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#$!18!R(,'$&@,&F7!$(&>;J $7'!? (?$&7!B 5$&$!5 $!8 1&3(>;E$)!'5 $!@ (7;7!1 8!. L!;3 (-;#-! Uc^W/!R('$&*!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*!@,'! '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;#-!'5$!@>11)J@&(;#!@(&&;$&*!1?$#$)!'5$!B(C!'1!D>;#;J D(>!(??>;D(';1#7!81&!>;N$&*!?(#D&$(';D!(#)!D(&);(D!.LM!Uc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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$!1>8(D'1&C!@,>@!(#)!;#!'5$!>('$&(>!1>J 8(D'1&C!'&(D'I!(#)!'5$!#$,&1#7!18!'5$!?;&;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(#!@ $! 7$$#!1 #!(!T VJB$;-5'$)!;3 (-$*!D1 3?(&$)!'1 !'5 $!7 (3$!7 $O,$#D$!@ $81&$!. #`>!;# _$D';1#!G1 @>;O,$!7 (-;''(>!N ;$B*! &$)!(&J &1B7H/!Y1'$! '5$!Z!7' &;?$7! '5('! (&$! D>$(&>C!N;7;@>$!;#!'5$! '$3?1&(>! (&$(*!'5$! >1B$&!1#$! G@>,$! (&&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$!U[[W* !7 ?;#(>!D 1&)! U[\J\aW!( #)!@&( ;#!U\VJ\fW* !;#! 31)$>7!18!;7 D5$3;(!U\cJ\iW*! (#)!;#!N (&;1,7! 31)$>7!18!@&( ;#! );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!),$!'1!'5$!D13@;#(';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 ',);$7!18!@&( ;#! D;&D,;'&C!,7 ;#-!' &(D'J'&(D;#-!.K .LM! '5('!B$&$!;#;';(>>C!>;3;'$)!'1!'5$!1>8(D'1&C!(#)!'5$!N;7,(>!7C7J '$37*!5( N$!#1B!@$ $#!?$ &81&3$)!; #!1' 5$&!@&( ;#!7 '&,D',&$7! ;#D>,);#-!' 5$! (,);'1&C!7 C7'$3!UVafJVa]W!( #)!N( &;1,7!)$ $?! 8;@$&!7C7'$37!'5('!D1,>)!@$!(DD$77$)!@C!7'$&$1'(=;D!;#_$D';1#7! 18!.#`>Z!UVa^JVaiW/! cJ!T&(D'J'&(D;#-!.K.LM!5(7!(>71!@$$#!?&1?17$)!(7!(!'11>! 81&!'5$!in vivo!7',)C!18!( =1#(>!'&(#7?1&'!Ufc*!caWI!'5;7!(7?$D'! B;>>!@$!);7D,77$)!;#!-&$('$&!)$'(;>!;#!'5$!81>>1B;#-!7$D';1#7/! .K.LM!(??>;D(';1#7!5(N$!@$$#!>;3;'$)!'1!&1)$#'!7',);$7! @,'!5(N$!@$$#!$='$#)$)!'1!1'5$&7!7?$D;$7!7,D5!(7!#1#J5,3(#! ?&;3('$7!Uf]* !^Z* !VVaW* !3 ;#;?;-7!UVVVW!( #)!7 1#-@;&)7/!T 5$! >(''$&!&$ ?&$7$#'7!( #!; #'$&$7';#-!3 1)$>!81&!' 5$!7 ',)C!18!@&( ;#! ?>(7';D;'C!UVVZJVV]W/!

