Parkinson’sDisease: Signs and Symptoms, Neural Mechanisms, …downloads.hindawi.com/journals/np/2001/127104.pdf · 2019-08-01 · PARKINSON’SDISEASE 101 CLINICALSIGNSANDSYMPTOMS

NEURAL PLASTICITY VOLUME 8, NO. 1-2, 2001

Parkinson’s Disease: Clinical Signs and Symptoms,Neural Mechanisms, Positron Emission T mography,

and Therapeutic Interventions

K.L. Leenders and W.H. Oertel2

Groningen University Hospital, Department ofNeurology, Hanzeplein 1PO Box 30. 001, 9700 RB Groningen, The Netherlands;

2Philipps-University Marburg, Klinikumfiir Neurologie, 35039 Marburg, Germany

SUMMARY

Parkinson’s disease is one of the mostfrequent neurodegenerative brain diseases. Itstime course is slow and is characterized byprogressive loss of dopaminergic and otherbrainstem neurons resulting in malfunctioning ofthe cerebral neuronal systems responsible formotor functions. The clinical signs are slownessof movement, muscle rigidity and rest-tremoramongst other features. The cause of the diseaseis unknown, but recently involvement of geneticfactors is being researched. Positron emissiontomography (PET) allows in vivo determinationof striatai dopaminergic activity. This hasincreased our insight in the pathophysiology ofthe disease and permits direct study of diseaseprogression at a biochemical level and equally tomonitor whether potential neuroprotective inter-ventions are indeed effective. Thus far no drughas emerged but promising substances arecurrently being studied.

KEYWORDS

Parkinson’s disease, FDOPA-PET, gene mutation,disease progression, neuroprotection

INTRODUCTION

Parkinson’s disease (PD) has for the first timebeen described in a comprehensive way in 1817 byJames Parkinson in an article entitled "An Essayon the Shaking Palsy". The disorder has since thenbeen named after him. The diagnosis PD is madeon clinical grounds solely since there does notexist a specific laboratory test to confirm thecharacteristic cerebral pathological alterationswhich lie at the basis of this condition. In mostcases the clinical pattern of signs and symptoms issufficiently clear to make the diagnosis withconfidence. However, a certain number of patientswill pose considerable difficulties as to the correct

diagnosis, particularly in early stages of theirdisease, even for an experienced neurologist.Overlap with diseases which are not PD, but areaccompanied with some form of parkinsonisticfeatures, may occur regularly.

In PD at least two of the three cardinal signsbradykinesia, rigidity and tremorneed to bepresent (Levy & Cummings, 1999). The tremor istypically prominent when the patient is at rest. Inaddition, a large number of other signs andsymptoms may be present at different stages of thedisease and in individually varying composition or

intensity: impaired postural reflexes, masked face,low speech volume, swallowing difficulty, micro

(C)Freund & Pettman, U.K., 2001 99

100 K.L. LEENDERS AND W.H. OERTEL

graphia, flexed posture, small shuffling steps, move-ment initiation problems, freezing. The clinicalpicture often is further complicated by depression.Certain neuropsychological functional impairmentsand even a dementing condition may develop atlater stages. The onset of PD is insidious andusually unilateral. Also with progression of thedisease, when both body sides are affected, theasymmetries remain. Most commonly the diseasestarts at middle age with increasing prevalenceabove the age of 50 years, but ’young onset cases’are not uncommon. Progression is in most casesslow but inexorable. The endstage of the disease isreached after many years, usually more than ten.

In this chapter, apart from clinical features,some aspects of the pathophysiology of the diseasewill be described. In particular the role of positronemission tomography (PET) will be highlighted.

