From Axonal Transport to Mitochondrial Trafficking

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croscopic video-imaging of single axons has led to the dem- onstration that ..... been reported to move slower down t he axon than what has been reported for ...

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Current Medical Imaging Reviews, 2011, 7, 16-27

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From Axonal Transport to Mitochondrial Trafficking

Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

MEMRI: BACK TO BASICS A Brief History of MEMRI .K.LM!;7!(!&$>(';N$>C!#$B!;3(-;#-!'$D5#;O,$!B517$!,7$! 5(7!$ =?(#)$)!& (?;)>C!),&; #-! '5$!?( 7'!) $D()$!Ucc* !c]W/ !0 ;7J '1&;D(>>C*!3 (#-(#$7$!B( 7! '5$!8; &7'! .L! D1#'&(7'!( -$#'!&$ J ?1&'$)/!M'7!$88$D'7!B$&$!)$7D&;@$)!;#!1#$!18!R(,'[email protected],&F7!$(&>;J $7'!? (?$&7!B 5$&$!5 $!8 1&3(>;E$)!'5 [email protected] (7;7!1 8!. L!;3 (-;#-! Uc^W/!R('$&*!3 (#-(#$7$! B(7!)$N$>1?$)!81&!,7 $!(7!(!7C7'$3;D! D1#'&(7'!(-$#'!'1!$#5(#D$!D1#'&(7'!;#!?$&;?5$&(>!1&-(#7/!T5;7! 8;$>)!18!(??>;D(';1#!B(7!;#;';(>>C!>;3;'$)!'1!?&$D>;#;D(>!7',);$7! @$D(,7$!1 8!'5 $!? 1'$#';(>!'1 =;D;'C!1 8!3 (#-(#$7$! Uc[*!c\W*[email protected],'! '5$!)$N$>1?3$#'!18! (! D5$>('$)!81&3 !18! 3(#-(#$7$!G .(#-(J #$7$J+X+XH*!B5;D 5!)$ D&$(7$)!; '7!' 1=;D;'C!( #)!?&$ N$#'$)!;'! 8&13!D&177;#-!'[email protected]>11)[email protected]&(;#[email protected](&&;$&*!1?$#$)!'5$!B(C!'1!D>;#;J D(>!(??>;D(';1#7!81&!>;N$&*!?(#D&$(';D!(#)!D(&);(D!.LM!Uc\J]VW/!! :;'5!& $-(&)!'1! '5$!,7 $!18!3 (#-(#[email protected]&( ;#!;3 (-;#-*! B5;D5!;7!'5 $!81D,7!18!'5$!?&$7$#'!&$N;$B*!'5;#-7!$N1>N$)!;#!(! );88$&$#'!3(##$&/!T5$!'1=;D!$88$D'!18! 3(#-(#$7$!1#! '5$!D$#J '&(>!#$&N1,7!7C7'$3*!;#D>,);#-!'5$!D5(&(D'$&;E(';1#!18!;'[email protected];1J );7'&;@,';1#! ;#! '[email protected]& (;#*!5( [email protected]$ $#!$ ='$#7;N$>C!7 ',);$)!U]Z J ]^W/!M#!8(D'*!'5$!8;&7'!?(?$&!&$?1&';#-!'5$!)$'$D';1#!18!3(#-(J #[email protected] C!. LM!;# ! '5$!& ('[email protected] &(;#!8 1D,7$)!1 #!; '7!? (''$&#!1 8!(DD, J 3,>(';1#!(#)!(771D;('$)!'1=;D;'C!U][W/!">317'!(!)$D()$!?(77$)! @$81&$!41&$ '7AC!( #)!5;7 !-&1,?!7 ,--$7'$)! '5('! [email protected]$ !

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Pre-injection T1-weighted image

Systemic Mn injection (i.v./i.p.) No task

Local Mn injection (e.g.: nasal)

Auditory task MEMRI

Conventional map

H24

No task

Odor task

Tract-tracing MEMRI

Activation map

H24

Conventional map

H2

Activation map

H2 !

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18 Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

Olfactory epithelium

Bertrand et al.

Olfactory bulb

Olfactory sensory neuron

Lateral olfactory tract

Mitral cell

Before Mn2+ injection

Piriform Cortex

Piriform cortex cell

24h after Mn2+ injection in the nostril

Olfactory Olfactory Lateral Piriform epithelium bulb olfactory tract cortex

! Fig. (2).!X&;#D;?>$!18!.K.LM!'&(D'J'&(D;#-!;#!'5$!1>8(D'1&C!7C7'$3/!dD5$3(';D(>>C*!'5$!1>8(D'1&C!7C7'$3!D13?&;7$7!f!3(;#!'C?$7!18!#$,&1#7e! '5$!1>8(D'1&C!7$#71&C!#$,&1#7*!>1D('$)!3(;#>C!;#!'5$!1>8(D'1&C!$?;'5$>;,3I!'5$!3;'&(>!D$>>7*!>1D('$)!;#!'5$!1>8(D'[email protected],>@!(#)!;#!'5$!>('$&(>!1>J 8(D'1&C!'&(D'I!(#)!'5$!#$,&1#7!18!'5$!?;&;81&3!D1&'$=/!TB$#'CJ81,&!51,&7!(8'$&!(!'1?;D(>!;#_$D';1#!18!.#`>Z!;#!'5$!#17'&;>*!(!D>$(&!$#5(#D$3$#'! 18!'5 $7$! (&$(7! D(#[email protected] $! 7$$#!1 #!(!T VJB$;-5'$)!;3 (-$*!D1 3?(&$)!'1 !'5 $!7 (3$!7 $O,$#[email protected] $81&$!. #`>!;# _$D';1#!G1 @>;O,$!7 (-;''(>!N ;$B*! &$)!(&J &1B7H/!Y1'$! '5$!Z!7' &;?$7! '5('! (&$! D>$(&>C!N;7;@>$!;#!'5$! '$3?1&(>! (&$(*!'5$! >1B$&!1#$! [email protected]>,$! (&&1B5$()H!D1&&$7?1#);#-!'1!'5$!>('$&(>!1>8(D'1&C! '&(D'*!(#)!'5$!,??$&!1#$!G1&(#-$!(&&1B5$()H!'1!'5$!?;&;81&3!D1&'$=/!!

