REVIEW ARTICLE

Parkinson's Disease: From Etiology to TreatmentYoshikuni Mizuno, Hideo Mori and Tomoyoshi Kondo

Wereview the recent progress in the research of the etiology, pathogenesis and treatment ofParkinson's disease. It has been postulated that mitochondrial respiratory failure and oxidativestress are two major contributors to nigral cell death in Parkinson's disease. Loss ofmitochondrialcomplex I and the a-ketoglutarate dehydrogenase complex in the substantia nigra has been

reported. Evidence to indicate oxidative stress includes a high dopamine content, increase insuperoxide dismutase activities, increase in iron, and decrease in glutathione in the substantianigra. The question posed is which one occurs first. We believe mitochondrial respiratory failureoccurs first, because slowing down of the electron transport induces an increase in the formationof activated oxygen species. The primary cause of Parkinson's disease is still unknown, but webelieve the interaction of environmental toxins and genetic predispositions is important. In thisrespect, molecular genetic studies on familial Parkinson's disease are very important.(Internal Medicine 34: 1045-1054, 1995)

Key words: pathogenesis, mitochondria, oxidative stress, familial parkinsonism, juvenile parkin-sonism

Introduction

Parkinson's disease was first described by James Parkinsonin 1817 (1). The disease is characterized clinically by restingtremor, cogwheel rigidity, akinesia, and loss of righting reflex,and pathologically by selective degeneration of the pigmentednucleiofthebrainstem, i.e., the substantia nigra and the locus

coeruleus; although degeneration of the dorsal motor nucleus of

the vagal nerve, the pedunculopontine nucleus (2), and thesubstantia innominata (3) has also been reported in Parkinson'sdisease, degeneration of the substantia nigra and the locuscoeruleus is the constant and the most severe finding. Anothercharacteristic is the presence of Lewy bodies in the remainingneurons; Lewy bodies are the intracytoplasmic eosinophilicinclusions with a pale halo surrounding the core in hematoxylin-eosin staining.

Within the substantia nigra, ventrolateral part is usuallymost severely affected (4), and this part mainly projects toputamen. The medial substantia nigra mainly projecting thecaudate nucleus is less involved and is believed to be related to

cognitive functions (5). Severe lesion in the rostral dorso-medial part of the substantia nigra may be the cause of cognitive

d

ysfunction and/or dementia (6).

The annual incidence rate of parkinsonism has not changedfor many years; it was estimated to be approximately 20.5 per100,000 population in Rochester, Minnesota; among them 86%had Parkinson's disease (7). The prevalence of Parkinson's

disease among white people has been variously reported from106 to 201 per 100,000 population (8). The prevalence rate inJapan is 80.6 per 100,000 population (9), and in China 57 per100,000 population (10). Usually Parkinson's disease has itsonset in the fifth decade or later; the peak age of onset is between55 and 65, but the age of onset ranges from 20 to 80 years.Patients with age of onset under 40 years have been grouped asjuvenile parkinsonism (1 1) or young onset parkinsonism (1.2).Most of the late onset patients are sporadic; concordance rateamong homozygotic twins is low (13). However, familialoccurrence is not rare among patients with the onset of ageunder40 years. Drug therapy ofParkinson' s disease has achieveda great success, and the life expectancy of patients with Parkin-son's disease has become very close to that of the generalpopulation ( 14), however, numerous problems may arise fromthe long-term drug treatment. To overcome those problems,elucidation of the etiology ofParkinson's disease and develop-ment of drugs which can protect nigral neurons from degenera-tion are mandatory. Here, we review the etiology and patho-genesis of Parkinson's disease and the recent progress in thetreatment of Parkinson's disease.

Etiology and Pathogenesis of

Parkinson's Disease

MPTP-induced parkinsonism The recent progress on the etiology and pathogenesis of

From the Department of Neurology, Juntendo University School of Medicine.Reprint requests should be addressed to Dr. Yoshikuni Mizuno, the Department of Neurology, Juntendo University School of Medicine, 2- 1 -1 Hongo, Bunkyo,

Tokyo113

InternalMedicineVol. 34, No. 1 1 (November 1995) 1 045

Mizunoet al

Parkinson's disease has been greatly dependent upon the dis-covery of MPTP-induced parkinsonism. MPTP (l-methyl-4-phenyl- l ,2,3,6-tetrahydropyridine), a meperidine analog, wasfound as a contaminant ofa home-madeillicit narcotic ( 15, 16).People who injected MPTP-contaminated narcotic drugs de-veloped severe parkinsonism with selective degeneration in thesubstantia nigra (15-17). Langston et al (16) identified MPTPas the most probable agent which induced parkinsonism int hose patients. MPTP is taken up into cerebral astrocytes where

MPTP is oxidized to MPP+ ( 1 -methyl-4-phenylpyridinium ion)b y monoamine oxidase B (18) (Fig. 1). MPTP itself is not toxic

but MPP+ is toxic. Then MPP+ is actively taken up into

dopaminergic nerve terminals (19, 20) through the dopaminet ransporter (21) leading to a marked concentration within

dopaminergic neurons (22). Such concentration of MPP+ doesnot occur in neurons which do not possess dopamine transport-ers. Dopamine transporters are expressed only in dopaminergicneurons; this is the mechanism of selective degeneration ofdopaminergic neurons in this model. Within nigral neurons,MPP+ is further concentrated in mitochondria (23, 24); asmitochondria respire, the inside ofmitochondria becomes elec-trically charged negative because of proton translocation fromthe matrix to the intermembrane space. MPP+is transported into

mitochondria according to this electric potential gradient asmany other cations are concentrated within mitochondria (25).In mitochondria, MPP+inhibits mitochondrial state 3 respira-tion by inhibiting complex I of the electron transfer chain (26-

28) and the oc-ketoglutarate dehydrogenase complex of thetricarboxylic acid cycle (29) with resultant impairment of ATPsynthesis. Thus energy crisis is induced within nigral neurons,

and this has been considered as the most important mechanismof nigral neuronal death in this model. Recently, a lowerconcentration ofMPP+ was found to induce apoptotic cell death(30, 31). This MPTP model has been considered as the best

model of Parkinson's disease available.

M

itochondria in Parkinson 's disease

Since the elucidation of the pathogenesis of MPTP-inducedparkinsonism, we and other groups have been interested inmitochondria in Parkinson's disease. Schapira et al (32, 33) firstreported a significant reduction in the biochemical activity ofcomplex I in the substantia nigra of patients who died ofParkinson's disease. Using an immunohistochemical method,

we found a decrease in the subunits of complex I in the striatalmitochondria (34) and immunoreactive complex I in the nigral

melanized neurons (35). However, these decreases were ofrather modest degree; the complex I activity in Parkinson'sdisease was only two-thirds of the control (32, 33), and in ourimmunohistochemicalmethod, nigral neurons retaining

immunostaining were also found. Thus loss of complex I alone

does not appear to sufficiently account for nigral degeneration.Recently Przedborski et al (36) postulated that loss of complexI might be a secondary phenomenon to levodopa treatment, aschronic treatment of experimental animals with levodopa re-sulted in reversible loss of complex I activity (37). However,Cooper et al (38) are opposed to this notionbecause the complexI activity of the striatum where complex I is exposed to a highconcentration of dopamine is not reduced in Parkinson's dis-

ease. Complex I activity was also measured in tissues other thanthebrain, however, a lot of controversies exist in the results

n n niir^fC0NH2y^^ MAOBs,^p . ^V^ i ^N^

^|02H20+e-V l02 H2OV i PCH3 CH3 CH3 : P

i iMPTP MPDP+ MPP+ å  Ribose

: iå  Adenine

i NAD+

Figure 1. Structure ofMPTP and its oxidation to MPP+ by monoamine oxidase B. MPP+ has a structuralsimilarity to NAD+; this may be a reason why MPP+ inhibits complex I.

