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VOL. 16, NO. 4 n The AmericAN JOurNAL Of mANAged cAre n S87

Managed Care &Healthcare Communications, LLC

IntroductionPa k nsons s as (Pd) s t s on ost o on n o n-at v so , a k by n as n ov nt- lat sab l ty,

n l n t o an b a yk n s a, pa balan an oo na-t on, an o n t v an s.1 it a ts p to 1 ll on p opl n tun t Stat s an p to 5 ll on wo l w .1 T p val n o Pd

n as s w t a , w t app ox at ly 1% o t os a 60 y a so ol a t , 4% o o o t os a 80 y a s o ol ,2 anapp ox at ly 5.2% o t os n n s n o s.3 g v n t ow n

l ly pop lat on n t un t Stat s, t n b o n v alsw t Pd s xp t to o bl by 2030.4

S an n as w ll pla a s n ant b n on alt asyst s an a v s v n t p o ss v nat o Pd, asso -at sab l ty, an s n ant a v n q n t lat sta so t s as . W t t xp t n as n Pd p val n , t anb ant pat t at t s as w ll ont n to xa t a s n ant

t an n t ono ost. T o t l ons at on ntot at nt s ons an s lt n o opt al alt a t l za-t on w t o t sa n alt - lat q al ty o l (hrQOL) an

ono osts.

Economic Costs of PD and Impact onHealth-Related Quality of Life

Ov all, t ann al ono pa t o Pd n t un t Stat ss st at at $10.8 b ll on, 58% o w s lat to t

al osts.5 Ann al t al osts p pat nt w t Pd ast at to b b tw n $10,043 an $12,491, o t an o bl

t at o pat nts w t o t t s as .5,6 P s pt on s a o nto app ox at ly 14% to 22% o osts, w t n s n o a t

la st o pon nt at app ox at ly 41%. Ann al n t osts,n l n lost wo k ays o pat nts an a v s, a st at at

$9135.5 As po tant as ono osts a to any s ss on o

Pd- lat so t l zat on, t s also t al t at pay s an p o-v s ons t s n ant pa t t s as as on hrQOL.hrQOL ass ss s an n v als p v t o t lln ss ont p ys al, psy olo al, an so al a ly l v s.7 it s po tant

n t n n t t v n ss o t ap s o Pd at bot tn v al an pop lat on l v ls.8 fo ana a p ov s,

t p s nts an po tant pa a t to as t t v n ss

Pa k nsons d s as :h alt -r lat Q al ty o L , e ono cost,

an i pl at ons o ea ly T at nt

Jack J. Chen, PharmD

n report n

AbstractParkinsons disease (PD) is the second most com-mon neurodegenerative disorder, marked by pro-gressive increases in movement-related disability,impaired balance, and nonmotor symptoms. Itsprevalence in the United States is expected todouble within the next 20 years as the percentageof the elderly in the population grows. Patientswith PD have twice the direct medical costs ofthose without PD, the majority of which occur laterin the disease as disability and therapy-relatedcomplications increase. Greater awareness of aprodromal/premotor stage of the disease, effortstoward early and accurate diagnosis, and thecontinuous refinement of treatment paradigmsprovide an opportunity for discussion on the use ofpotential disease-modifying agents to slow or haltthe progression of motor and nonmotor disabil-ity. Such compounds could not only significantlyimprove patient and caregiver quality of life, butsubstantially reduce direct and indirect costs. Todate, numerous compounds have been evaluatedin clinical trials, including coenzyme Q10, creatine,levodopa, pramipexole, rasagiline, ropinirole, andselegiline. None has demonstrated irrefutable andenduring disease-modifying qualities, althoughthe best available clinical evidence appears mostpromising for rasagiline.

(Am J Manag Care. 2010;16:S87-S93)

For author in ormation and disclosures, see end o text.