ZJ!b ,#D';1#(>!7 ',);$7!,7 ;#-! .K.LM!5( N$!?&1N; )$)!?( 'J '$!18! (D';N(';1#!; #!); N$&7$! D1#);';1#7e!),&; #-!D 1-#;';N$! ?&1D$77$7!U[aW*!#1&3(>!(-;#-!UcaW*!(8'$&!'5$!()3;#;7'&(';1#!18! )&,-7!1&!#$,&1?$?';)$7!Ufa*![VJ[^W*!;#!31)$>7!18!;#_,&C!'1!'5$! 1?';D!#$ &N$!U[[W* !7 ?;#(>!D 1&)! U[\J\aW!( #)[email protected]&( ;#!U\VJ\fW* !;#! 31)$>7!18!;7 D5$3;(!U\cJ\iW*! (#)!;#!N (&;1,7! 31)$>[email protected]&( ;#! );7$(7$!G)$ -$#$&(';N$!); 7$(7$7!Ufc* !ia* !iVW* !$ ?;>$?7C!UiZW* ! 3,>';?>$!7 D>$&17;7!UifW* !#$ ,&1>,?,7!UicW* !' ,31&7!Ui]* !i^W* ! 1D,>(&!);7$(7$7!Ui[JVaZWH/!`13?(&$)!B;'5!%jR+J8,#D';1#(>! .LM!G% jR+J8.LMH*!8,#D ';1#(>!.K .LM!?&1N; )$7!-&$ ('$&! (#('13;D(>!)$'(;>7!),$!'1!'[email protected];#(';1#!18!TVJD1#'&(7'!(#)! ?$&7;7'$#'!7;-#(>!;#'$#7;'C!D5(#-$7!(8'$&!3(#-(#$7$!;#_$D';1#*! B5;D5!$#(@>$7!>1#-$&!;3(-$!(DO,;7;';1#!';3$7/! fJ!d ',);[email protected]&( ;#! D;&D,;'&C!,7 ;#-!' &(D'J'&(D;#-!.K .LM! '5('!B$&$!;#;';(>>C!>;3;'$)!'1!'5$!1>8(D'1&C!(#)!'5$!N;7,(>!7C7J '$37*!5( N$!#[email protected]$ $#!?$ &81&3$)!; #!1' [email protected]&( ;#!7 '&,D',&$7! ;#D>,);#-!' 5$! (,);'1&C!7 C7'$3!UVafJVa]W!( #)!N( &;1,7!)$ $?! 8;@$&!7C7'$37!'5('!D1,>)[email protected]$!(DD$77$)[email protected]!7'$&$1'(=;D!;#_$D';1#7! 18!.#`>Z!UVa^JVaiW/! cJ!T&(D'J'&(D;#-!.K.LM!5(7!(>[email protected]$$#!?&1?17$)!(7!(!'11>! 81&!'5$!in vivo!7',)C!18!( =1#(>!'&(#7?1&'!Ufc*!caWI!'5;7!(7?$D'! B;>>[email protected]$!);7D,77$)!;#!-&$('$&!)$'(;>!;#!'5$!81>>1B;#-!7$D';1#7/! .K.LM!(??>;D(';1#7!5([email protected]$$#!>;3;'$)!'1!&1)$#'!7',);$7! @,'!5([email protected]$$#!$='$#)$)!'1!1'5$&7!7?$D;$7!7,D5!(7!#1#J5,3(#! ?&;3('$7!Uf]* !^Z* !VVaW* !3 ;#;?;-7!UVVVW!( #)!7 1#[email protected];&)7/!T 5$! >(''$&!&$ ?&$7$#'7!( #!; #'$&$7';#-!3 1)$>!81&!' 5$!7 ',)[email protected]&( ;#! ?>(7';D;'C!UVVZJVV]W/!