1046 Internal Medicine Vol. 34, No. 1 1 (November 1995)

Etiology and Treatment of Parkinson' s Disease

(39).

As MPP+ inhibits not only complex I but also the a-ketoglutarate dehydrogenase complex (29), we studied thisenzyme complex immunohistochemically (40). As expected,

immunostaining for this enzyme complex was also reduced in

Parkinson'sdisease, and there was a rough correlation between

the severity of degeneration and the loss of immunostainingintensity. Therefore, complex I and the oc-ketoglutarate dehy-

drogenase complex appear to be particularly vulnerable inParkinson's disease. The effect of dual loss of complex I and the

a-ketoglutarate dehydrogenase complex on the electron trans-

fer and ATP synthesis would be enormous, because the a-ketoglutarate dehydrogenase complex provides succinate as asubstrate for complex II. Unless succinate is sufficiently pro-vided, alternate electron transfer via complex II cannot com-

pensate for the reduced electron transfer via complex I of

Parkinson's disease.M

itochondrial DNA

Each mitochondrion has 2 to 10 copies of double-strandedcircular DNA consisting of 16,569 base-pairs (41). Mitochon-drial DNA encodes 13 subunits of the electron transfer com-plexes, 22 transfer RNAs, and 2 ribosomal RNAs. Complex Iconsists of41 subunits (42) and seven out of the 41 subunits areencoded by mitochondrial DNA (43 , 44). Therefore, we consid-ered that mutations in mitochondrial DNA might cause thedecrease in the complex I activity. Thus we studied mitochon-drial DNA for large deletions and point mutations (45, 46). Firstofall, by the PCR method, Ikebe et al (45) found mitochondriawith a 5-kb deletion using striatal DNA preparation. Thisdeletion was located between the 13 base-pair direct repeatsequences encompassing the ND 5 (NADH dehydrogenasesubunit 5) gene and the ATPase 6/8 gene; between these twogenes, genes for ND 2, ND 3, ND 4, ND4L, and CCO (cyto-chrome c oxidase) 3 are located. But subsequent studies re-

vealed that those 5-kb deletions are frequently found in agedand aging tissues including the brain (47^-9), the cardiac

muscle (50, 51), the skeletal muscle (52, 53), and the liver (53,

54). This 5-kb deletion appears to represent the aging processrather than the disease-specific change, however, as aging isone of the most important risk factors of Parkinson's disease,this deletion may contribute to the progression of the degenera-

t

ion in Parkinson's disease.

Regarding point mutations of mitochondrial DNA, Ikebe etal (46) sequenced total mitochondrial DNA offive patients withParkinson's disease and compared those sequences with those

of more than 30 control subjects. Each of the five patients hadat least one point mutation which would cause amino acid

substitution in at least one of the subunits of complex I;however, the locations of the mutations were different from onepatient to another. Shoffner et al (55) reported a higher inci-dence ofA to G mutation at nucleotide 4336 oftRNAgln gene inParkinson's disease, however, we could not reproduce their

results. Thus although the possibility that accumulation ofmitochondria DNA mutations may constitute a risk factor forParkinson's disease, mitochondrial DNA does not appear to

play a primary role in the neurodegeneration in Parkinson'sdisease.

C

onsequence of mitochondria! respiratory failureIn acute mitochondrial respiratory failure, an energy crisis is

induced due to the lack of ATP synthesis, and neurons mayundergo necrotic death. But when mitochondrial respiratory

failure progresses more slowly, numerous protean adverseeffectsare induced in neurons. One such effect is the disruption

o

fcalcium homeostasis.

When the cellular level of ATP goes down, the activity ofNa-K ATPase decreases and Na+ transport from the inside tooutside diminishes; then Na+ must be expelled by exchangewith Ca2+ in the extracellular space (56). Thus the intracellularCa2+increases. An increase in intracellular Ca2+ induces activa-

tion of degradation enzymes such as neutral proteases (calpines) ,phospholipasps, and endonucleases; the latter mediate cleavage

of nuclear DNA in oligonucleosome-length fragments; activa-tion of an endogenous endonuclease is involved in programmedcell death and apoptosis in many systems (57). Thus, theincrease in the cellular Ca2+ level may induce apoptosis (58).

Interestingly, mitochondrial respiratory inhibitors can induceapoptotic cell death (59, 60). Calcium homeostasis is alsoimportant for normal mitochondrial function. Another adverseeffect of mitochondrial respiratory failure is the increase in theformation of cytotoxic activated oxygen species within mito-

chondria.

O

xidative stress in Parkinson 's diseaseOxidative stress denotes the condition in which the forma-

tion of oxygen free radicals is increased. Oxygen free radicalsinclude superoxide anions, hydrogen peroxide, hydroxyl radi-cals, and singlet oxygen. These species are produced in a smallamount in every respiring cell; they are highly reactive andcytotoxic. In particular hydroxyl radicals are believed to medi-ate many cytotoxic reactions (61). Oxidative stress has beenconsidered to be one of the most important contributors to nigralcell death in Parkinson's disease in addition to mitochondrial

respiratory failure. The oxidative stress hypothesis has beenproposed based on four observations. First of all, a high content

of dopamine in the nigral neurons predisposes those neurons tooxidativestress, as hydrogen peroxide is formed when dopamine

is oxidized by monoamine oxidase. Secondly, superoxidedismutase (SOD) activities appear to be increased in the sub-stantia nigra. In 1988, Marttila et al (62) reported a significantincrease in Cu-Zn SOD but not in Mn SOD in the substantianigra ofParkinson's disease, while Saggu et al (63) reported anincreasein MnSOD but not Cu-Zn SOD. Although the resultsof these two studies did not agree, the increase in SOD activitywas interpreted as a reaction to the increased formation of

superoxide anions. Probably an increase in Mn SOD activity ismore meaningful in Parkinson's disease, because mitochon-

drial respiratory failure increases the formation of activatedoxygen species (64). Hydroxyl radicals enhance lipid

peroxidation, and as expected lipid peroxidation is reported tobe increased in the substantia nigra of patients with Parkinson's

InternalMedicineVol. 34, No. 1 1 (November 1995) 1 047

Mizuno et al

disease (65). Thirdly, iron is increased in the substantia nigra of

Parkinson's disease (66-7 1 ). Most tissue iron exists in the ferricform (Fe3+), however, Fe3+ may be reduced to the ferrous form(Fe2+) in the presence of neuromelanin (67). Fe2+ is highlyreactive and it may induce free radical reactions. Fe2+ catalyzesthe Fenton reaction and Fe3+ mediates the iron-catalyzed Haber-

Weiss reaction (Fig. 2) (72); both reactions produce hydroxylradicals from hydrogen peroxide. Finally, glutathione is re-duced in Parkinson's disease (73-75). Glutathione is a natural

a

ntioxidant and it is a substrate for glutathione peroxidase.