CAUSE

To date the cause of idiopathic Parkinson’sdisease is still unknown. Accelerated aging hasbeen discussed as a possibility, but is nowdiscarded mainly because the brainstem pathologyfound in post-mortem PD tissue is clearly differentfrom the patterns of alteration seen with aging(Hirsch et al., 2000). Genetic and environmentalfactors have been investigated over the last decadeswithout, as yet, a clear-cut unifying unimodalcausative model. During the last few years,possible genetic influences have become the focusof attention. Only in a minority of cases PD occursin a familial context, although an overall increasedrelative risk (compared to the population at large)of two to three for family members of PD patientsto become afflicted has been found. This is

comparable to the situation in Alzheimer’s disease.Mutation ofthe alpha-synuclein gene (chromo-

some 4q21-23) has been identified in one large

Italian family and in five Greek families. Thatmutation gave rise to an autosomal dominantpattern of inheritance of parkinsonism. Theclinical expression of the disease, however, wasnot quite typical for PD in the case of theAla53Thr point mutation of the chromosome. Forinstance, the disease manifested itself at earlyages. The Ala30Pro point mutation, recentlydiscovered in a German family, however, resultedin a syndrome which phenotypically was muchmore like that seen in idiopathic sporadic PD(Kruger et al., 2001).

Mutation of the Parkin gene (chromosome6q25-27) has been identified as the cause of anautosomal-recessive juvenile form of parkinsonism,although the start of the disease at an early age andother atypical neuropsychological features againdistinguish this condition somewhat from the’common’ form of PD. In the meantime, aspectrum of different alterations of the chromo-some (various deletions or point mutations andothers) have been found in the reported families.Thus, apparently a widely varying number ofgenetic pathological changes of several chromo-somes can ’give rise to parkinsonism (Klein et al.,2000).

It neds to b ralizd, howwr, that in thowrwhdming majority of familial ass ofParkinson’s disease, or in sporadi PD patients forthat matter, no gneti abnormality has bnidentified. In th majority of ass, therefore, it isblivd that nvironmental factors, possibly onthe basis of som form of gnti susceptibility,play a major hitherto unknown rol. Som hawsuggested that th pla of birth and rsidnsem to play a greater rol than the ra. Afro-Americans living in th U.$. hav a narly fiwtims higher risk as Africans living in Nigeria.Afro-Americans and Caucasians living in th sameommunity in th U.S. have similar risks ofdvloping Parkinson’s disease.

PARKINSON’S DISEASE 101

CLINICAL SIGNS AND SYMPTOMS

The patients usually notice rest tremor orslowing of movements in one form or the other asa first sign or symptom. Rigidity in the form ofstiffness and pain, on the other hand, is rarelyreported as the main complaint by the patient,although it is a characteristic sign often to befound at patient examination. Rigidity is determinedby passive movement by the examiner of the neck,upper and lower limbs of the patient. Increasedmuscle tone throughout the range of motion islooked for. If the rigidity is mild, it may beaccentuated by letting the patient move thecontralateral limb by opening and closing the hand.Rigidity should be distinguished from spasticitybecause the increase in tone in that condition ismore prominent with the initiation of passivemovement and is greater in one direction than inthe other. Spasticity results from a lesion at thelevel of the upper motor neuron and is accom-panied by an increased stretch reflex and otheralterations. These latter findings are not seen inpatients with rigidity.

Postural instability is not a presenting symptomor sign of PD but can certainly arise in the courseof the disease. This needs to be tested specificallywhen the patient is examined in order to categorizethe patient in the widely used Hoehn and Yahrscale: if the postural reflexes are affected, thepatient is assigned to category III instead of II of atotal five categories.

There are numerous other signs and symptomsof PD that are often brought to the physician’sattention by the patient or family members. Micro-

graphia is a common early sign, characterized by a

slowness or smallness to the handwriting. Maskfacies is another bradykinetic symptom characteristicof Parkinson’s disease. Also, slowing of dailyliving activities occurs, including such activities as

dressing, bathing, turning in bed, getting in and outof a chair. Well-known are the problems with gait

in PD" some shuffling or dragging of a leg. Theposture is often stooped with flexion of the knees,hips, trunk, and neck. Bradykinetic or hypophonicspeech, which may require the patient to repeathimself frequently, is one of the bulbar symptoms.Drooling is also common and choking may occur.The loss of the sense of smell, or anosmia, inrelation to alterations of the dopaminergic pathwayprojecting to the bulbus olfactorius, has been well-documented in Parkinson’s disease. It is alsopossible that patients will present with a footdystonia, in which the foot will turn in and withinvoluntary curling of the toes, especially in themorning. This may be an unpleasant symptom,often accompanied by pain. If it occurs later in thedisease it usually signifies a relative understimu-lation of the dopaminergic system due to lowblood drug levels, particularly early in the momingwhen during the night no medication has beentaken.