Biological Basis of MEMRI: Which Mechanisms Does Manganese Propagation Reflect? .(#-(#$7$! $#'$&7!' [email protected]&( ;#! via!) ;88$&$#'!D (&&;$&7*! (#)! >;A$>C!$ =;'7!' [email protected]&( ;#[email protected]!); 88,7;1#!3 $D5(#;737!UVV^* !VV[W I! D13?>$'$!D$& [email protected]&(>!D> $(&(#D$!1 8!3 (#-(#$7$!(8 '$&! .K.LM! $=(3;#(';1#! '(A$7! (@1,'! (!3 1#'5!UVV\W/ !j#D $!; #!' [email protected]&( ;#*! 3(#-(#$7$!$#'$&7!#$,&1#7!via!N1>'(-$J)$?$#)$#'!`( Zh!D5 (#J #$>7!UZiJfZW*!(#)!'5$#!?&1-&$77$7!(>1#-!'5$!#$,&1#!;#!(#!(#J '$&1-&()$!8(75;1#!Uf]*!f[*!f\[email protected]$81&$!;'7!&$>$(7$!;#'1!'5$!7C#J (?';D!D>$8'[email protected]!?&$J7C#(?';D!N$7;D>$7!(#)!;'7!,>';3('$!,?'([email protected]! '5$!#$='!#$,&1#!Uf]Jf\W!Gb ;-/! 3H/! T5$!$N ;)$#D$!'5 ('! 3(#-(J #$7$! '&(N$>7!;#!# $,&1#7! via!3 ;D&1',@,>$J)$?$#)$#'! #$,&1#(>! '&(#7?1&'!D 13$7!8&13 !7 ',);$7!,7 ;#-!D 1>D5;D;#$*! (!3 ;D&1',J @,>$J)$?1>C3$&;E;#-!)&,-* !B5; D5!5( [email protected]$ $#!7 51B#!' 1!)&( J 3(';D(>>C!;3?(;&!'5$!?&1-&$77;1#!18!3(#-(#$7$*!'5,7!7,--$7'J ;#-!' 5('!3 (#-(#$7$!;7 !' &(#7?1&'$)!?&$ )13;#(#'>[email protected]!( D';N$! 3$D5(#;737!&( '5$&! '5(#[email protected]!?( 77;N$!); 88,7;1#!UfZJfcW /! .K.LM!7 ',);$7!5(N$!&$?1&'$)!(#!(??(&$#'!7?$$)!18!3 (#-(J #$7$! '&(#7?1&'!& (#-;#-!8&13 !a/ V\!' 1!V /Vf! !3l7*!B ;'5! (!? &$J )13;#(#'!'&$#)[email protected]$'B$$#!a/f!(#)!a/f]!!3l7*!B5;D5!;7!D>17$!'1! '5$!7?$$)!18!8( 7'!(=1#(>!'&(#7?1&'!(7!3 $(7,&$)[email protected]!N; )$1!3;J D&17D1?C!GV! !3l7H!Uf*!f]*!ca*!]i*!VVZ*!VVfW/! T5,7*! .K.LM! 5([email protected]$ $#!?&1?17 $)!( 7!( !,#; O,$! in vivo! '11>!81&!' 5$!#1#J ;#N(7;N$!7 ',)C!18!#$ ,&1#(>!' &(#7?1&'! ;#[email protected]' 5!#1&3 (>!( #)! ?('51>1-;D(>! D1#);';1#7!Ufc* !caW/ !01B $N$&*!1 '5$&!?17 7;@>$! 71,&D$7!18!3 (#-(#$7$!D1#'&(7'!$#5(#D$3$#'!3,7'[email protected]$!A$?'!;#! 3;#)!B5$#!(#(>CE;#-!7,D5!$=?$&;3$#'(>>C!)$&;N$)!)('(e! VJ!d ',)C;#-!( =1#(>!' &(#7?1&'[email protected]! .K.LM! assumes that both neuronal uptake (Ca2+ channel activity) and neu-

From Axonal Transport to Mitochondrial Trafficking

Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

19

! Fig. (3).!X&1?17$)!31)$>!81&!'5$!?&1-&$77;1#!18!3(#-(#$7$!;#!#$,&1#[email protected](7$)!1#!D,&&$#'!)('(!8&13!'5$!>;'$&(',&$/!M#!?5C7;1>1-;D(>!D1#);';1#7*! 3(#-(#$7$!; 7!' (A$#!,?! via!N 1>'(-$J-('$)!` (Zh!D5(##$>7! UZiJfZW*!; 7!7$O,$7'$&$)!;#!3;'1D51#)&;(!(#)!;#! '&(#7?1&'!N$7;D>$7*!B5;D5!(&$!'&(#7J ?1&'$)!(>1#-!'5$!3;D&1',@,>$!7C7'$3!UfZJfcW*! (#)!;7!&$>$(7$)!('!'5$!7C#(?';D! D>$8'!317'[email protected](@>C!;#!7C#(?';D!N$7;D>$7*!'[email protected]$!'(A$#!,[email protected]!' 5$! #$='!#$,&1#!Uf]Jf\W/!!