The current question is which occurs earlier, mitochondrialrespiratory failure or oxidative stress. Jenner et al (76) and

Dexter et al (77) have attempted to answer this question bycomparing the glutathione content and complex I activity in thesubstantia nigra of incidental Lewy body disease; the incidentalLewy body disease has been considered as a preclinical state ofParkinson's disease (78). Jenner et al (76) found a significant

loss of glutathione in the substantia nigra, however, complex Iactivity, although it was reduced, did not reach statistical

significance, and the loss of complex I activity was slightly lessthan that of glutathione (75). Based on these findings, they

concluded that oxidative stress occurs first in Parkinson'sdisease, and that respiratory failure is secondary to oxidative

stress.Wefeel the reverse is true because not only complex I but

also the a-ketoglutarate dehydrogenase complex is reduced inParkinson's disease (40). The reduction in state 3 respiration

from the dual loss of complex I and a-ketoglutarate dehydroge-nase complex is far greater than that from loss of complex Ialone, and it may exceed the loss of glutathione. Furthermore,it has been shown that mitochondria produce free radicals suchas superoxide anions (79), hydrogen peroxide (80), hydroxylradicals, and semiubiquinone (81), and when mitochondrial

electron transport slows down, a significant increase in theformation of oxygen free radicals occurs (64). Thus oxidativestress is induced as a result ofmitochondrial respiratory failure.

P

rimary cause of Parkinson 's diseaseThis question has not been answered yet. It has been postu-

lated that Parkinson's disease may be caused by the chronicaccumulation of substances toxic to mitochondria in the sub-stantia nigra. Based on this assumption, many substances which

Fenton reaction

H2O2+Fe2+ > -OH + Fe3++ OH-

Iron catalyzed Haber-Weiss reaction

02-+H2O2 > OH + OH-+O2Fe3+

Figure 2. Fenton reaction and iron catalyzed Haber-Weiss

r

eaction. Both reactions produce hydroxyl radicals in the presenceof iron.

have a structural similarity to MPTP and MPP+have been testedfor nigral as well as mitochondrial toxicity. Among thesesubstances, tetrahydroisoquinolines and (3-carbolines have

most extensively been studied. Tetrahydroisoquinolines are agroup of compounds that are formed by condensation of aphenylethylamine and an aldehyde (Fig. 3), and (3-carbolines

represent substances derived by condensation of tryptamineand an aldehyde. These compounds may be metabolized to theN-methylated form by an N-methyltransferase, and may befurther oxidized by monoamine oxidase or by autoxidation (82,83). Some of these substances are toxic to mitochondria respi-ration (84) and to the cultured nigral neurons (85, 86). However,compared to MPTP or MPP+, they are much weaker mitochon-drial toxins. Typical parkinsonism has not yet been produced bythese compounds, although striatal loss of dopamine was pro-duced (87). P-carbolines are also toxic to mitochondria (88). Itis interesting to note that some tetrahydroisoquinoline com-pounds are contained in foods (89), and they are easily trans-ported into the brain (90).

Epidemiological studies offer another approach to deter-mine environmental risk factors; subsequently rural living andwell water use (91-93), and exposure to pesticides and herbi-cides (93, 94) and industrial chemicals (95) have been reportedasrisk factors for Parkinson's disease, however, some contro-versies exist (92, 96). When those environmental neurotoxinsare combined with poor metabolizing systems for those sub-stances, such neurotoxins may become more toxic. Based onthis concept, studies on genetic background are becoming moreand more important. Genetic predisposition may be encoded insubtle difference in the base sequences of genes for proteins andenzymes as DNA polymorphisms. The first gene studied in thisrespect was CYP2D6 gene; its mutations which result in poormetabolizers of debrisoquine are associated with a higher riskforParkinson's disease (97, 98), which was estimated to be two-fold higher compared to those without mutations. The mutategene frequency among Japanese patients with Parkinson dis-ease, however, was not significantly different from the controlpopulation (99). Recently, Tsuneoka et al (100) found a newmutation in the CYP2D6 gene which results in poor metabolismof debrisoquine; 1 1.1% of Parkinson's disease patients and2.2% of control subjects had this mutation, and the risk factor

f

or the mutant homozygote was estimated to be 5.56.S-methylation is another detoxifying system for exogenous

substances. Waring et al (101) reported reduced activity of

erythrocyte S-methyltransferase in Parkinson disease, how-ever, wecould not reproduce their result in Japanese patients

(102).

Kurth et al (103) reported the association of a monoamineoxidase B allele with Parkinson' s disease, however, this findingwas not confirmed by a subsequent study (104). Hotamisligil etal (105) reported association of Parkinson's disease with aMAO A allele. Association between Parkinson's disease andgenes for glutathione peroxidase, tyrosine hydroxylase, brainderived neurotrophic factor, catalase, amyloid precursor pro-tein, Cu-Zn superoxide dismutase have been ruled out inautosomal dominant familial Parkinson's disease (106).

1048 Internal Medicine Vol. 34, No. 1 1 (November 1995)

Etiology and Treatment of Parkinson' s Disease

HCHO

NH2 NH2 "å 

Phenylalanine Phenylethyla mine TIQ

^PH ^NMT

HO^" NH, U^C" >U^NXH3Tyrosine N-Me-TIQ N-Me-Isoquinolinium ion

1 TH HCHO

H°TY^rC00H aad>°t^iPi>HQ^1OHO^^ NH2 HO^^ NH2 HO^^^NH

DOPA Dopamine Norsalsolinol

>Lnmtr_j f\ 1-T O

HO ^^^ CHs HO ^^^ CHs

N-Me-Norsalsolinol N-Me-Norsalsolinium ion

Figure 3. Some of the representative tetrahydroisoquinoline compounds and N-methylation and oxidation process.

Familial and Juvenile Parkinsonism

As the primary cause of Parkinson's disease is still un-known, molecular genetic studies on familial patients withParkinson's disease are very important. Patients with parkin-sonism with the age of onset before the age of 40 are usuallygrouped as juvenile parkinsonism (ll, 107) or early onsetparkinsonism ( 1 2); Quinn et al ( 1 2) proposed to reserve the term"juvenile" to those patients with the age of onset before 20years. Familial incidence among early onset parkinsonism ismuch higher than that among late onset patients; the familialincidence may be as high as 40% (107). Early onset parkinson-ism is not a single disease entity, but a group of disorders withdifferent modes of inheritance; the following familial typeshave

been reported.Lewy body-positive familial Parkinson 's disease

This is the most common form offamilial parkinsonism. Theage of onset is usually between 30 and 40 years of age, however,onset before 30 years and after 40 years is also known. Auto-somal dominant inheritance appears to be more common ( 1 08-1 10), but autosomal recessive forms also exist (1 1 1). Clinicalmanifestations do not differ much from those of sporadic lateonset Parkinson's disease: these patients tend to show a goodresponse to a relatively small amount of levodopa with a

tendency to develop severe motor fluctuations and dyskinesias.