Idiopathic PD needs to be differentiated fromother conditions causing parkinsonism (Levy &Cummings, 1999). Certain drugs like neurolepticsbut also others may induce parkinsonism. AtypicalPD can occur in the context of other diseases like

Progressive Supranuclear Palsy (PSP) or multiplesystem atrophy (MSA). If a supranuclear gazepalsy, particularly a downgaze palsy, is present, aPSP is more likely. In that condition, also frequentfalls early in the disease are characteristic inaddition to more axial (nuchal) rigidity comparedto limb rigidity. The signs are often symmetrical,and a resting tremor is absent or only mild.

Response to parkinsonian drugs is commonly pooror absent, although early on there may occasionallybe a good effectivity. An MSA is suspected ifinvolvement of the upper motor neuron or a

cerebellar syndrome is found. Often the autonomicnervous system is affected too, resulting, forexample, in micturition problems or orthostatichypotension. Also MSA develops usually ratherrapidly, symmetrically, and without much of a


hypotension. Also MSA develops usually ratherrapidly, symmetrically, and without much of atremor and does not respond well on anti-parkinsonian medication. Patients with early-onsetor rapidly progressive dementia, accompanied withvisual hallucinations not induced by medication,are more likely to have diffuse Lewy body diseaseor Alzheimer’s disease. Patients with an earlyonset of urinary incontinence should be evaluatedfor normal pressure hydrocephalus.

Even though a patient with parkinsonism canusually be classified correctly during life, adefinitive diagnosis of PD can be made only byautopsy (see below). Neuroimaging studies applyingradiotracers during life can reliably demonstratethe presence of a presynaptic dopaminergic defectin the nigrostriatal neuronal system, but as such,this does not differentiate between the variousforms of parkinsonism. Usage of a combination ofvarious tracers, however, can help to clarify thebiochemical changes and thus assist in making a

diagnosis.

PATHOLOGY

A normal midbrain at post-mortem shows thesubstantia nigra (Latin for ’black substance’) asdark black/brown colored areas between thecerebral peduncles and the nucleus ruber. Thisabundant pigmentation is caused by the neuro-melanin accumulation in the cell bodies of the

nigral dopaminergic neurons. In PD, the nigraldopaminergic neurons are gradually and to a

certain extent lost, particularly in the lateral andventral parts of the substantia nigra. Therefore, themidbrain of a PD patient looks bleak because ofdepigmentation. Microscopically there is alsosome gliosis in the substantia nigra in PD. Manylesioned dopaminergic neurons contain abnormalinclusion bodies, the Lewy body inclusions. These

are characterized by a dense pink center and a

lighter pink periphery. The combined loss ofdopaminergic neurons in the substantia nigra,together with the inclusion ofLewy bodies, is seenas the pathological hall-mark of idiopathic PD.

There are speculations about why in PDusually only the lateral and ventral part of thesubstantia nigra is affected. It has been found thatthe glial cells in that particular part of thesubstantia nigra have different biochemicalproperties (Hirsch, 2000). Possibly in the case ofPD, protective properties of glial cells in thoseregions of the substantia nigra are not operationalor not sufficiently effective.

Various biochemical deficits or cell biologicalalterations in the brain tissue of PD patients havebeen found: mitochondrial complex I is impairedin the substantia nigra, iron accumulation isincreased, and signs of increased oxidative stressand reduced defenses against this stress have beenfound, also increased apoptosis has been reported.It is generally supposed that all these cellularphenomena are the expression of dysregulationrelatively far down the cascade of events active inthe impaired neurons in PD. The quest will be tofind the key step(s) which initiates all the abovementioned pathological mechanisms.