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r po ts

S88 n www.aj . o n mArch 2010

o ana nt st at s an q al ty o a .7 hrQOLas s a also po tant n ass ss n t val o

t apy, pa t la ly o on on t ons s as Pd, ann t n n t app op at pla nt o at ons on

plan o la s.9,10 As wo l b xp t o any on an p o s-

s v ly wo s n n so , Pd as a s n ant pa t on thrQOL o bot pat nts an t a v s.11 in a laV t ans A n st at on o o t, pat nts w t Pd x b tlow s o s on t p ys al an ntal alt ns onso hrQOL o pa w t pat nts w t 8 ot n oloo on on t ons, n l n ab t s, on st v a t

a l , an na/ o ona y a t s as , an st ok .12 O not ,non oto sab l ty, pa t la ly p ss on, nso n a, anot ntal alt a to s, app a to av a at n at v

t on hrQOL t an oto ts.8,13-15

Etiology and Clinical Course of PDA n , n a t on to lt pl ot a to s, app a s to

ont b t to t pat o t olo y o Pd. App ox at ly 5% to10% o pat nts onst at a a l al patt n o t s as ,so o w a asso at w t l nka s to a oz n -

nt n tat ons.16 env on ntal a to s l k ly nt a tw t n t a to s to n as t sk o Pd, n l n

b o p st xpos .17-20 int st n ly, p o-lo st s av ons st ntly asso at an nv s o la-t on b tw n a tt s ok n an o ons pt on ot l t v lop nt o Pd.21

T b a ns o n v als w t Pd a a k by n-at on an loss o opa n n ons n t s bstant a

n a.1 Non opa n pat ways a also nvolv , n l -n ol n an no p n p n n ons n t basal o -

b a n, s oton n n ons n t b a n ap , an otn ons n t b a n st , sp nal o , an p p al a to-no n vo s syst . Pat olo y n any o t s n onalsyst s l k ly ont b t s to t non oto an stat ons o t s as .16,22

mo ntly, t as b n post lat t at Pd ay ba p on so v n t p on-l k b av o o alp a-syn l n p ot n a at s. T s a at s o p s as n ant po t on o t L wy bo s t at a a ll la

all a k o Pd.23

T l n al o s o Pd o t n b ns w t non otosy pto s s as onst pat on, ypos a ( s nso s ll), an ap y ov nt (rem) sl p b av o

so (rBd). Pat nts a s ally not a nos , ow v ,nt l t y x b t obv o s oto sy pto s, ons st n o

st n t o , ty, an /o slown ss o ov nt (b a-

yk n s a).1,24,25

Abo t on t o pat nts o not v lop

a st n t o , an t s as b n po t to b p o nosto a o ap ly p o ss v s as o s .26 As t s asp o ss s, pat nts x b t sab l ty to b a yk n s a

ty, a t an balan lty, an alls.24 A t onally,opa n - lat s ts o at ons b oo p obl at . in o a van sta s o t s as ,

sabl n o n t v sy pto s, s as nt a, a oo on. 24

S v al ass ss nt an at n s al s p ov l n allypo tant n o at on on an s n Pd s v ty an s-

ab l ty. T s n l t un Pa k nsons d s asrat n S al (uPdrS), w s n o n v s on tob tt a o nt o non oto sy pto s, W bst s col b aun v s ty rat n S al (curS), No t w st n un v s tyd sab l ty S al (NudS), an t ho n an Ya s al .27 A nt analys s o lat sab l ty w t t uPdrS an

nt sp oto an total s o s to ass st l n ann t n n l n ally an n l an s n Pd p o s-

s on an spons to t apy.28

Implications of Prodomal/Premotor StagePd s o p s o oto an non oto s ns an

sy pto s. it s o n z t at xt an al n opat oloan s p t n at on o n ost atal opa n-

n ons; t s, non oto at s ant at t ons to oto at s. how v , a nost t a o Pd aval at bas on oto at s. P oto l n al at s

n l a tono ys n t on ( pa ol a t on, a asy pat t n vat on, na y st ban s), ast o nt s-t nal st ban s ( onst pat on), n opsy at so( p ss on, l o n t v pa nt, rBd), an s nso y

so s (pa n, stl ss l s syn o ). S sy pto s ayo p to 10 y a s p o to oto sy pto s an a no-s s.29-32 T tabl s b s non oto sy pto s t at ay bp s nt n t p oto sta o Pd.