L

ewy body-negative autosomal recessive typeThe age of onset tends to be younger (15 to 30 years of age)

than Lewy body-positive autosomal recessive Parkinson's dis-ease (1 12). These patients respond quite well to a small amountof levodopa, better than the Lewy body-positive patients; theydevelop dyskinesia and motor fluctuations more easily. Inaddition, they may show spontaneous fluctuations in parkinso-nian symptoms with improvement after sleep. Dystonic posturein feet are not uncommon.Postmortem examination showssimple atrophy of the substantia nigra without Lewy bodies

(113).

This hereditary Lewy body-negative autosomal recessiveparkinsonism has some similarity to Segawa's disease (1 14)

and dopa-responsive dystonia (1 15), in that both respond tolevodopa very well; both have spontaneous motor fluctuationswith improvement after sleep. But the differences are absenceof rigidity and tremor in Segawa's disease; the cardinal symp-tom of Segawa's disease is dystonic posture induced in theupper and lower extremities. Furthermore, Segawa's disease isinherited as an autosomal dominant trait with linkage to chro-mosome 14 (116); recently point mutations in the GTP

cyclohydrolase gene have been reported (1 17).

Internal Medicine Vol. 34, No. 1 1 (November 1995) 1 049

Mizuno et al

Autosomal dominant Lewy body-negative type

Nukada et al (1 18) reported a large Japanese family withautosomal dominant parkinsonism; the age of onset was be-tween 38 and 78; the clinical characteristics were essentially thesame as those of adult onset sporadic parkinsonism. Recentlythe autopsy findings in one of the family members revealedextensive nigral degeneration without Lewy bodies (personalcommunication with Dr. Kowa). Recently Dwork et al (1 19)reported a large family with autosomal dominant form ofparkinsonism; the age of onset of the propositus was 28 years;he responded to levodopa well, however, severe motor fluctua-tion developed. The question of whether or not Lewy body-negative patientsshould be termed as Parkinson's disease requires further re-search. Linkage studies on these families are very important inthat the information obtained from familial patients wouldprovide clues to the investigation of the pathogenesis of spo-radic Parkinson's disease.

Treatment of Parkinson's Disease

Treatment of motor fluctuations Levodopa is still the standard treatment for Parkinson'sdisease. Recently, an algorithm for drug treatment of Parkin-son's disease was proposed by Koller et al (120). The questionof whether or not the use oflevodopa should be delayed until theadvanced stage of Parkinson's disease has long been debated,however, the current trend appears to be starting levodopatreatment whenever the patient starts to show difficulty inmoving in ordinary daily living or there is threat of losing hisjobs. In our opinion, the use oflevodopa should not be delayedintentionally.

Motor fluctuations from long-term levodopa treatment is abig problem. Newer drugs have been developed to decrease theseverity and the incidence of motor fluctuations. Among thenewly developed dopamine agonists, cabergoline is a new D2receptor agonist of an ergot compound with an extremely longhalf-life of about 65 hours (121), and it was reported to havereduced the mean percentage "off" time by 31% in one report(122). Talipexol is a presynaptic dopamine agonist as well as apotent post-synaptic D2 receptor agonist when the dopaminergicterminals are degenerated ( 1 23) ; the incidence ofgastrointestinalside effects tends to be lower with this than with the conven-tional dopamine agonists ( 1 24). Deprenyl, a selective monoam-ine oxidase B inhibitor, is also effective in reducing the "off"time of motor fluctuations; Golbe et al (125) reported 56%increase d hourly self-assessed gait disturbance of fluctuatingParkinson's disease patients; levodopa dose was also reducedby 17% in their study.

Catechol-O-methyltransferase (COMT) inhibitors appear tobe promising adjunctive treatment for symptom fluctuations ofadvanced Parkinson's disease. A fair amount of levodopa ismetabolized to 3-O-methyldopa by COMT in systemic organs,and 3-<9-methyldopa may interfere with the transport of levo-dopa to brain. Concomitant use of a COMT inhibitor withlevodopa increases the bioavailability of levodopa to the brain

without increasing the peak height of the plasma levodopa level(126). The combined use oflevodopa and tolcapone is reportedto prolong the anti-parkinsonian response by 67% (127). OtherCOMT inhibitors such as nitecapone (128), entacapone (126),and CGP 28014 (129) are also effective in reducing the plasma

3

-(9-methyldopa level.

Levodopa is absorbed from the duodenum and the upperjejunum (1 30), and gastric acidity influences the absorption oflevodopa; as the gastric pH goes up, absorption of levodopa isimpaired. Therefore, concomitant use of an anti-acid or intakeof a large volume of food may interfere with the absorption oflevodopa with resultant poor improvement in motor symptoms.Avoidance of large meals and antacids is a simple way to

i

mprove the response to levodopa.Peripheral dopamine receptor blockers may increase levo-

dopa absorption by enhancing gastric mortility ( 13 1); recentlycisapride, a prodrug of a metoclopramide-like peripheraldopamine receptor blocker, is reported to enhance levodopa

absorption.

F

uture neuroprotective therapyAs the mechanism of nigral cell death has in part been

elucidated, research on nigral neuroprotective therapy is arapidly growing field. Deprenyl, a monoamine oxidase B in-hibitor, is reported to slow the progression of disabilities ofParkinson's disease by the DATATOP study (132, 133). The

question of whether or not deprenyl has a truly neuroprotectiveeffect on nigral cells has been debated. IfMPTP-type bioactivatedneurotoxinsare involved in Parkinson's disease, monoamine

oxidase inhibitors may well be neuroprotective at least in part.Other potentially neuroprotective drugs include dopamine trans-porter blockers, anti-oxidants, iron-chelators, calcium antago-nists, glutamate receptor blockers , and dopamino-neurotrophins.

S

tereotaxic surgery and thalamic stimulationThe effect of stereotaxic thalamotomy has been well estab-

lished for tremor and rigidity. Drug-resistant tremor patients aregood candidate for stereotaxic thalamotomy. The nucleus inter-medius is the target for tremor and the nucleus ventrolateralisthe target for rigidity (134). Thalamic stimulation is also effec-

tive in alleviating tremor (135). Recently, posterolateralpallidotomy has been found to be effective for drug-resistantgait disturbance, akinesia, and motor fluctuations (136). Thisnew finding is based on the recent progress in neurophysiologyof the basal ganglia. Two pathways, the indirect and the direct,have been shown to exist between the striatum and the internalsegment of the globus pallidus (137); the indirect pathwayoriginates mainly in the GABA-enkephalin neurons in the

striatum and they change neurons in the external segment of theglobus pallidus and in the subthalamic nucleus ending in the

internal segment of the globus pallidus. The loss of striataldopamine ends up with a marked increase in the activity of

glutamatergic neurons in the subthalamic nucleus, and thisincreased excitatory input to GABAergic neurons in the inter-nal segment of the globus pallidus strongly inhibits thalamicneurons causing severe akinesia (136). The principle of the

1050 InternalMedicineVol. 34, No. 1 1 (November 1995)

Etiology and Treatment of Parkinson' s Disease

posterolateral pallidotomy is to remove this inhibitory input tothe thalamus from the internal segment of the globus pallidus.

T

ranspla n ta tion

Transplantation procedures using the adrenal medulla, supe-rior cervical ganglion, or fetal mesencephalons have beenperformed only on a research basis. Transplantation of theadrenal tissue has rather limited effects and the operative

morbidity is substantial (138), and, in our opinion, it should notbe attempted any further. Transplantation offetal mesencephalonappears to give better results (139) compared to adrenal trans-plantation, however, it may provoke ethical problems. Trans-plantation should be carried out only in centers specialized inthebasic, clinical as well as technical aspects of transplantation.

