tryptophan and competing neutral amino acid levels were found to be diminished

7/28/2019 Tryptophan and Competing Neutral Amino Acid Levels Were Found to Be Diminished

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J o u r n a l o f N e u r o l o g y , N e u r o s u r g e r y , a n d P s y c h i a t r y , 1 9 7 9 , 4 2 , 6 4 0 - 6 4 1

P l a s m a a n d c e r e b r o s p i n a l f l u i d t r y p t o p h a n i n m u l t i p l es c l e r o s i s a n d d e g e n e r a t i v e d i s e a s e sF. MONACO, S . FUMERO, A. MONDINO, AND R. MUTANIFrom t h e Department o f N e u r o l o g y , U n i v e r s i t y o f S a s s a r i , a n d t h e RBM I n s t i t u t e o f B i o m e d i c a lR e s e a r c h , I v r e a , I t a l y

SUMMARY T r y p t o p h a n a n d c o m p e t i n g n e u t r a l a m i n o a c i d l e v e l s were f o u n d t o b e d i m i n i s h e di n t h e p l a s m a o f p a t i e n t s w i t h m u l t i p l e s c l e r o s i s a n d d e g e n e r a t i v e d i s e a s e s , t h e g r e a t e s t d e c r e a s eb e i n g o f t r y p t o p h a n . C e r e b r o s p i n a l f l u i d t r y p t o p h a n was d e c r e a s e d i n m u l t i p l e s c l e r o s i s a n dmotor n e u r o n e d i s e a s e , w h i l e l e u c i n e a n d v a l i n e were i n c r e a s e d . T h e s e c h a n g e s m i g h t l e a d t od e c r e a s e d s y n t h e s i s o f b r a i n s e r o t o n i n and b r a i n p r o t e i n s . The r a t i o between n e u t r a l amino a c i d sa n d t r y p t o p h a n m i g h t b e u s e d a s an a n c i l l a r y t e s t i n t h e s c r e e n i n g o f d e g e n e r a t i v e d i s e a s e s .T y r o s i n e a n d p h e n y l a l a n i n e s h a r e w i t h l e u c i n e ,i s o l e u c i n e , a n d v a l i n e t h e s a m e t r a n s p o r t c l a s sa c r o s s t h e b l o o d - b r a i n b a r r i e r , a n d a l l o f t h e mc o m p e t e w i t h t r y p t o p h a n f o r c e r e b r a l u p t a k e( L a j t h a , 1 9 7 4 ) . S i n c e a n i n c r e a s e d t y r o s i n e -p h e n y l a l a n i n e q u o t i e n t h a s b e e n s h o w n i n s e r u mo f p a t i e n t s w i t h m u l t i p l e s c l e r o s i s ( K i s s e r a n dH a r r e r , 1 9 7 4 ) , we d e t e r m i n e d t h e c o n c e n t r a t i o n so f b o t h p l a s m a a n d c e r e b r o s p i n a l f l u i d t r y p t o p h a na n d c o m p e t i n g a m i n o a c i d s i n a g r o u p o f p a t i e n t sw i t h m u l t i p l e s c l e r o s i s a n d o t h e r d e g e n e r a t i v ed i s e a s e s .P a t i e n t s a n d m e t h o d sT h i r t y - t w o p a t i e n t s o f b o t h s e x e s , a g e d 2 2 - 4 7y e a r s , w e r e i n c l u d e d i n t h e s t u d y , p r o v i d e d t h a tt h e y p r e s e n t e d a t l e a s t f i v e o f t h e f o l l o w i n g s i g n sa n d s y m p t o m s : e y e s q u i n t w i t h d i p l o p i a , c e r e -b e l l a r a t a x i a o r d y s m e t r i a o r b o t h , d y s a r t h r i a ,p y r a m i d a l t r a c t s i g n s w i t h l o s s o f a b d o m i n a l r e -f l e x e s , t e m p o r a l a t r o p h y o f t h e o p t i c d i s c , i m p a i r -ment o f m i c t u r i t i o n . I n 2 1 p a t i e n t s t h e d i a g n o s i sw a s c o n f i r m e d b y a CSF g a m m a g l o b u l i n e l e c t r o -p h o r e t i c p a t t e r n . At l e a s t t h r e e n e u r o l o g i s t s a g r e e don t h e d i a g n o s i s i n e a c h c a s e . I n 1 9 c a s e s t h ed i s e a s e w a s a t i t s o n s e t ; w h i l e i n t h e r e m a i n d e rt h e h i s t o r y w a s o f c h r o n i c i l l n e s s . None o f t h e mw a s o n t h e r a p y a t t h e t i m e o f t h e i n v e s t i g a t i o n . Asa c o n t r o l g r o u p we h a d 5 0 h e a l t h y v o l u n t e e r s f o rp l a s m a ( M o n a c o e t a l . , 1 9 7 5 ) a n d 1 0 f o r CSFA d d r e s s f o r r e p r i n t r e q u e s t s : D r F . M o n a c o , C l i n i c a N e u r o l o g i c a ,V i a l e S . P i e t r o 1 0 , 1 - 0 7 1 0 0 S a s s a r i , I t a l y .A c c e p t e d 1 3 J a n u a r y 1 9 7 9