BASAL GANGLIA CIRCUITS

The cerebral stations which plan and execute

movements are organized in a complex way.Motor plans are stored, composed, and activatedby many parietal and frontal cortical regions. Inaddition, two major systems interact with thecortical action to make movements possible. Thecerebellum is necessary, for example, for obtainingaccuracy and context-shaping of movements. Thebasal ganglia (mainly the striatum, pallidum,subthalamic nucleus, as well as the thalamus) have


a role in learning automated skilled movements,but their role is much more difficult to formulatein physiological terms. They do seem to influencetemporal and spatial discrimination.

Within the cortex, the neurons have dense andcomplicated cortico-cortical interconnections. Incontrast, the connections between the cortex andstriatum, between striatum and pallidum, betweenpallidum and thalamus, and between thalamus andcortex are all formed by single-layered elements.This has been the basis for the efforts to determinewhich synaptic transmission is excitatory orinhibitory via the type of neurotransmitter at thespecific connections. Thus, a system of integratedinfluence, either activating or inhibiting, could beproposed for the basal ganglia system of cortico-subcortico-cortical loops.

A central role in this system is played by thedopaminergic nigrostriatal projection, which modifiesin various ways the transmission of the cortico-striatal signals to the striato-pallidal projectionneurons. Since the dopaminergic neuronal systemis impaired in PD (see above), the basal gangliacircuits are therefore in disarray (Bergman et al.,1998). Ultimately this results in an altered firingpattern of the internal part of the globus pallidus towhich the basal ganglia massively converge asmajor output station. In particular, the functionalfiring segregation between the pallidal neurons islost, leading to oscillatory activity of the pallidumwhich is normally not present (Raz et al., 2001).The pallidum has, in turn, an enormous divergentconnection with the cortex through the thalamus. Ittherefore is understandable that the pathologicallyaltered firing pattern of the globus pallidus has a

deeply disturbing influence on the cortical functions.The major projection of the basal ganglia is to thesupplementary cortex, which is an important motorplanning area: for example, initiation of movementpatterns, organization of sequential movements,and other aspects are prepared there.

CLINICAL PHYSIOLOGICAL CONSEQUENCES

The clinical hallmarks of PDakinesia (unableto start a movement), bradykinesia (slowness ofmovement), and tremor---can thus be traced to thearrangement of brain regions and their impairedfunction. PD patients show a slow reaction timeand prolonged movement time. It appears thatvelocity modulation during movements is affectedrather than an overall reduction of velocity.Sequential movements of PD patients are impaired,and also simultaneous actions are difficult toperform. An often observed phenomenon is that apatient has to stop a certain movement in order tobe able to answer, when the patient is askedsomething during the performance of a movement.Apparent is the slowing of cognitive speed ifchoice complexity increases. On the other hand, thecentral processing of information is qualitativelypreserved, for example, use of advance informationfor motor preparation.

18F-FLUORODOPA PET

Positron Emission Tomography (PET) is aradiotracer method using special computer tomo-graphic equipment to register the signals emergingfrom the body after application of appropriateradiotracers. The radiolabel is an isotope ofphysiological atoms like carbon-11, oxygen-15 or

fluor-18, and these have certain characteristics:they are short lived (minutes to hours) and emittwo high-energy gamma rays in opposite directions,which enables regional quantitation of the signal at

high sensitivity. A further feature of these tracersis that they usually are substances of a physio-logical nature like derivatives of glucose, aminoacids, enzyme substrates, or receptor bindingsubstances. Taken together, the method allows in a

computer tomographic way to measure regional


activity in vivo of biochemical or physiologicalprocesses in man or in experimental animals. Thiscan be done for the whole body, but here we limitourselves to the brain. Particularly for slowlyprogressing degenerative brain diseases like PD,such a method constitutes an important addition tothe possibilities of investigating patients with thisdisease, since the brain is hardly accessible in adirect way.