ronal release (at the synapses) are conserved, ,#>$77!'5$7$! ?(&(3$'$&7!(&$!'(A$#!;#'1!(DD1,#'[email protected]!' 5$!31)$>!,7$)!81&!' 5$! (#(>C7;7/!M#!' 5$!7 (3$!N$ ;#*!81> >1BJ,?!.K .LM!7 ',);$7!( 7J 7,3$!' 5('! no neuronal loss [email protected] $'B$$#!'5 $!$= (3;#(J ';1#7/! ZJ!T5$&$!(&$!'B1!D(#);)('$!7'&,D',&$7!81&!' 5$!'&(#7?1&'!18! 3(#-(#$7$!( >1#-!3 ;D&1',@,>$7e!' &(#7?1&'!N$ 7;D>$7!U]iW!( #)! 3;'1D51#)&;(!U^i* !VViW/ !M#'$ &$7';#->C*!3 ;'1D51#)&;(!5( N$! @$$#!&$?1&'$)! '1!31N$!7>1B$&!)1B#!' 5$!(=1#!'5(#!B5('!5(7! @$$#!&$?1&'$)!81&!8(7'!(=1#(>!'&(#7?1&'!18!N$7;D>$7!UVZa*!VZVW/! T5;7!& ('$! ;7!;# !'5 $!& (#-$!1 8!a /Z! !3l7!UVZa* !VZVW* !B5;D 5! ;7! &$3;#;7D$#'!18!' 5$!7?$$)!18!3 (#-(#$7$!'&(#7?1&'!&$?1&'$)[email protected]! .K.LM!Uf* !f]* !ca* !]i* !VVZ* !VVfW/ !T 5,7*!( 77,3;#-!' 5('!' 5$! &$>(=;N;'C!18!3 (#-(#$7$! ;7!7 ;3;>(&! ;#[email protected]' 5!7 '&,D',&$7*!' 5;7! 7,--$7'7!'5('! 3;'1D51#)&;(!3 (C!&$?&$7$#'!(#!;3 ?1&'(#'!?(&'! 18!3 (#-(#$7$! '&(#7?1&'/!` 1#7$O,$#'>C*! changes in the number or the mobility of mitochondria will likely impact MEMRI signal changes/!01B$N$&*!'5$!1N$&$=?&$77;1#! 18!'5$!3;'1D51#)&;(>!$#EC3$!.(#-(#$7$!d,?$&1=;)$!+;73,J '(7$!G .(#-(#$7$Jdj+H!)1$ 7!#1'!7 $$3! '1!;#),D$! D5(#-$7!;#! TV!D1 #'&(7'[email protected] $81&$!1 &! (8'$&!3 (#-(#$7$!;# _$D';1#!B 5$#! D13J ?(&$)!'1!D1#'&1>!(#;3(>7!UiVW/!! fJ!j,'7;)$!'5$!#$ ,&1#*! manganese also accumulates in astrocytes*!B5$&$! ;'[email protected];#)7!'1!- >,'(3;#$! 7C#'5$'(7$! (#)! .#J dj+!UVZZ* !VZfW/ !T 5;7!- >;(>[email protected](7$)! 3(#-(#$7$!,?' (A$!D (#! D(,7$!(! >1D(>! ;#D&$(7$!1 8!7 ;-#(>!;# '$#7;'C! '5('!;7!, #&$>('$)!' 1! #$,&1#(>!( D';N;'C/! T5;7!?5$ #13$#1#!5( [email protected]$ $#!& $?1&'$)! ;#! 31)$>7!1 8! [email protected]&(>! ;7D5$3;(! 7',);$)[email protected] C!. K.LM*!B 5$&$!'5 $! (&$(7!18!7;-#(>!$#5(#D$3$#'!3('D5!'5$!(&$(7!18!&$(D';N$!->;1J 7;7!U\]*!\^W/! cJ!T5 $!$= D;'1'1=;D!# $,&1'&(#73;''$&!- >,'(3('$!D (#!(D D$>J $&('$! '5$!$ #'&C!18 !3 (#-(#$7$! ;#'1!#$ ,&1#7*!7 ,--$7';#-! '5('! 3(#-(#$7$!D (#!( >71!$ #'$&!#$ ,&1#7! via!Y .+"!&$ D$?'1&7!; #! ?('51>1-;D(>!D 1#);';1#7!U]\* !VZcW/ !` 1#7$O,$#'>C*!; '!3 ,7'[email protected]$ ! A$?'! ;#!3 ;#)!' 5('! an increase in manganese uptake as measured by MEMRI does not necessarily mean that the

neuron is increasing its normal activity: it may also reflect excitotoxic stimulation. 01B$N$&*!$= D;'1'1=;D;'C!5 (7! (>[email protected]$$#!&$?1&'$)!'1!;#5;@;'!3;'1D51#)&;(>!31N$3$#'*!B5;D5! B1,>)!?1'$#';(>>C!)$D&$(7$!'5$!'&(#7?1&'!18!3(#-(#$7$!UVZ]W/! ]J!"=1#( >!' &(#7?1&'!;7 !( !?5$ #13$#1#!' 5('! ;7!&$ >('$)!' 1*! @,'!); 7';#D'!8&13 *! '5$!$ >$D'&;D(>!( D';N;'C!18!( !#$ ,&1#/!j#$ ! 7',)C!751B$)!'5('!'5$!D13?>$'$!;#5;@;';1#!18!$>$D'&;D(>!(D';NJ ;'C!;#!&$';#(>!-(#->;1#!D$>>7!)1$7!#1'!?&$N$#'!'5$!'&(#7?1&'!18! .(#-(#$7$!' 1!' 5$!7 ,?$&;1&!D 1>>;D,>,7*!7 ,--$7';#-!' 5('!3 (#J -(#$7$! D(#[email protected]$ !' &(#7?1&'$)!?( 77;N$>C!( #)!#1' !1#> [email protected]!( D';N$! 3$(#7!UVZ^W/ !01B$ N$&*! ;'!5( 7! (>[email protected]$ $#!7 51B#! '5('!( =1#(>! '&(#7?1&'!;7!3(;#'(;#$)!$N$#!),&;#-!'5$!D13?>$'[email protected]>1DA()$!18! $>$D'&;D(>!( D';N;'C!UVZ[* !VZ\W/ ! If axonal transport can be upregulated by an increase of electrical activity, it does not appear to be stopped by the complete inhibition of electrical activity/! Evaluation of Neuronal Transport by MEMRI: Various Techniques .K.LM!5( [email protected]$ $#!,7 $)!' 1!7 ',)C!# $,&1#(>!' &(#7?1&'! ;#! N(&;1,7!8;@$&!7C 7'$37!G1>8(D'1&C!7C 7'$3*!N ;7,(>!7C 7'$3*!) $$?! 8;@$&7!' &(D'7H!( #)! ;#!N( &;1,7!7 ?$D;$7!G3 ;D$*!& ('7*!7 1#[email protected];&)7! (#)!?&;3('$7H/!0 ;-5J8;$>)!3 (-#$'7!5 ([email protected]$ $#!,7 $)!81&!3 17'! 18!'5$7$!7 ',);$7*!$N$#!'51,-5!V/]T!7 C7'$37!(&$!7 ,88;D;$#'!'1! (DO,;&$!;#81&3(';N$!.K.LM!;3(-$7!;#!&('7!Uca*!cVW/!Z+!7?;#! $D51!7 $O,$#D$7!5( [email protected]$ $#!B; )$>C!,7 $)!Ufc* !iV* !VVZJVVc *! VZiW*!C$'!-&();$#'!$D51!1&!',[email protected]?;#!$D51!7$O,$#D$7!(&$!31&$! $88;D;$#'*!( 7!' 5$C!( >>1B!81&!' 5$! (DO,;7;';1#!18 !( !f+!N1> ,3$! B;'5;#!(!&$(71#(@>$!(DO,;7;';1#!';3$!Gm!V]!3;#H!UfiJcV*!Vfa*! VfVW/!T5$!,7$!18!T V!3(??;#-!?&1'1D1>7!5([email protected]$$#!?&1?17$)! '1!;# D&$(7$! .K.LM!7 $#7;';N;'C! (#)[email protected] $''$&! $7';3('$!>1 D(>! .(#-(#$7$!D 1#D$#'&(';1#7I!' 5$7$!51B $N$&*!D 13$!B ;'5!' 5$! D17'!18! $='$#)$)!$ =?$&;3$#'! ';3;#-!UVfZ* !VffW!( #)!> 1#-$&! '$3?1&(>!&$71>,';1#!81&!)C#(3;D!7',);$7/!! dD5$3(';D(>>C*! ;3(-$!( DO,;7;';1#!?&1' 1D1>7!D (#!8( >>!; #'1! 'B1!); 88$&$#'!D ('$-1&;$7*! single-examination!1&! multi-