( M u t a n i e t a l . , 1 9 7 4 ) , a l o n g w i t h 1 1 p a t i e n t sa f f e c t e d w i t h m o t o r n e u r o n e d i s e a s e a n d s i x w i t hh e r e d i t a r y a t a x i a s .P l a s m a a n d CSF w e r e c o l l e c t e d e a r l y i n t h em o r n i n g a f t e r a 1 2 h o u r f a s t . We made s u r e t h a to n t h e d a y s i m m e d i a t e l y b e f o r e e x a m i n a t i o np a t i e n t s w e r e c o n s u m i n g a d i e t w i t h a s i m i l a ramount o f p r o t e i n , c a r b o h y d r a t e , a n d f a t s i no r d e r t o o b t a i n a n a d e q u a t e i n t a k e o f a l l a m i n oa c i d s . C e r e b r o s p i n a l f l u i d , t o g e t h e r w i t h s e r u mo b t a i n e d b y c e n t r i f u g a t i o n a t 3 5 0 0 rpm f o r 1 0m i n u t e s , w a s i m m e d i a t e l y d e p r o t e i n i s e d w i t h s u l -p h o s a l y c i l i c a c i d a f t e r b e i n g t r e a t e d w i t h a 0 . 5 %a q u e o u s s o l u t i o n o f s o d i u m d o d e c y l s u l p h a t e , t oo b t a i n t o t a l t r y p t o p h a n r e c o v e r y ( M o n d i n o e t a l . ,1 9 7 5 ) . The d e t e r m i n a t i o n o f t r y p t o p h a n a n d c o m -p e t i n g n e u t r a l a m i n o a c i d s w a s t h e n p e r f o r m e d b yi o n - e x c h a n g e c h r o m a t o g r a p h y u s i n g a r o u t i n et e c h n i q u e ( M o n d i n o , 1 9 7 0 ) .R e s u l t sT r y p t o p h a n , l e u c i n e , i s o l e u c i n e , v a l i n e , t y r o s i n e ,a n d p h e n y l a l a n i n e w e r e a l l d i m i n i s h e d i n t h ep l a s m a o f p a t i e n t s w i t h m u l t i p l e s c l e r o s i s ( T a b l e )b u t b y f a r t h e g r e a t e s t d e c r e a s e wa s i n t h e t r y p t o -p h a n l e v e l ( t > 1 1 ) , a s w e l l a s t y r o s i n e a n d p h e n y l -a l a n i n e ( t > 4 ) , a l l o f t h e m h a v i n g a P v a l u e o f< 0 . 0 0 1 . A s i m i l a r r e s u l t wa s s e e n i n t h e p l a s m ao f p a t i e n t s w i t h motor n e u r o n e d i s e a s e , b u t t h et r y p t o p h a n f i g u r e s were l e s s s i g n i f i c a n t ( P < 0 . 0 5 ) .N o d i f f e r e n c e w a s o b s e r v e d b e t w e e n p l a s m a f r o mc a s e s o f motor n e u r o n e d i s e a s e a n d h e r e d i t a r ya t a x i a s . I n a l l d i s e a s e s e x a m i n e d t h e CSF c o n c e n -

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P l a s m a a n d c e r e b r o s p i n a l f l u i d t r y p t o p h a n i n m u l t i p l e s c l e r o s i s a n d d e g e n e r a t i v e d i s e a s e sT a b l e P l a s m a a n d CSF t r y p t o p h a n a n d c o m p e t i n g n e u t r a l amino a c i d c o n c e n t r a t i o n s i n p a t i e n t s w i t hm u l t i p l e s c l e r o s i s ( M S ) , m o t o r n e u r o n e d i s e a s e (MND), a n d h e r e d i t a r y a t a x i a s ( H A ) c o m p a r e d w i t h n o r m a lc o n t r o l s u b j e c t s ( N ) . YNAA/TRY i s t h e r a t i o b e t w e e n n e u t r a l a m i n o a c i d s a n d t r y p t o p h a n . V a l u e s( r o u n d e d o f f t o f u l l number w h e n e v e r p o s s i b l e ) a r e e x p r e s s e d i n , u m o , / l ( m e a n + S D )P l a s m a C SFAmino a c i d N ( 5 0 ) MS(32) M N D ( I I ) H A ( 6 ) N ( 1 0 ) M S ( 3 2 ) MND(II) H A ( 6 )T r y p t o p h a n 549 3 1 8 * * * 267* 318*** 52 42* 22*** 3 1L e u c i n e 12827 1 1 4 2 5 * 8 9 2 6 * * * 1 0 0 2 4 * 42 1 0 4 * * * 106* 8 5I s o l e a c i n e 621 5 5614 4212*** 4813* 3 1 42 3 . 5 2 . 3 2.12V a l i n e 24248 20849** 1 5 9 4 2 * * * 1 8 1 5 3 * * 95 1 7 8 * * * 139 1 07T y r o s i n e 63 1 3 439*** 378*** 3812*** 31 52 5 . 5 2 . 8 52P h e n y l a l a n i n e 5412 427*** 3 7 9 * * * 4022* 3 2 7 7 44 4 2NAA/TRY 9 . 6 3 . 4 1 6 5 * 1 4 5 * 1 2 4 **=P


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doi: 10.1136/jnnp.42.7.6401979 42: 640-641J Neurol Neurosurg Psychiatry

F Monaco, S Fumero, A Mondino, et al.

and degenerative diseases.tryptophan in multiple sclerosisPlasma and cerebrospinal fluid

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tryptophan and competing neutral amino acid levels were found to be diminished

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