Acknowledgements: This study was in part supported by Grant-in-Aidfor Priority Areas and Grant-in-Aid for Neuroscience Research fromMinistryofEducation,Science, and Culture, Japan, Grant-in-Aid for Intractable Dis-orders from Ministry of Health and Welfare, Japan, and Center of Excellence-GrantfromNationalParkinsonFoundation,Miami, Florida, U.S.A.

References1) ParkinsonJ. AnEssay on the ShakingPalsy. Sherwood, Neely, andJones,

London, 1817.2) Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in

the pedunculopontine tegmental nucleus in Parkinson disease and inprogressive supranuclear palsy. Proc Natl Acad Sci 84: 5976, 1987.

3) Whitehouse PJ, Hedreen JC, White CL III, Price DL. Basal forebrainneurons in the dementia ofParkinson disease. Ann Neurol 13: 243, 1983.

4) Gibb WRG, Lees AJ. Anatomy, pigmentation, ventral and dorsalsubpopulations of the substantia nigra, and differential cell death inParkinson's disease. J Neurol Neurosurg Psychiatry 54: 388, 1991.

5) DeLong MR, Georgopoulos AP, Crutcher MD. Cortico-basal gangliarelations and coding of motor performance. Exp Brain Res Suppl 7: 30,1983.

6) Rinne JO, Rummukainen J, Palijarv L, Rinne UK. Dementia in Parkin-son's disease is related to neuronal loss in the medial substantianigra. AnnNeurol 26: 47, 1989.

7) Rajput AH, Offord KP, Beard CM, KurlandLT. Epidemiology ofparkin-sonism: incidence, classification, and mortality. Ann Neurol 16: 278,

1984.

8) Marttila RJ, Rinne UK. Epidemiology ofParkinson's disease in Finland.Acta Neurol Scand 53: 81, 1976.

9) Harada H, Nishikawa S, Takahashi K. Epidemiology of Parkinson'sdisease in a Japanese city. Arch Neurol 40: 151, 1983.

10) Li SC, Schoenberg BS, Wang CC, Chen XM, Rui DY, Bolis CL,Schoenberg MS. A prevalence survey of Parkinson's disease and othermovement disorders in the People's Republic of China. Arch Neurol 42:655, 1985.

1

1 ) Yokochi M. Nosological concept ofjuvenile parkinsonism with referenceto the dopa-responsive syndrome, in: Advances in Neurology, Vol. 60,Narabayashi H, Nagatsu T, Yanagisawa N, Mizuno Y, Eds. Raven Press,New York, 1993, p. 548.

1

2) Quinn N, Critchley P, Marsden CD. Young onset Parkinson's disease.Mov Disord 2: 73, 1987.

13) Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldrige R, Calne DB.Parkinson's disease in 65 pairs of twins and in a set of quadruplets.Neurology 33: 815, 1983.

1

4) Diamond SG, Markham CH, Hoehn MM,McDowell FH. Multi-centerstudy of Parkinson mortality with early versus later dopa treatment. AnnNeurol 22: 8, 1987.

1

5) Davis GC, Williams AC, Markey SP, EbertMH, Caine ED, ReichertCM,Kopin IJ. Chronic parkinsonism secondary to intravenous injection of

meperidine analogues. Psychiatry Res 1: 249, 1979.Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism inhumans due to a product of meperidine-analog synthesis. Science 219:979, 1983.

B

allard PA, Tetrud JW, Langston JW. Permanent human parkinsonismdue to l -methyl-4-phenyl-l ,2,3,6-tetrahydropyridine (MPTP): Sevencases. Neurology 35: 949, 1985.Chiba K, Trevor AJ, Castagnoli N Jr. Metabolism of the neurotoxictertiary amine, MPTP, by brain monoamine oxidase. Biochem BiophysRes Commun120: 574, 1984.

C

hiba K, Trevor A, Castagnoli N Jr. Active uptake of MPP+, metabolite

ofMPTP, by brain synaptosomes. Biochem Biophys Res Commun128:

1228, 1985.

J

avitchJA, D'Amato RJ, Strittmatter SM, Snyder SH. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl- l ,2,3 ,6-tetrahydropyridine:uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neu-rons explains selective toxicity. Proc Natl Acad Sci USA 82: 2173, 1985.Ricaurte GA, Langston JW, Delanney LE, Irwin I, Brook JD. Dopamineuptake blockers protect against the dopamine depleting effect of 1-methyl-4-phenyl- l ,2,3 ,6-tetrahydropyridine (MPTP) in the mouse stria-turn.Neurosci Lett 59: 259, 1985.Irwin I, Langston JW. Selective accumulation of MPP+ in the substantianigra: a key to neurotoxicity? Life Sci 36: 207, 1985.Frei B, Richter C. N-Methyl-4-phenylpyridine (MMP+) together with 6-hydroxydopamine or dopamine stimulates Ca2+ release from mitochon-dria. FEBS Lett 198: 99, 1986.Ramsay RR, Singer TP. Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-

1,2,3,6-tetrahydropyridine, by mitochondria. J Biol Chem 261: 7585,1986.

Hoppel CL, Greenblatt D, Kwok HC, Arora PK, Singh MP, Sayre LM.Inhibition of mitochondrial respiration by analogs of 4-phenylpyridineand l-metnyl-4-phenylpyridinium cation (MPP+), the neurotoxicmetabolite of MPTP. Biochem Biophys Res Commun148: 684, 1987.Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidationin brain mitochondria by 1 -methyl-4-phenyl-pyridine, a metabolite of theneurotoxin, l -methyl-4-phenyl- l ,2,5,6-tetrahydropyridine. Life Sci 36:2503, 1985.Ramsay RR, Salach JI, Dadgar J, Singer TP. Inhibition of mitochondrialNADHdehydrogenase by pyridine derivatives and its possible relation toexperimental and idiopathic parkinsonism. Biochem B iophys Res Commun135: 269, 1986.

M

izuno Y, Sone N, Saitoh T. Effects of l-methyl-4-phenyl-l,2,3,6-

tetrahydropyridine and l -methyl-4-phenylpyridinium ion on activities ofthe enzymes in the electron transport system in mouse brain. J Neurochem48: 1787, 1987.

Mizuno Y, Saitoh T, Sone N. Inhibition of mitochondrial alpha-ketoglu-tarate dehydrogenase by l-methyl-4-phenylpyridinium ion. BiochemBiophys Res Commun143: 971, 1987.Dipasquale B, Marini M, Youl RJ. Apoptosis and DNA degradation by 1 -methyl-4-phenylpyridinium in neurons. Biochem Biophys Res Commun181: 1442, 1991.

M

ochizukiH, Nakamura N, Nishi K, Mizuno Y. Apoptosis is induced byl -methyl-4-phenylpyridinium ion (MPP+) in a ventral mesencephalic-

striatal co-culture. Neurosci Lett 170: 191, 1994.Schapira AHV, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD.Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1:1269, 1989.

Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD.Mitochondrial Complex I deficiency in Parkinson's disease. J Neurochem54: 823, 1990.

M

izuno Y, Ohta S, Tanaka M, et al. Deficiencies in Complex I subunits

of the respiratory chain in Parkinson's disease. Biochem Biophys ResCommun163: 1450, 1989.