Relevant for the study of PD is the possibilityto use the tracer FDOPA (6-[F-18]-fluoro-L-dopa)and PET. This tracer serves as a substrate for theenzyme dopa-decarboxylase and is then accumulatedas fluorodopamine in the dopaminergic nerveterminals. Particularly, the striatal capacity todecarboxylase and store this tracer can beperformed quantitatively (Melega et al., 1991) InPD patients, this conveys the degree of dopa-minergic nigrostriatal neuronal impairment sinceloss of nigral dopaminergic neurons will beaccompanied by a loss of striatal dopaminergicnerve endings. However, also nigral dopaminergicneurons which still are present but do not functionproperly will most likely contribute to impairedendogenous nerve terminal function. The parameterto compare subjects can be a simple ratio betweenthe activity in the target striatal regions and a non-dopaminergic brain reference region, for example,occipital lobe or cerebellum.

Alternatively, a more complicated measure canbe derived from the dynamic time curves ofmeasured activity from the moment of applicationof the radiotracer onwards. From these tracer-kinetic models a specific constant can be calculatedreflecting specific regional tracer uptake. Thisconstant is generally named Ki. If the reference oftracer input is the arterial plasma then the unitshould be written as Ki (plasma), but if thereference is the occipital lobe the unit may bedenoted as Ki(occipital) or briefly Kocc. This unitis expressed as per minute (1/min).

In PD the decrease in specific FDOPA uptake

is not uniformly distributed. The nigrostriatalneuronal system of the most affected part in thesubstantia nigra (lateral and ventral part) projectsmainly to the putamen. In the cross-sectionalimages obtained via PET (see Fig. 1), it can beseen that indeed the posterior parts of the striatumshow the largest decrease in FDOPA uptake whilethe caudate nucleus regions are relatively spared.In asymmetric PD patients the FDOPA uptake isusually also asymmetrically impaired: the contra-lateral side shows the highest decrease.

On average, in well established PD patientsthe specific FDOPA uptake in putamen is about40% to 45% of that in healthy age-matched controls(Leenders et al., 1990).

START OF DOPAMINERGIC DECLINE

The decline of the striatal dopaminergic neuro-modulation must have begun some time before theclinical signs and symptoms appear. There hasbeen some speculation about how many years thisperiod in general might be. Post-mortem investiga-tions suggest about 4 years. The progression dataobtained via FDOPA PET would support thiscontention (Leenders, 1997). From Fig. 2 it can beseen that indeed extrapolation from the estimatedperiod of clinical duration of the disease in a groupof patients towards the mean of healthy controlvalues there is an approximate time lag of 5 to 6years before the striatal dopaminergic capacity toaccumulate FDOPA has decreased to a level whenthe signs and symptoms appear. It can also be seenthat the striatal activity is not very low when thedisease manifests itself clinically. One interpret-ation is, that the endogenous dopamine productionis very low indeed, at a stage when there still are a

sufficient number of nerve terminals left (althoughmalfunctioning) to take up exogenous levodopa or

FDOPA. It would explain why in the beginning ofthe disease levodopa medication is so effective.


Fig. I" Transaxial representation of cerebral FDOPA uptake in one healthy volunteer (left panel) and one PD patient(right panel). The front ofthe brain is on the top ofthe image. Specific uptake oftracer (see text) is indicatedby a linear color scale, red being maximal uptake. The striatum on both sides ofthe brain is indicated by thehigh intensity uptake of tracer in the healthy volunteer. It can be seen that in the PD patient the uptake intostriatum is diminished, particularly in the more posterior regions.

Ki x 10-16

14

12

10

-5 0 5 10 15 20

Years

Correlation between specific FDOPA uptake (expressed as Ki see text) in putamen and disease duration inpatients with PD. Values are compared to healthy age-matched control mean and two SD. Open circles are PDpatients and the open diamond is the mean of the controls.