T a s v al sta s lat to n onal an s, w ta l sta s o n n a as ot t an t s bstant a

n a. As B aak an s oa t o s not : W t to b oposs bl to a nos Pd n t p sy pto at sta s 1 o2, an w a a sal t apy to b o ava labl , t s bs -q nt n onal loss n t s bstant a n a o l b nt lyp v nt .32,33 By t t pat nts a a nos , ow v ,s bstant al n onal a a as al a y o n ts bstant a n a, w t opa n l v ls at l ast 30% to 40%low t an no al.16,34

g at awa n ss an o n t on o t p s n o p oto sy pto s o Pd av a s t poss b l ty o v y a ly a nos s (b o app a an o oto at s).

i a n st s t l z n opa n t anspo t t a s an

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h alt -r lat Q al ty o L , e ono cost, an i pl at ons o ea ly T at nt


n al lt aso n t o s onst at t pot nt al os n a l a nos s.34 g v n n as knowl o

t p oto p notyp o Pd, a batt y o t sts n l nass ss nt o non oto at s, ol a to y t st n , a as nt ap y, an n o a n ay on ay p ov a

ans o l ably a nos n Pd at an a ly sta o ts as . i ally, t n, s as - o y n (n op ot -

t v ) t ap s s n to slow o alt s as p o ss onwo l b n t at . Alt o s as - o y n t ap s

ay p ov a b n t n o at -to-a van Pd, n -t at on o t apy n a ly s as wo l p ov atb n t.

S app oa s o l s lt n s n ant t ann t ost sav n s as w ll as p ov pat nt an a -

v q al ty-o -l n ato s. As not a l , t b lk o

t al osts o n t lat sta s o t s asPa t o t at s lat to t l vo opa- n ysk n s at at pat nts v lop a t s v al y a s on t . A

nt v w o st s o n t at app ox at ly 25% oall pat nts v lop l vo opa- lat ysk n s a b tw n2.5 an 3.5 y a s, an p to 39% b tw n 4 an 6 y a s.35 S ann al t al osts w o t an o bl npat nts w t Pd xp n n s v ysk n s a o paw t t os w t o t oto o pl at ons.36 L vo opa- n

ysk n s a also as a s n ant n at v pa t on pat ntq al ty-o -l s o s an p ss on s v ty.36 in a t on,app ox at ly 15% to 20% o pat nts on opa n a on sts

x b t p ls ont ol so b av o ( , a bl nyp s x al ty), pos n a s n ant ono an q al ty

o -l b n on pat nts an t a v s.37

n Table. Symptoms in the Premotor Phase of Parkinsons Disease (PD) and Their Neuropathologic Substrates

Nonmotor Symptoms in PD

Presumed Underlying

Brain Structures

Nonmotor SymptomsWell Documented in the

Premotor Phase

Corresponding

Braak Stage

Ol action: impairments in

odor detection, identifcation, anddiscrimination

Ol actory bulb; anterior

ol actory nucleus; amygdala;perirhinal cortex

Ol actory impairment 1

Ol actory bulb and anteriorol actory nucleus

Dysautonomia

Gastrointestinal disturbances:gastroparesis, constipation

Urinary dys unction: urinaryrequency and urgency, nocturia

Sexual dys unction: Menimpairederection and ejaculation dys unction;Womenimpaired vaginal lubrication,problems in reaching orgasm

Orthostatic hypotension

Amygdala; dorsal nucleus othe vagus; intermediolateralcolumn o the spinal cord;sympathetic ganglia; entericand abdominopelvicautonomic plexuses

Constipation; genitourinarydys unctionCardiac postganglionicsympathetic denervation

1Dorsal nucleus o thevagus (sympatheticganglia; enteric andabdominopelvic autonomicplexi?)