H

attori N, Tanaka M, Ozawa T, Mizuno Y. Immunohistochemical studieson Complex I, II, III, and IV ofmitochondria in Parkinson's disease. AnnNeurol 30: 563, 1991.

Internal Medicine Vol. 34, No. 1 1 (November 1995) 1051

Mizuno et al

Przedborski S, Jackson-Lewis V, Fahn S. Antiparkinsonian therapies andbrain mitochondrial complex I activity. Mov Disord 10: 312, 1995.Przedborski S, Jackson-Lewis V, Muthane U, et al. Chronic levodopaadministration alters cerebral mitochondrial respiratory chain activity.Ann Neurol 34: 715, 1993.Cooper JM, Daniel SE, Marsden CD, Schapira AHV. L-Dihydroxyphe-nylalanine and complex I deficiency in Parkinson's disease brain. MovDisord 10: 295, 1995.DiMauro S. Mitochondrial involvement in Parkinson's disease: the

controversy continues. Neurology 43: 2170, 1993.Mizuno Y, Matuda S, Yoshino H, Mori H, Hattori N, Ikebe S. Animmunohistochemical study on oc-ketoglutarate dehydrogenase complexin Parkinson's disease. Ann Neurol 35: 204, 1994.Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization ofthe human mitochondrial genome. Nature 90: 457, 1981.Walker JE. The NADH: ubiquinone oxidoreductase of respiratory chains.Q Rev Biophys 25: 253, 1992.Chomyn A, Mariottini P, Cleeter MWJ, et al. Six unidentified readingframes of human mitochondrial DNA encode components of the respira-tory-chain NADH dehydrogenase. Nature 314: 592, 1985.Chomyn A, Cleeter MWJ, Ragan CI, Riley M, Dolittle RF, Attardi G.URF6, last unidentified reading frame of human mtDNA codes for anNADH dehydrogenase subunit. Science 234: 614, 1986.

Ikebe S, Tanaka M,Ohno K, et al. Increase of deleted mitochondrial DNA

in the striatum in Parkinson's disease and senescence. Biochem BiophysRes Commun170: 1044, 1990.

Ikebe S, Tanaka M, Ozawa T. Point mutations ofmitochondrial genome

in Parkinson's disease. Mol Brain Res 28: 281, 1995.Simonetti S, Chen X, DiMauro S, Schon EA. Accumulation of deletions

in human mitochondrial DNA during normal aging: analysis ofquantita-tive PCR. Biochim Biophys Acta 1180: 1 13, 1992.

Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace

D. Mitochondrial DNA deletions in human brain: regional variability andincrease with advanced age. Nature Genetics 2: 324, 1992.Soong K, Hinton DR, Cortopassi G, Arnheim N. Mosaicism for a specificsomatic mitochondrial DNA mutation in adult human brain. NatureGenetics 2: 318, 1992.Cortopassi GA, Arnheim N. Detection of a specific mitochondrial DNAdeletion in tissues of older humans. Nucleic Acids Res 18: 6927, 1990.Hattori K, Tanaka M, Sugiyama S, et al. Age-dependent increase indeleted mitochondrial DNA in the human heart: possible contributoryfactor to presbycardia. Am Heart J 121: 1735, 1991.Cooper JM, Mann VM, Schapira AHV. Analyses of mitochondrialrespiratory chain function and mitochondrial DNA.deletion in humanskeletal muscle: effect of ageing. J Neurol Sci 113: 91, 1992.Zhang C, Baumer A, Maxwell R, Linnane AW, Nagley P. Multiplemitochondrial DNA deletions in an elderly human individual. FEBS Lett297: 34, 1992.

Yen T-C, Su J-H, King K-L, Wei Y-H. Ageing-associated 5 kb deletionin human livermitochondrial DNA. Biochem Biophys Res Commun 178:124, 1991.

Shoffner JM, Brown MD,Torroni A, et al. Mitochondrial DNA variants

observed in Alzheimer disease and Parkinson disease patients. Genomics17: 171, 1993.

Reeves JP. Molecular aspects of sodium-calcium exchange. Arch BiochemBiophys 292: 329, 1992.Arends MJ, Morris RG, Wyllie AH. Apoptosis: the role of the endonucle-ase. AmJ Pathol 136: 593, 1990.Orrenius S, McConkey DJ, Nicotera F. Role of calcium in toxic andprogrammed cell death. Adv Exp Med Biol 283: 419, 1991.Wolvetang EJ, Johnson KL, Krauer K, Ralph SJ, Linnaine W.Mitochon-drial respiratory chain inhibitors induce apoptosis. FEBS Lett 339: 40,1994.

Hartley A, Stone JM, Heron C, Cooper JM, Schapira AHV. Complex Iinhibitors induce dose-dependent apoptosis in PC12 cells: relevance toParkinson's disease. J Neurochem 63: 1987, 1994.Halliwell B. Oxidants and the central nervous system: some fundamental

questions. Acta Neurol Scand 126: 23, 1989.Marttila RJ, Lorentz H, Rinne UK. Oxygen toxicity protecting enzymesin Parkinson's disease: increase of superoxide dismutase-like activity inthe substantia nigra and basal nucleus. J Neurol Sci 86: 321, 1988.Saggu H, Cooksey J, DexterD, Wells FR, Lees A, JennerP, Marsden CD.A selective increase in particulate superoxide dismutase activity inparkinsonian substantia nigra. J Neurochem 53: 69, 1989.Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalianorgans. Physiol Rev 59: 527, 1979.

D

exter DT, Carter CJ, Wells FR, et al. Basal lipid peroxidation insubstantia nigra is increased in Parkinson's disease. J Neurochem 52:381, 1989.

R

iedererP, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K,

Youdim MBH. Transition metals, ferritin, glutathione, and ascorbic acidin parkinsonian brains. J Neurochem 52: 515, 1989.

Y

oudim MBH, Ben-Shachar D, Riederer P. Is Parkinson's disease aprogressive siderosis of substantia nigra resulting in ion and melanininduced neurodegeneration? Acta Neurol Scand 126: 47, 1989.

D

exter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD.Increased nigral iron content and alterations in other metal ions occurringin brain in Parkinson's disease. J Neurochem 52: 1830, 1989.

H

irsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y. Iron and

aluminum increase in the substantia nigra of patients with Parkinson'sdisease: an X-ray microanalysis. J Neurochem 56: 446, 1991.Jellinger K, Kienzl E, Rumpelmair G, et al. Iron-melanin complex insubstantia nigra parkinsonian brains : an X-ray microanalysis. J Neurochem59: 1168, 1992.

G

ood PF, Olanow CW,Perl DP. Neuromelanin-containing neurons of thesubstantia nigra accumulate iron and aluminum in Parkinson's disease: aLAMMAstudy. Brain Res 593: 343, 1992.Burkitt ML, Bilbert BC. Model studies of the iron-catalyzed Haber-Weisscycle and the ascorbate-driven Fenton reaction. Free Rad Res Commun10: 265, 1990.

Perry TL, Yong VW.Idiopathic Parkinson's disease, progressive supra-nuclear palsy and glutathione metabolism in the substantia nigra ofpatients. Neurosci Lett 67: 269, 1986.Sofic E, Lange KW, Jellinger K, Riederer P. Reduced and oxidizedglutathione in the substantia nigra of patients with Parkinson's disease.Neurosci Lett 142: 128, 1992.