20 Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

Bertrand et al.

examinations*!$ (D5!B ;'5!) ;88$&$#'! ()N(#'(-$7!(# )! D(N$('7! '5('!(& $!) $'(;>$)! ;#!b ;-/!G 4H/! "8'$&!. L!;3 (-$!(DO ,;7;';1#*! a normalization of signal intensity!;7!#$$)$)*!'1!( DD1,#'!81&! N(&;(@;>;'[email protected]$'B$$#!$=?$&;3$#'7*!(#)!(>71!'1!D1&&$D'!81&!#1# J 7?$D;8;D!$# 5(#D$3$#'!& $>('$)!'1 !'5 $!7 C7'$3;D!& $);7'&;@,';1#! 18!.(#-(#$7$!UVfcW/!T1!(DD13?>;75!'5;7*!(!#,[email protected]$&!18!-&1,?7! 5(N$!, 7$)!(# !(& $(!1 8!'5 [email protected] &(;#!(B (C!8 &13!'5 $!7 ',);$)!? ('5J B(C!( 7! (!&$ 8$&$#D$!Uf]* !Va\* !VVf* !VVc* !VZ^W/ !">' $&#(';N$>C*! (&$(7!>1D('$)!1,'7;)$!'[email protected]&(;#!7,D5!(7!'$3?1&(>!3,7D>$!Ufc*! iVW*!5( [email protected]$ $#!7 ,--$7'$)/! L$D$#'>C*!` 5,(#-!( #)!41&$ '7AC! ?&1?17$)!'5$!,7 $!18!' 5$!?;',;'(&C!->(#)!(7! (#!;#'$&#(>!& $8$&J $#D$!' 1! (DD1,#'!81&!#1#7 ?$D;8;D! .K.LM! $#5(#D$3$#'7!&$ J >('$)!'1!'5$!7C7'$3;D!&$D;&D,>(';1#!18!.(#-(#$7$!UVfcW/!