Biological Basis of MEMRI: Which Mechanisms Does Manganese Propagation Reflect? .(#-(#$7$! $#'$&7!' 5$!@&( ;#! via!) ;88$&$#'!D (&&;$&7*! (#)! >;A$>C!$ =;'7!' 5$!@&( ;#!@C!); 88,7;1#!3 $D5(#;737!UVV^* !VV[W I! D13?>$'$!D$& $@&(>!D> $(&(#D$!1 8!3 (#-(#$7$!(8 '$&! .K.LM! $=(3;#(';1#! '(A$7! (@1,'! (!3 1#'5!UVV\W/ !j#D $!; #!' 5$!@&( ;#*! 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\W!@$81&$!;'7!&$>$(7$!;#'1!'5$!7C#J (?';D!D>$8'!@C!?&$J7C#(?';D!N$7;D>$7!(#)!;'7!,>';3('$!,?'(A$!@C! '5$!#$='!#$,&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$&;E;#-!)&,-* !B5; D5!5( 7!@$ $#!7 51B#!' 1!)&( J 3(';D(>>C!;3?(;&!'5$!?&1-&$77;1#!18!3(#-(#$7$*!'5,7!7,--$7'J ;#-!' 5('!3 (#-(#$7$!;7 !' &(#7?1&'$)!?&$ )13;#(#'>C!@C!( D';N$! 3$D5(#;737!&( '5$&! '5(#!@C!?( 77;N$!); 88,7;1#!UfZJfcW /! .K.LM!7 ',);$7!5(N$!&$?1&'$)!(#!(??(&$#'!7?$$)!18!3 (#-(J #$7$! '&(#7?1&'!& (#-;#-!8&13 !a/ V\!' 1!V /Vf! !3l7*!B ;'5! (!? &$J )13;#(#'!'&$#)!@$'B$$#!a/f!(#)!a/f]!!3l7*!B5;D5!;7!D>17$!'1! '5$!7?$$)!18!8( 7'!(=1#(>!'&(#7?1&'!(7!3 $(7,&$)!@C!N; )$1!3;J D&17D1?C!GV! !3l7H!Uf*!f]*!ca*!]i*!VVZ*!VVfW/! T5,7*! .K.LM! 5(7!@$ $#!?&1?17 $)!( 7!( !,#; O,$! in vivo! '11>!81&!' 5$!#1#J ;#N(7;N$!7 ',)C!18!#$ ,&1#(>!' &(#7?1&'! ;#!@1' 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'!@$!A$?'!;#! 3;#)!B5$#!(#(>CE;#-!7,D5!$=?$&;3$#'(>>C!)$&;N$)!)('(e! VJ!d ',)C;#-!( =1#(>!' &(#7?1&'!@C! .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(#-(#$7$!;#!#$,&1#7!@(7$)!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'!?&1@(@>C!;#!7C#(?';D!N$7;D>$7*!'1!@$!'(A$#!,?!@C!' 5$! #$='!#$,&1#!Uf]Jf\W/!!

ronal release (at the synapses) are conserved, ,#>$77!'5$7$! ?(&(3$'$&7!(&$!'(A$#!;#'1!(DD1,#'!@C!' 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 occurs!@ $'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&'!&$?1&'$)!@C! .K.LM!Uf* !f]* !ca* !]i* !VVZ* !VVfW/ !T 5,7*!( 77,3;#-!' 5('!' 5$! &$>(=;N;'C!18!3 (#-(#$7$! ;7!7 ;3;>(&! ;#!@1' 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'!@ $81&$!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$&$! ;'!@;#)7!'1!- >,'(3;#$! 7C#'5$'(7$! (#)! .#J dj+!UVZZ* !VZfW/ !T 5;7!- >;(>J@(7$)! 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$#1#!5( 7!@$ $#!& $?1&'$)! ;#! 31)$>7!1 8! D$&$@&(>! ;7D5$3;(! 7',);$)!@ 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,$#'>C*!; '!3 ,7'!@$ ! 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! (>71!@$$#!&$?1&'$)!'1!;#5;@;'!3;'1D51#)&;(>!31N$3$#'*!B5;D5! B1,>)!?1'$#';(>>C!)$D&$(7$!'5$!'&(#7?1&'!18!3(#-(#$7$!UVZ]W/! ]J!"=1#( >!' &(#7?1&'!;7 !( !?5$ #13$#1#!' 5('! ;7!&$ >('$)!' 1*! @,'!); 7';#D'!8&13 *! '5$!$ >$D'&;D(>!( D';N;'C!18!( !#$ ,&1#/!j#$ ! 7',)C!751B$)!'5('!'5$!D13?>$'$!;#5;@;';1#!18!$>$D'&;D(>!(D';NJ ;'C!;#!&$';#(>!-(#->;1#!D$>>7!)1$7!#1'!?&$N$#'!'5$!'&(#7?1&'!18! .(#-(#$7$!' 1!' 5$!7 ,?$&;1&!D 1>>;D,>,7*!7 ,--$7';#-!' 5('!3 (#J -(#$7$! D(#!@$ !' &(#7?1&'$)!?( 77;N$>C!( #)!#1' !1#> C!@C!( D';N$! 3$(#7!UVZ^W/ !01B$ N$&*! ;'!5( 7! (>71!@$ $#!7 51B#! '5('!( =1#(>! '&(#7?1&'!;7!3(;#'(;#$)!$N$#!),&;#-!'5$!D13?>$'$!@>1DA()$!18! $>$D'&;D(>!