SianJ, Dexter DT, Lees AJ, et al. Alterations in glutathione levels inParkinson's disease and other neurodegenerative disorders affectingbasal ganglia. Ann Neurol 36: 348, 1994.

J

enner P, Dexter DT, Sian J, Schapira AHV, Marsden CD. Oxidativestress as a cause ofnigral cell death in Parkinson's disease and incidentalLewy body disease. Ann Neurol 32: S82, 1992.

D

exterDT, Sian J, Rose S, et al. Indices ofoxidative stress and mitochon-drial function in individuals with incidental Lewy body disease. AnnNeurol 35: 38, 1994.

G

ibb WRG,Lees AJ. The relevance of the Lewy body to the pathogenesisof idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51:745, 1988.

L

oschenG, Azzi A, Richter C, Flohe L. Superoxide radicals as precursorsof mitochondrial hydrogen peroxide. FEBS Lett 42: 68, 1974.

B

overis A, Chance B. The mitochondrial generation of hydrogen perox-ide. Biochem J 134: 707, 1973.

W

ei YH, Scholes CP, King TW. Ubisemiquinone radicals from thecytochrome b-cl complex of mitochondrial electron transport chaindemonstration ofQP-S radical formation. Biochem Biophys Res Commun99: 1411, 1981.

N

aoiM, Matuura S, Takahashi T, Nagatsu T. A N-methyltransferase inhuman brain catalyzes N-methylation of 1 ,2,3,4-tetrahydroisoquinolineinto N-methyl-1,2,3,4-tetrahydroisoquinoline, a precursor of adopaminergic neurotoxin N-methyl-isoquinolinium ion. Biochem BiophysRes Commun161: 1213, 1989.

N

aoiM, Matsuura S, Parvez H, et al. Oxidation of N-methyl-1,2,3,4-tetrahydroisoquinoline into the N-methyl-isoquinolinium ion by monoam-ine oxidase. J Neurochem 52: 653, 1989.

1052 InternalMedicineVol. 34, No. 1 1 (November 1995)

Etiology and Treatment of Parkinson' s Disease

8

4) Suzuki K, Mizuno Y, Yamauchi Y, Nagatsu T, Yoshida M. Selectiveinhibition of complex I by N-methylisoquinolinium ion and N-methyl-

1

,2,3,4-tetrahydroisoquinoline in isolated mitochondria prepared frommouse brain. J Neurol Sci 109: 219, 1992.

8

5) Niijima K, Araki M, Ogawa M, et al. N-methylisoquinolinium ion(NMIQ+) destroys cultured mesencephalic dopamine neurons. BiogAmines 8: 61, 1991.

86) Nishi K, Mochizuki H, Furukawa Y, Mizuno Y, Yoshida M.Neurotoxiceffects of l-methyl-4-phenylpyridinium (MPP+) and tetrahydro-isoquinoline derivatives on dopaminergic neurons in ventral mesen-cephalic-striatal co-culture. Neurodegeneration 3: 33, 1994.

87) Yoshida M, Niwa T, nagatsu T. Parkinsonism in monkeys produced bychronic administration of an endogenous substance of the brain,tetrahydroisoquinoline : the behavioral and biochemical changes. NeurosciLett 119: 109, 1990.

8

8) Albores R, HeafseyEJ, DruckerG, Fields JZ, Collins MA. Mitochondrialrespiratory inhibition by N-methylated beta-carboline derivatives struc-turally resembling N-methyl-4-phenylpyridine. Proc Natl Acad Sci USA87: 9368, 1990.

89) Makino Y, Ohta S, TachikaWa O, Hirobe M. Presence oftetrahydroisoquinoline and 1 -methyl-tetrahydro-isoquinoline in foods :compounds related to Parkinson's disease. Life Sci 43: 373, 1988.

9

0) Niwa T, Takeda N, Tatematsu A, Matsuura S, Yoshida M, Nagatsu T.Migration oftetrahydroisoquinoline, a possible parkinsonian neurotoxin,into monkey brain from blood as proved by gas chromatography-massspectrometry. J Chromatogr 452: 85, 1988.

9

1) RajputAH, UittiRJ, SternW, LavertyW. Early onsetParkinson's diseasein Saskatchewan - Environmental considerations for etiology. Can JNeurol Sci 13: 312, 1986.

9

2) Koller W, Vetere-Over field B, Gray C, et al. Environmental risk factorsin Parkinson's disease. Neurology 40: 1218, 1991.

9

3) Hubble JP, Cao T, Hassanein RES, Neuberger JS, Koller WC. Riskfactors for Parkinson's disease. Neurology 43: 1693, 1993.

9

4) Semchuck KM, Love EJ, Lee RG. Parkinson's disease: a test of themultifactorial etiologic hypothesis. Neurology 43: 1 173, 1993.

9

5) Tanner CM, Chen B, Wang W,et al. Environmental factors and Parkin-son's disease: A case-control study in China. Neurology 39: 660, 1989.

9

6) Stern M, Dulaney E, Gruber SB, et al. The epidemiology ofParkinson'sdisease. A case-control study of young-onset and old-onset patients. ArchNeurol 48: 903, 1991.

9

7) Armstrong M, Daly AK, Cholerton S, Bateman DN, Idle JR. Mutantdebrisoquine hydroxylation genes in Parkinson's disease. Lancet 339:1017, 1992.

9

8) Smith CA, Gough AC, Leigh PN, et al. Debrisoquine hydroxylase genepolymorphism and susceptibility to Parkinson's disease. Lancet 339:1375, 1992.

9

9) Kondo I, Kanazawa I. Association of Xba I allele (Xba I 44kb) of thehuman cytochrome P-450dbI (CYP2D6) gene in Japanese patients withidiopathic Parkinson's disease, in: Advance in Neurology, Vol. 60,Parkinson' s Disease. From Clinical Aspects to Molecular Basis, NagatsuT, Narabayashi H, YoshidaM, Eds. Springer-Verlag, Wien, 1991 , p.1 1 1.

100) Tsuneoka Y, Matsuo Y, Iwahashi K, Takeuchi H, Ichikawa Y. A novelcytochrome P-450IID6 gene associated with Parkinson's disease. JBiochem 114: 263, 1993.

1

01) Waring RH, Steventon GB, Sturman SG, Heafield MTE, Smith MCG,Williams AC. S-methylation in motoneuron disease and Parkinson'sdisease. Lancet 2: 356, 1989.

1

02) Nakagawa-Hattori Y, Hattori T, Kondo T, Mizuno Y. S-methylation inParkinson's disease. Neurology 45: 1995 (in press).

1

03) Kurth JH, Kurth MC, Poduslo SE, Schwankhaus JD. Association of amonoamine oxidase B allele with Parkinson's disease. Ann Neurol 33:368, 1993.

1

04) Ho SL, Kapadi AL, Ramsden DB, Williams AC. An allelic associationstudy of monoamine oxidase B in Parkinson's disease. Ann Neurol 37:403, 1995.

1

05) Hotamisligil GS, Girmen AS, Fink JS, et al. Hereditary variations inmonoamineoxidase as a risk factor for Parkinson's disease. Mov Disord

9: 305, 1994.