Mood disorders(behavioral/emotional dys unction):depression, anxiety

Locus coeruleus; raphenuclei; amygdala; mesolimbic,mesocortical cortex

Depression; anxiety 2-3Locus coeruleus;raphe nuclei

Sleep disturbances: REM behaviordisorder, restless legs syndrome

Dorsal midbrain; nucleus sub-coeruleus; pedunculopontinenucleus; pons

REM behavior disorder;restless legs syndrome

2Nucleus subcoeruleus;pedunculopontine nucleus;dorsal midbrain; pons

Other nonmotor symptoms:pain, apathy, atigue

Unclear Unknown Unclear

Cognitive dys unction Frontal and ventral temporallobe/neocortex; hippocampus;amygdala; nucleus basalis oMeynert; locus coeruleus

?a 5-6

REM indicates rapid eye movement.a Cognitive impairment can be considered as a possible premotor mani estation o PD. When severe cognitive impairment (dementia) occurs be oremotor symptoms, it is regarded, arbitrarily, as the early mani estation o dementia with Lewy bodies and not as a premotor mani estation o PD.Adapted with permission rom Tolosa E, et al. Neurology . 2009;72(7 suppl):S12-S20.

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r po ts


N o s p a a olo at ons a ava labl tot at a ly Pd, n l n a anta n , ant ol n a nts,

opa n a on sts, l vo opa, an onoa n ox as typB (mAO-B) n b to s. A t onal ta l on a ly p a -

a olo t at nt s lo at n t a t l by ha s38 n t s s ppl nt. how v , non a o t n ly s o

o n o t at nt n pat nts w t asy pto atoto Pd. 39,40 inst a , t at nt s t a t onally lay nt l

pat nts x b t n t onal pa nt. T s l ts xposto t a v s ts o ant pa k nson at ons as w llas lays t lon -t n at v ts o l vo opa- n

oto o pl at ons s b a l .41 g v n t s n ant ono b n o Pd an knowl-

o t p oto p as , t s s n ant nt st nnt y n s as - o y n o po n s t at an b n t -

at v y a ly n t s as , poss bly b o any n t onaloto pa nt o sab l ty app a s. Not to b s ss ,n pat nts w t o at -to-a van sta s o Pd, t a-

p s t at lay t ons t o a t an balan pa nt ano n t v pa nt w ll also allow pat nts to n t on n -

p n ntly o a lon p o o t , t s n osts anp s v n hrQOL.36 ev n al a y s ows t at n t al t -apy w t nonl vo opa a nts s ost- t v , p olon s t tol vo opa n t at on, an lays t ons t o ysk n s a.42,43

N o s ta ts o n op ot t on av b n nt -, n l n ox at v st ss, n o n la at on, p ot n

a at on an s ol n , x totox ty, apoptos s, an losso t op a to s.44 cl n al t als to t st s as o at on,

ow v , av b n pa t la ly lt to s n an on t.A on t all n s a t n to nt y an t lan b s o nt at pat nts w t a ly Pd; t o n ty o

t a s to val at s as p o ss on; la k o a spb o ak o s as p o ss on; la k o a nt on t a -n t o t t at s o l b xp t o a s as - o y na nt; an lty nt at n b tw n sy pto at an

s as - o y n ts o t nt v nt on.45,46 To ov ot s last ba , s a s av t l z a lay -sta t s n

n w pat nts a an o z to b n t at nt w t tst y o pla bo o a ta n a o nt o t , a t wt pla bo o p s sw t to t st y an ollow ,alon w t t nt v nt on o p, o t a n o tst y. A s sta n n ( p ov nt) n t a ly-sta t

o p a t t s on p as o t t al s sts t at a lyt at nt on s a b n t t at wo l not app a t w nt o lat n t s as ( lay sta t).47

Clinical Trials With Disease-Modifying AgentsTo at , at l ast 23 t als w t pot nt al s as - o y n

a nts av b n on t o a on o n .46

T AdAgiO (Att n at on o d s as P o ss on w tAz l t g v n On -da ly) t al s t la st s st y. itwas a p osp t v , lt nt , pla bo- ont oll , o bl -bl n l n al t al w t a lay -sta t s n v lop toass ss t a y o asa l n as a s as - o y n opo n n 1176 pat nts w t a ly, non sabl n Pd. TAdAgiO t al was n t at bas on s lts o a p l -na y t al w s st t at asa l n v n a ly n t