( D';N;'C!UVZ[* !VZ\W/ ! If axonal transport can be upregulated by an increase of electrical activity, it does not appear to be stopped by the complete inhibition of electrical activity/! Evaluation of Neuronal Transport by MEMRI: Various Techniques .K.LM!5( 7!@$ $#!,7 $)!' 1!7 ',)C!# $,&1#(>!' &(#7?1&'! ;#! N(&;1,7!8;@$&!7C 7'$37!G1>8(D'1&C!7C 7'$3*!N ;7,(>!7C 7'$3*!) $$?! 8;@$&7!' &(D'7H!( #)! ;#!N( &;1,7!7 ?$D;$7!G3 ;D$*!& ('7*!7 1#-@;&)7! (#)!?&;3('$7H/!0 ;-5J8;$>)!3 (-#$'7!5 (N$!@$ $#!,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$7!5( N$!@$ $#!B; )$>C!,7 $)!Ufc* !iV* !VVZJVVc *! VZiW*!C$'!-&();$#'!$D51!1&!',&@17?;#!$D51!7$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(N$!@$$#!?&1?17$)! '1!;# D&$(7$! .K.LM!7 $#7;';N;'C! (#)!@ $''$&! $7';3('$!>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!#$$)$)*!'1!( DD1,#'!81&! N(&;(@;>;'C!@$'B$$#!$=?$&;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*!(!#,3@$&!18!-&1,?7! 5(N$!, 7$)!(# !(& $(!1 8!'5 $!@ &(;#!(B (C!8 &13!'5 $!7 ',);$)!? ('5J B(C!( 7! (!&$ 8$&$#D$!Uf]* !Va\* !VVf* !VVc* !VZ^W/ !">' $&#(';N$>C*! (&$(7!>1D('$)!1,'7;)$!'5$!@&(;#!7,D5!(7!'$3?1&(>!3,7D>$!Ufc*! iVW*!5( N$!@$ $#!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(7!@$$#! (#(>CE$)!,7;#-!?5$#13$#1>1-;J D(>!31)$>7!@C!8;'';#-!'1!$;'5$&!(!7;-31;)!8,#D';1#!UVa\*!VVZJ VVc*!VfVW!1&!(!3(77!'&(#78$&!8,#D';1#!UcaW/!T5;7!8;'';#-!?&1DJ $77! (>>1B7!81&! '5$!$ 7';3(';1#!18! 7,??>$3$#'(&C!?( &(3$'$&7! D5(&(D'$&;E;#-!. (#-(#$7$! '&(#7?1&'e! maximal signal intensity*!time to maximal intensity G1&!'1!5(>8!18!'5$!3(=;3,3H*! maximal slope!( #)! area under the curve/!" >>!'5 $7$!? (J &(3$'$&7!D(#!@$!7',);$)!B;'5;#!7$>$D'$)!&$-;1#7!18!;#'$&$7'*!1&! &$?&$7$#'$)!? ;=$>J@CJ?;=$>!1#!( !- >1@(>!3 (?!18!' 5$!@&( ;#!(#)! D13?(&$)!@$ 'B$$#!-&1,?7 !,7 ;#-!7 '(';7';D(>!?( &(3$'&;D!3 (?7! UfiJcVW/!! T5$!@; 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,>)!@$!)$J ?$#)$#'!1#!'5$!,?'(A$!18!3(#-(#$7$!via!`(Zh!D5(##$>7!(#)!;#! 1&-(#$>>$7/!T 5$!'; 3$!$ >(?7$)!@$ 'B$$#!' 5$!?$ (A7!18!' B1!&$ J -;1#7!18!; #'$&$7'! 751,>)!&$8>$D'!'5$!7 ?$$)!18!#$ ,&1#(>! '&(#7J ?1&'!@$ '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 !@ $!( 77$77$)! (#)!N (>;)('$)!$= J ?$&;3$#'(>>C/!

T5$! rate of signal intensity changes induced by manganese over time!;7!(!7;3?>$!?(&(3$'$&!'5('!5(7!@$$#!B;)$>C! ,7$)!81&!$ N(>,(';#-! .(#-(#$7$!'&(#7?1&'/!M '! D(#!@ $! ;#8$&&$)! @C!$;'5$&!3 $(7,&;#-!'5$!'$3?1&(>!);88$&$#D$!;#!7 ;-#(>!;#'$#J 7;'C!@$'B$$#!'B1!7;#->$!';3$!?1;#'7*!1&!@C!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 (7!@ $$#! ?&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#!'1!@>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#!@$'B$$#!7D(#7*! 7$?(&('$)!@C!;#'$&N(>7!18!';3$!B5$&$!'5$!(#;3(>!;7!(B(A$!(#)!8&$$>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'$)!'1!;#N1>N$!(#!(>'$&(';1#!18!(=1#(>!'&(#7?1&'! UfW/!! ACKNOWLEDGEMENTS T5;7! 3(#,7D&;?'!B( 7!7 ,??1&'$)! ;#!?(&'!@C! '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,#)$)!@C!'5$!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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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

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