3,>';J$=(3;#(';1#!?&1' 1D1>7*!' 5$!D ,&N$!18!7 ;-#(>!; #'$#7;'C! D5(#-$7!1N$&!';3$!5([email protected]$$#! (#(>CE$)!,7;#-!?5$#13$#1>1-;J D(>!31)$>[email protected]!8;'';#-!'1!$;'5$&!(!7;-31;)!8,#D';1#!UVa\*!VVZJ VVc*!VfVW!1&!(!3(77!'&(#78$&!8,#D';1#!UcaW/!T5;7!8;'';#-!?&1DJ $77! (>>1B7!81&! '5$!$ 7';3(';1#!18! 7,??>$3$#'(&C!?( &(3$'$&7! D5(&(D'$&;E;#-!. (#-(#$7$! '&(#7?1&'e! maximal signal intensity*!time to maximal intensity G1&!'1!5(>8!18!'5$!3(=;3,3H*! maximal slope!( #)! area under the curve/!" >>!'5 $7$!? (J &(3$'$&7!D(#[email protected]$!7',);$)!B;'5;#!7$>$D'$)!&$-;1#7!18!;#'$&$7'*!1&! &$?&$7$#'$)!? ;=$>[email protected]?;=$>!1#!( !- >[email protected](>!3 (?!18!' [email protected]&( ;#!(#)! D13?(&$)[email protected]$ 'B$$#!-&1,?7 !,7 ;#-!7 '(';7';D(>!?( &(3$'&;D!3 (?7! UfiJcVW/!! [email protected]; 1>1-;D(>!7 ;-#;8;D(#D$!18!' 5$7$!N( &;1,7!?( &(3$'$&7! &$3(;#7!5C?1' 5$';D(>/!T 5$!?$ (A!18!3 (=;3(>!7 ;-#(>!; #'$#7;'C! &$8>$D'7!'5$!>1D(>!(31,#'!18!3 (#-(#$7$*!'5;7!;'!751,>)[email protected]$!)$J ?$#)$#'!1#!'5$!,?'(A$!18!3(#-(#$7$!via!`(Zh!D5(##$>7!(#)!;#! 1&-(#$>>$7/!T 5$!'; 3$!$ >(?7$)[email protected]$ 'B$$#!' 5$!?$ (A7!18!' B1!&$ J -;1#7!18!; #'$&$7'! 751,>)!&$8>$D'!'5$!7 ?$$)!18!#$ ,&1#(>! '&(#7J ?1&'[email protected]$ 'B$$#! '5$3/!b ;-/!G 5H!7 ,33(&;E$7! '5$!8 &(3$B1&A!B $! ?&1?17$!81&!' 5$!;#'$&?&$'(';1#!18!' 5$7$!?(&(3$'$&7/!01B$N$&*! '5$7$!( 77,3?';1#7!& $3(;#!'1 [email protected] $!( 77$77$)! (#)!N (>;)('$)!$= J ?$&;3$#'(>>C/!

T5$! rate of signal intensity changes induced by manganese over time!;7!(!7;3?>$!?(&(3$'$&!'5('!5([email protected]$$#!B;)$>C! ,7$)!81&!$ N(>,(';#-! .(#-(#$7$!'&(#7?1&'/!M '! D(#[email protected] $! ;#8$&&$)! @C!$;'5$&!3 $(7,&;#-!'5$!'$3?1&(>!);88$&$#D$!;#!7 ;-#(>!;#'$#J 7;'[email protected]$'B$$#!'B1!7;#->$!';3$!?1;#'7*[email protected]!8;'';#-!'5$!(N$&(-$! 7>1?$!18!7 ;-#(>! ;#'$#7;'C! (77,3;#-!>; #$(&! D5(#-$!),& ;#-!( ! 751&'!' ;3$JB;#)1B!Gb ;-/! 4H!Ufc* !fiJcV* !iV* !VVZ JVVcW/!T 5$! rate of signal intensity change over a distance!5 ([email protected] $$#! ?&1?17$)!( 7!( !?( &(3$'$&!' 5('!D (#!&$ 8>$D'!' 5$!' &(#7J7C#(?';D! 8>,=!18!.( #-(#$7$!G1&!3 (#-(#$7$! '&(#78$&!; #)$=H!UVZiW/ !M #!

Single examination protocol signal

Multi examination protocol

Our study

signal

time

time

- Single MR examination - No image registration - Simple algorithm

- Multiple MR examination - Image registration needed - Fitting process needed

- Few parameters: intensity, slope

- Multiple parameters: intensity, peak, time-to-peak, maximal slope, integral - Multiple neurons can be studied - Region of interest can be fixed retrospectively 1 - Temperature monitoring is not needed

- Single neuron study - Time window and slice to be defined in advance - Temperature monitoring is critical

!

Fig. (4).!TB1!);88$&$#'!'C?$!18!?&1'1D1>!81&!.K.LM!7',);$7!18!(=1#(>!'&(#7?1&'/!Single-examination protocols G>$8'!?>1'H!D1#7;7'!18!'5$!&$?$';J ';1#!18!(!8(7'!7$O,$#D$*!,7,(>>C!;#!Z+*!),&;#-!'5$!7(3$!.L!$=(3;#(';1#/!R;#$(&!&$-&$77;1#!18!'5$!#1&3(>;E$)!7;-#(>!;#'$#7;'C!(7!(!8,#D';1#!18! ';3$! (>>1B7! 81&!' 5$!D( >D,>(';1#! 18!' 5$!& ('$! 18! 7;-#(>!; #'$#7;'C! D5(#-$7!( >1#-! ';3$!G 7>1?$! 18!' 5$! >;#$H/! T5;7! ?&1'1D1>!7 ',);$7!'5$!' &(#7?1&'!18! 3(#-(#$7$!'5('!1DD,&7!during!.L!(DO,;7;';1#/!0$#D$*!3(;#'(;#;#-!'5$!(#;3(>!,#)$&!#1&31'5$&3;(!),&;#-!'5$!D1>>$D';1#!18!.L!)('(!;7!D&;';J D(>*!(7!5C?1'5$&3;(!B(7!751B#!'[email protected]>1DA!#$,&1#(>!'&(#7?1&'!(#)!3(#-(#$7$!?&1?(-(';1#!UfcW/!Multi-examination protocols!G&;-5'!?>1'H!D13J ?&;7$!3,>';?>$!.L!(DO,;7;';1#7!18!'5$!7(3$!7$O,$#D$*!;)$(>>C!(!f+J7$O,$#D$!B;'5!;71'&1?;D!&$71>,';1#!'1!$#(@>$!D1&$-;7'&(';1#[email protected]$'B$$#!7D(#7*! 7$?(&('$)[email protected]!;#'$&N(>7!18!';3$!B5$&$!'5$!(#;3(>!;7!(B(A$!(#)!8&$$>C!31N;#-/!T5;7!?&1'1D1>!(>>1B7!81&!'5$!7',)C!18!3(#-(#$7$!'&(#7?1&'!'5('! 1DD,&7!between!.L!(DO,;7;';1#7I!5$#D$*!'$3?$&(',&$!31#;'1&;#-!),&;#-!7D(#7!;7!#1'!D&;';D(>/!T5;7!?&1'1D1>!-;N$7!(DD$77!'1!31&$!?(&(3$'$&7! 18!3(#-(#$7$!'&(#7?1&'!'5(#!'5$!7;#->$J$=(3;#(';1#!?&1'1D1>/!