1

06) Gasser T, Wszolek ZK, Trofarter J, et al. Genetic linkage studies inautosomal dominant parkinsonism: evaluation of seven candidate genes.Ann Neurol 36: 387, 1994.

1

07) Yokochi M.Juvenile Parkinson' s disease. Part I. Clinical aspects. ShinkeiKenkyu Shimpo (Prog Neurosci) 23: 1048, 1979.

1

08) Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A largekindred with autosomal dominant Parkinson's disease. Ann Neurol 27:276, 1990.

1

09) Wszolek ZK, Pfeifer B, Fulgham JR, et al. Western Nebraska family(family D) with autosomal dominant parkinsonism. Neurology 45: 502,1995.

1 10) Inose T, Miyakawa M, Miyakawa K, Mizushima S, Oyanagi S, Ando S.Clinical and neuropathological study of a familial case of juvenileparkinsonism. Jpn J Psychiatry Neurol 42: 265, 1988.

1

1 1) Mizutani Y, Yokochi M, Oyanagi S. Juvenile parkinsonism: a case withfirst clinical manifestation at the age of six years and with neuropathologi-cal findings suggesting a new pathogeneiss. Clin Neuropathol 10: 91,1991.

1

12) Yamamura Y, Sobue I, Ando K, Iida M, Yanagi T, Kono C. Paralysis

agitans of early onset with marked diurnal fluctuation of symptoms.Neurology 23: 239, 1973.

1

1 3) Takahashi H, Ohama E, Suzuki S, et al. Familial juvenile parkinsonism:clinical and pathologic study in a family. Neurology 44: 437, 1994.

1

14) Segawa M, Nomura Y, Kase M. Diurnal fluctuating hereditary progres-sive dystonia. in Handbook of Clinical Neurology, Vol. 5 (49) RevisedSeries: Extrapyramidal Disorders, Vinken PJ, Bruyn GW, Klawans HL,

Eds.Elsevier, Amsterdam, 1986, p.529.

1

15) Nygaard TG, Marsden CD, Fahn S. Dopa-responsive dystonia: long-termtreatment response and prognosis. Neurology 41: 174, 1991.

1

16) Nygaard TG, Wilhelmsen KC, Risch NJ, et al. Linkage mapping ofdopa-responsive dystonia (DRD) to chromosome 14q. Nature Genet 5: 386,1993.

1

17) Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystoniawith marked diurnal fluctuation caused by mutations in the GTPcyclohydrolase I gene. Nature Genet 8: 236, 1994.

1

18) NukadaH, KowaH, Saito T, Tasaki Y, Miura S. A big family of paralysisagitans. Rinshoshinkei (Clin Neurol) 18: 627, 1978.

1 19) Dwork AJ, Balmaceda C, Fazzini EA, MacCollin M, Cote L, Fahn S.Dominantly inherited, early-onset parkinsonism: neuropathology of anewform. Neurology 43: 69, 1993.

1

20) Koller WC, Silver DE, Lieberman A. An algorithm for the managementofParkinson's disease. Neurology 44: SI, 1994.

1

21) Ferrari C, Barbueri C, Caldara R, et al. Long-lasting prolactin-loweringeffect of cabergoline, a new dopamine agonist, in hyperprolactinemicpatients. J Clin Endocrinol Metab 63: 941, 1986.

1

22) Lieberman A, Imke S, Muenter M,et al. Multicenter study ofcabergoline,a long-acting dopamine receptor agonist, in Parkinson' s disease patientswith fluctuating responses to levodopa/carbidopa. Neurology 43: 1 98 1 ,1993.

1

23) Hinzen D, Hornykiewicz O, KobingerW, PichlerL, Pifl C, Schingnitz G.The dopamine autoreceptor agonist B-HT 920 stimulates denervatedpostsynaptic brain dopamine receptors in rodent and primate models ofParkinson's disease: a novel approach to treatment. Eur J Pharmacol 131:75,1986.

1

24) Mizuno Y, KowaH, Nakanishi T, YanagisawaN. Preliminary study ofB-HT 920, a novel dopamine agonist for the treatment of Parkinson'sdisease. Drug Invest 5: 186, 1993.

125) Golbe LI, Lieberman AN, Muenter MD,et al. Deprenyl in the treatmentof symptom fluctuations in advanced Parkinson's disease. ClinNeuropharmacol ll: 45, 1988.

126) Kaakkola S, Teravaunen H, Ahtila S, Rita H, Gordin A. Effect ofentacapone, a COMT inhibitor, on clinical disability and levodopametabolism in parkinsonian patients. Neurology 44: 77, 1994.

1

27) Roberts JW, Cora-Locatelli G, Bravi D, Amantea MA,Mouradian MM,Chase TN. Catechol-O-methyltransferase inhibitor tolcapone prolongslevodopa/carbidopa action in parkinsonian patients. Neurology 44: 2685 ,

InternalMedicineVol. 34, No. 1 1 (November 1995) 1053

Mizuno et al

1994.

1

28) Kaakkola S, Gordin A, Jarvinen M, et al. Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa inhealthy volunteers. Clin Neuropharmacol 13: 436, 1990.

1

29) BieckPR, Autonin KH, FargerG, et al. Clinical pharmacology ofthenewCOMT inhibitor CGP 28 014. Neurochem Res ll: 1 163, 1993.

1

30) Bianchine JR, Calimlim LR, Morgan JP, Dujuvne CA, Lasagna L.Metabolism and absorption ofL-3,4-dihydroxyphenylalanine in patients

with Parkinson's disease. Ann NY Acad Sci 179: 126, 1971.

1

3 1) NeiraWD, SanchezV, MenaMA, deYebenesJG. Theeffects ofcisaprideon plasma L-dopa levels and clinical response in Parkinson's disease.MovDisord 10: 66, 1995.

1

32) The Parkinson Study Group. Effect of deprenyl on the progression ofdisability in early Parkinson's disease. N Engl J Med 321: 1364, 1989.

1

33) The Parkinson Study Group. Effect of tocopherol and deprenyl on theprogression of inability in early Parkinson's disease. N Engl J Med 328:176, 1993.

1

34) Narabayashi H, Ohye C. Importance of microencephalotgomy for tremoralleviation. Appl Neurophysiol 40: 222, 1980.

135) Caparros-Lefebure D, Ruchoux MM, Blond S, Petit H, Percheron G.Long-term thalamic stimulation in Parkinson's disease: postmortemanatomoclinical study. Neurology 44: 1856, 1994.

1

36) Delong MR. Primate models of movement disorders of basal gangliaorigin. Trends Neurosci 13: 281, 1990.

1

37) Alexander CE, Crutcher MD. Functional architecture of basal gangliacircuits: neural substrates of parallel processing. Trends Neurosci 13:266, 1990.

1

38) Goetz CG, Olanow CW, Koller WG, et al. Multicenter study of autolo-gous adrenal medullary transplantation to the corpus striatum in patientswith advanced Parkinson's disease. N Engl J Med 320: 337, 1989.

139) Lindvall O, Widner H, Rehncrona S, et al. Transplantation of fetaldopamine neurons in Parkinson' s disease: One-year clinical and neuro-physiological observations in two patients with putaminal implants. AnnNeurol 31: 155, 1992.

1054 InternalMedicineVol. 34, No. 1 1 (November 1995)