In the early stages of the disease, when thereare only a few signs and symptoms, there areindications that the tracers which measure dopa-mine reuptake sites (that is, the CIT-derivedsubstances, Benamer et al., 2000) either measuredwith SPECT or with PET) are more reduced thanFDOPA. Later when the disease has been clearlyestablished, the two types of tracer indicate thesame degree of striatal dopaminergic impairment.In our own data (to be published separately) it hasbeen shown that [I-123]-FP-CIT had a striataluptake of 40% compared with age-matched healthycontrols in de novo PD patients with a UPDRS-IIImotor score of less than 20. On the other hand,FDOPA uptake in a similar group of PD patientswas 82% of healthy control values. One interpreta-tion could be that the dopamine re-uptake sites atthe nerve terminals in the striatum of PD patientsare downregulated in an early stage of the diseasedue to the low endogenous dopamine productionand, in turn, low dopamine concentration in thesynaptic cleft. Since the nerve terminals may stillbe present at that stage (see above), it is under-standable that these different uptake measures arefound. It emphasizes that the investigator shouldknow well at which biochemical features he islooking. If this finding is confirmed, then it wouldmean that in very early stages of PD, the dopaminereuptake tracers might be more sensitive in detectingpathology compared to FDOPA.

GENETIC INFLUENCE ON FDOPA UPTAKE

Various members of families in which genealterations have been found have been investigatedwith FDOPA PET.

Alpha-Synuclein gene

Eleven subjects of a family were investigated(Kruger et al., 2001). Five were carriers of a mutation

of the alpha-Synuclein gene (Ala30Pro pointmutation). Of these five subjects, three had PD andtwo had subtle signs. The symptoms in thesepatients started at ages 54 to 76. PET scans on twoof the symptomatic subjects, two brothers, and onone of the ’non’ symptomatic subjects, a sister ofthe two PD patients, were performed (Kruger et al,2001). The two brothers (aged 65 and 57), off-spring of non-consanguinent parents, presented as

patients with dopa-responsive PD. They werefound to have the mutant gene 4q21-q23 (alpha-synuclein). The oldest brother (65) started withmicrographia at age 54. Gradually a morepronounced general hypokinesia developed. Initiallevodopa therapy resulted in an improvement ofmotor signs, but despite additional pharmaco-therapy, he developed severe bradykinesia, more

pronounced on the left side, rigidity, and moderatepostural imbalance. Recently choreatic peak dosedyskinesia, mainly axially, occurred. Up till nowtremor, autonomic failure, or a marked cognitiveimpairment remained absent. The UnifiedParkinson’s Disease Rating Scale III (MotorExamination Score) was 55 and his Hoehn & YahrStage wis Ill-IV (while on medication). Theyoungest brother (57) suffered from (mainly rightsided) hypokinesia and mild limb rigidity since 3years. Combined pharmacotherapy (levodopa anddopamine agonist) attenuated motor signssuccessfully, and no other parkinsonian, cognitive,or autonomic signs have occurred till now. TheUnified Parkinson’s Disease Rating Scale Ill

(Motor Examination Score) was 12 and his Hoehn& Yahr Stage was II (while on medication). Theirsister (52), who also had been tested positive forthe mutant gene, had no history of parkinsonismand was clinically unaffected. Their mother, whosuffered from parkinsonism, died at the age of 60.No other family members are known to havemovement disorders or related diseases. The two

patients had a reduced FDOPA uptake in striatumbetween 40% and 54% of normal control values,


whereas the sister had normal uptake values. Inthese subjects, also FDG PET scans whichmeasure regional cerebral glucose consumption,were performed. Several brain regions showedenergy consumption deficits in accordance withsome neuropsychological deficits. The otherbrother and even the sister had some FDG uptakeimpairments. This was also consistent with somedeficits apparent at neuropsychological testing.

