarction can be prevented regardless of the constitution

The density of the serum folic acid rose

MTHFR C677T

according to gene multi type

Den

sity

of s

erum

folic

aci

d　

（ng

/ml)

Guidance before

Guidance after

before

after before

before

p<0.0001 p<0.05 p<0.0001 p<0.01

0

5

10

15

20

25

0

5

10

15

20

25CC CT TTn=27 n=27 n=11

after after

Folic acid and constitution of diabetic

Meal, movement, brain gymnastics

The acknowledgment syndrome can be prevented by the folic acid, the balance food, the exercise, and the brain activity

Bad lifestyle, Folic acid lack and depolarization Appearance of diseaseB

A

Co

nscio

us b

y th

e gen

etic test