From Axonal Transport to Mitochondrial Trafficking

Peak value

2.4

UPTAKE channels - Mitochondria - Transport vesicles

2.2

Curve of normalized signal intensity as a function of time in 2 region g ( ) of interest (ROI)

2.0 1.8

S((t)

Beware of: B f - Neuronal loss - Gliosis c toto c ty - Excitotoxicity

21

2.6

= Ca2+

Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

1.6 1.4 1.2 1.0

0.8 0

Time between k peaks 2000

4000

= 6000

TRANSPORT b t between th the 2 ROI

8000

t (min.)

10000 12000 !

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22 Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

Bertrand et al.

A Basal Forebrain

Olfactory Bulb

Hippocampus

Cortex

hAPP Total APP 2

% Normalized Control

B 125

8

2

2

8

2

8

100

*

75

**

50 25 0 3-4 m

C

8

Tubulin Age (m)

WT

7-8 m 11-14 m Tg2576 Age (m)

!SI/Time (min)

3-4 m 0.00797 ! 0.0019 N=4 7-8 m 0.00676 ! 0.0013 N=6 11-14 m 0.00975 ! 0.0023 N=4

Tg2576

!SI/Time (min)

3-4 m 0.00737 ! 0.0015 N=4 7-8 m 0.00353 ! 0.0004 N=6 11-14 m 0.00178 ! 0.0004 N=4

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!" Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

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24 Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

'5('!(&$!7,7?$D'$)!'1!;#N1>N$!(#!(>'$&(';1#!18!(=1#(>!'&(#7?1&'! UfW/!! ACKNOWLEDGEMENTS T5;7! 3(#,7D&;?'!B( 7!7 ,??1&'$)! ;#!?(&'[email protected]! '5$!!"$&;D(#! 0$(>'5! "77;7'(#D$!#$,#)(';1#!"+ L!G"Zaa\JV]]H!(%)!&'(! ">E5$;3$&!")71D;(';1#!GMM*+Ja\JiV^V\H!&$!61,))(,!9-! :()-5;&;/!!"##$!%$&'&(#)!;7!8,#)$)[email protected]!'5$!b&$#D5!d1D;$'C!18! L();1>1-C*! '5$!b &$#D5!.$D;$'C!18!/(,&1&();1>1-C*!'5$!X 5;>J ;??$!b1,#)(';1#!(#)!'5$!b&$#D5!.;#;7'&C!18!b1&$;-#!"88(;&7/! :$!'5(#A!.&!%$#_(3;#!%(&'$>>$!81&!5;7!;#7;-5'7!;#'1!.(#-(J #$7$012$>1-C/!+&7 /!X (N(#!4&;7 5#(3,&'5C*!K N$>C#! %-!k1,&( ! (#)!.(';>)$!M#->$7$!(&$!(DA#1B>$)-$)!81&!'5$;&!8$$)@(DA!(#)! D&;';D(>!?&118&$();#-!18!'5;7!3(#,7D&;?'/!!:$!B1,>)!(>71!>;A$! '1!$='$#)!(!7 ;#D$&$! '5(#A!C1,!' 1!+&7 /! K;#(&!d ;-,&)771#!(#)! +(#;$>!0/! T,&#@,>>*!(7!B $>>!(7! '1!'5$;&!&$7?$D';N$!>(@! '$(37*! 81&!'5$;&!D1#';#,$)!5$>?!(#)!7,??1&'/! REFERENCES UVW!!

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From Axonal Transport to Mitochondrial Trafficking

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Current Medical Imaging Reviews, 2011, Vol. 7, No. 1 U^^W!! U^[W!!

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26 Current Medical Imaging Reviews, 2011, Vol. 7, No. 1 U\\W!! U\iW!! UiaW!! UiVW!!

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From Axonal Transport to Mitochondrial Trafficking

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Current Medical Imaging Reviews, 2011, Vol. 7, No. 1