s as t av s as - o y n b n ts.48 Pat nts n t AdAgiO t al ( an at on o s aso t t o a nos s, 4.5 ont s; bas l n an total

uPdrS s o , 20.4) w o v asa l n 1 / ay o 72w ks (t a ly-sta t o p) x b t at p ov nt( , a s all an n as ) n t uPdrS s o b tw nw ks 12 an 36 t an t pla bo o p (t s on -

n a y lat v to pla bo), an l ss wo s n n ov allb tw n bas l n an w k 72 t an t lay -sta t, a t v -t at nt o p (t s on n t at a l n t at on o

asa l n s asso at w t b tt o t o s o pa w tlat n t at on).49

Not all o t n po nts w t w t a 2- / ay oso asa l n .49 how v , a post o s b o p analys s s owt at pat nts w t t st q a t l bas l n uPdrSs o s (>25.5) w o v asa l n 2 / ay t allp a y n po nts. A on pat nts v n asa l n 1 an2 / ay, t os n t a ly-sta t (a t v t at nt) o ps

a s n antly l ss wo s n n o uPdrS s o s b tw nbas l n an w k 72 (- 3.40 po nts an - 3.63 po nts, sp -t v ly) o pa w t t lay -sta t (a t v t at nt)

o ps (P = .04 o bot ). Pat nts w t t st q a t lbas l n uPdrS s o s v n asa l n 1 / ay an 2 /

ay also onst at s n antly at p ov nt o s o s o bas l n to w k 36 (- 6.43 po nts an - 7.13po nts, sp t v ly;P

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ans to ons b nn n asa l n t at nt n n t on-ally n pa pat nts ( , not y t q n l vo opa o

opa n a on sts).T o t o s asso at w t asa l n s o l not b

ons a lass t o mAO-B n b to s. Sp ally,t s lts o AdAgiO annot n ssa ly b xt apo-lat to s l l n , anot ava labl mAO-B n b to .S l l n s tabol z to t a p ta n vat v sL- t a p ta n an L-a p ta n ,51 w a p s-

nt n s nt on nt at ons to p o s ts npat nts w t Pd. A t onally, on xpos to t s

o po n s as b n s own to n n otox ty n an -al an labo ato y st s,52,53 an st s onst at t at

L- t a p ta n n b ts t pot nt al n op ot t va t v t s o s l l n .54 rasa l n , on t ot an , s

vo o a p ta n - v o n otox tabol t s.T s, t p a a olo n s b tw n asa l n ans l l n p l any an n l o pa sons o l n al

a y o sa ty.S l l n was val at as a poss bl s as - o -

y n a nt n dATATOP (d p nyl an To op olAnt ox at v T apy o Pa k nson s ), a la t al

s n to ass ss t ab l ty o a ly nt v nt on w ts l l n o to op ol to postpon l vo opa n t at on n800 pat nts. W l to op ol s ow no b n t, pat nts

v n s l l n as onot apy w abl to s n antlylay t n o l vo opa t apy o pa w t t o p

v n pla bo an onst at a s n ant t onn s as p o ss on as as by t uPdrS (P

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r po ts


Pd, n l n o nzy Q10, at n , l vo opa, p a p x-ol , asa l n , op n ol , an s l l n . Non o t s s

av onst at lon -last n s as - o y n ts;ow v , t b st ava labl v n s sts t at asa l nol s p o s n t t at nt o a ly Pd.

Author Affiliation: d pa t nt o N olo y, Lo a L n a un v s ty,Lo a L n a, cA.

Funding Source: f nan al s ppo t o t s wo k was p ov by T va N os n s, in .

Author Disclosure: d c n po ts v n ono a a o an p o-v n l t s p o T va.

Authorship Information: con pt an s n; a q s t on o ata; a t-n o t an s pt; an t al v s on o t an s pt o po tantnt ll t al ont nt.

Address correspondence to: Ja k J. c n, P a d, Asso at P o ssoo N olo y, Lo a L n a un v s ty, 11262 ca p s St t, W st hall, r1304, Lo a L n a, cA 92350. e- a l: jj n@LLu. .

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