>(=(';1#!';3$7!),&;#-!? 17'#('(>!) $N$>1?3$#'/!o!.(-#!L$71#!M3(-J ;#-!Zaa[I!Z]e!fZJ\/! T([email protected](>1!d*!+(),DD;!"*!b;1&;#;! d, et al.!K=?$&;3$#'(>!?&1'1D1>!81&! (D';N(';1#J;#),D$)!3 (#-(#$7$J$#5(#D$)!. LM!G "[email protected](7 $)! 1#!O,(#';'(';N$!)$'$&3;#(';1#!18!.#!D1#'$#'!;#!&('[email protected]&(;#[email protected]!8(7'!TV! 3(??;#-/!.(-#!L$71#!.$)!ZaaiI!^Ze!Va\aJc/! `5,(#-!4 0*!4 1&$'7AC!" X/!" DD1,#';#-!8 1&!# 1#7?$D;8;D!$#5 (#D$J 3$#'!;#!#$,&1#(>!'&(D'!'&(D;#-!,7;#-!3(#-(#$7$!$#5(#D$)!3(-#$';D! &$71#(#D$!;3(-;#-/!.(-#!L$71#!M3(-;#-!ZaaiI!Z[e!]icJ^aa/! T(A$)(!" /!. (#-(#$7$!(D' ;1#!; #[email protected]& (;#!8 ,#D';1#/!% &(;#!L $7!L $N! ZaafI!cVe![iJ\[/! "7D5#$&!.*!K&;A71#!4.*!0$&&$&1!0$&#(#)$E!K*!T_(>A$#7!L/!.(#J -(#$7$!(#)!;'7!&1>$!;#!X(&A;#71#r7!);7$(7$e!8&13!'&(#7?1&'!'1!#$,&1J ?('51>1-C/!Y$,&131>$D,>(&!.$)!ZaaiI!VVe!Z]ZJ^^/! `(#(>7!d*!% $C$&>$;#!.*! 4$>>$&!" R*!.,&(C(3(!6 *!R1-1'5$';7!Y 4/! .(-#$';D!&$71#(#D$!;3(-;#-!18!D1&';D(>!D1##$D';N;'C!in vivo/!Y$,J &1;3(-$!Zaa\I!cae!c]\J[Z/! T5,$#!.*!%$&&C!.*!X$)$&7$#!T%, et al.!.(#-(#$7$J$#5(#D$)!.LM! 18!'5$!& ('!N;7,(>!?('5B(Ce!(D,'$!#$,& (>!'1=;D;'C*!D1#'&(7'!$#5(#D$J 3$#'*!(=1#!&$71>,';1#*!(=1#(>!'&(#7?1&'*!(#)!D>$(&(#D$!18!.#GZhH/!o! .(-#!L$71#!M3(-;#-!Zaa\I!Z\e!\]]J^]/! %1DA!Y "*!X(;N(!bb*!d;>N(!" `/! b&(D';1#('$)!3 (#-(#$7$J$#5(#D$)! .LM/!Y.L!%;13$)!Zaa\I!ZVe!c[fJ\/! K7D5$#A1!j *!` (#(>7!d *!d ;3(#1N(!M , et al.!. (??;#-! 18! 8,#D';1#(>! @&(;#!(D';N;'C!;#!8&$$>[email protected]$5(N;#-!&('7!),&;#-!N1>,#'(&C!&,##;#-!,7 J ;#-!3(#-(#$7$J$#5(#D$)!.LMe!;3?>;D(';1#!81&!>1#-;',);#(>!7',);$7/! Y$,&1;3(-$!ZaVaI!cie!Z]ccJ]]/! K7D5$#A1!j *!` (#(>7!d *!d ;3(#1N(!M *!R 1-1'5$';7!Y 4/!% $5(N;1&(>*! $>$D'&1?5C7;1>1-;D(>!( #)! 5;7'1?('51>1-;D(>!D 1#7$O,$#D$7! 18!7 C7J '$3;D!3(#-(#$7$!()3;#;7'&(';1#!;#!.K.LM/!.(-#!L$71#!M3(-;#-! ZaVaI!Z\G\He!VV^]J[c/!! T18'!4 s*!0 ,7'N$)'!d j*!s &(#'!+ , et al.!. $'(@1>;73!( #)! ?5(&3(J D1A;#$';D7!18!.#+X+X!;#!3(#/!"D'(!L();1>!Vii[I!f\e!^[[J\i/! o,#-!s*!0$;#)$>!:*!4&(5$!T, et al.!M#8>,$#D$!1 8!'5 $!5 $?('[email protected];>;(&C! D1#'&(7'!(-$#'!3(#-(81);?;&!'&;71);,3!G.YJ+X+XH!1#!'5$!;3(-;#-! ?&1?$&';$7! 18!(@ )13;#(>!1& -(#7/!. (-#!L $71#!M 3(-;#-! Vii\I!V ^e! iZ]JfV/! L$;3$&!X *!d D5#$;)$&!s *!d D5;3(!:/!0 $?('[email protected];>;(&C!D 1#'&(7'!( -$#'7! 81&!D1#'&(7'J$#5(#D$)!.LM!18 !'5$!> ;N$&e!?& 1?$&';$7*!D>;#;D(>!)$N$>J 1?3$#'!(#)!(??>;D(';1#7/!K,&!L();1>!ZaacI!Vce!]]iJ[\/! 07;(1!4*!`5(?3(#!X*!Y;>7$#!d, et al.!`1&&$>(';N$!3$31&C!)$8;D;'7*! "@$'(!$>$N(';1#*!(#)!(3C>1;)!?>(O,$7!;#!'&(#7-$#;D!3;D$/!dD;$#D$! Vii^I!Z[ce!iiJVaZ/! :(#-!u R*!X $&&C!s *!d 3;'5!." *!9 5,!u :/!" 3C>1;)[email protected]$'(J+$&;N$)! +;88,7;@>$!R;-(#)7!`(,7$!M3?(;&$)!"=1#(>!T&(#7?1&'!18!.;'1D51#J )&;(!;#!Y$,&1#7/!Y$,&1)$-$#$&!+;7!ZaVaI![e!]^Ji/! .;#175;3(!d*!`&177!+ /! In vivo!;3(-;#-!18!(=1#(>!'&(#7?1&'!,7 ;#-! .LMe!(-;#-!(#)!">E5$;3$&r7!);7$(7$/!K,&!o!Y,D>!.$)!.1>!M3(-;#-! Zaa\I!f]!Gd,??>!VHe!d\iJiZ/!

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