In summary, the findings in this familyindicate that this particular genetic mutation leadsto a form of parkinsonism that is very much likethe common idiopathic form of PD. In will be ofinterest to follow the unaffected sister in order todetect in which sequence the clinical and cerebralbiochemical impairments will arise.

Parkin gene

Mutations in the Parkin gene (chromosome6q25-27) yield an autosomal recessive form ofjuvenile PD. Exons 3 to 7 are usually affected. Aparticular characteristic is that no Lewy bodieshave been found at post-mortem examination. Twobrothers from an Israeli study were investigatedwith FDOPA PET (Portman et al., 2001). Bothbrothers were homogenous for large deletions ofexon 4, 5, and 6. They were first degree cousins.The eldest started with clinical signs andsymptoms at age 35 and had his PET investigationat age 55. The youngest brother started at age 28and was PET investigated at age 49. Their clinical

stage was Hoehn & Yahr Stage IV to V (withoutmedication). FDOPA uptake in putamen was 13%to 28% and in caudate nucleus 13% to 33% ofhealthy control values. These findings are similarto those reported earlier (Broussolle et al., 2000).These authors described three non-related patientswho had the disease for a very long time and in

whom various deletions and mutations of theParkin gene were found. The FDOPA uptake in

putamen in these patients was between 28% and44% of normal.

In summary, it can be said that the abnormalitiesfound with FDOPA PET are different from thosefound in idiopathic PD: the decreases are moresevere and also the caudate nucleus is heavilyaffected. This would bein concordance with theclinical picture which usually is different from PD,particularly concerning the early age of start.However, a recent paper (Klein et al., 2000)presented a family with Parkin gene mutations inwhom the affected family members were clinicallyindistinguishable from idiopathic sporadic PD.

Twin studies

One study reported FDOPA results in 18monozygotic and 16 dizygotic twin pairs, of whomone had PD (Piccini et al., 1999). At baseline theconcordance for the FDOPA uptake (reduced inthe clinically not-affected twin) was significantlyhigher in the monozygotic (55%) than in thedizygotic twin pairs (18%). The asymptomaticmonozygotic cotwins all showed progressive lossof dopaminergic function over seven years andfour developed clinical PD. None of the dizygotictwin pairs became clinically concordant. Thesefindings support some role for genetic factors inthe causation of PD. However, the expression ofgenetic susceptibility must be rather varying since

the latencies for clinical concordance vary greatlyand may last for many decades. Twin studies have

appealing characteristics but also a number of

pitfalls, for example, the heavy selection bias andthe particular biological situation of the subjectsinvolved. Another recent paper studying a largecohort of twins (Tanner et al., 1999) again foundno genetic component to be evident when thedisease begins after age 50 years. However, geneticfactors appear to be important when the disease

begins at or before age 50 years.


Disease progression

As PD progresses, specific FDOPA uptakeinto putamen decreasesthis is a marker that thedopamine-producing cells in the substantia nigraprojecting to the putamen are continuing to diewith relatively the highest rate of decline in thefirst years ofthe disease (see Fig. 2).

In the literature, only a few reports areavailable to assess properly the percentage declineof specific striatal FDOPA uptake per year in anaverage PD population. The percentages varybetween 1% and 18%, although most figures liebetween 5% and 10%. In healthy controls, thedecline is less than 1% per year. In view of theslow decline of dopaminergic function in PDpatients and knowing that in the early phases of thedisease a large number of striatal nerve terminalsshould still be present, albeit malfunctioning, thereis therefore a basis to propose neuroprotectivestrategies if such strategies indeed are available.

Neuroprotection

Animal experiments have been positive inadministering one or other intervention to protectcells from dying or assisting them in recoveringfrom damage. However, to date no such designshave been convincingly successful in man.

Selegiline, a MAO (monoamine oxidase) inhi-bitor has been extensively tested in, for example,the DATATOP PD study. The basic idea was toblock MAO and thus diminish oxidative stress tothe dopaminergic system. Selegiline exerts neuro-protection in various cellular and animal modelswhich are independent of MAO-B inhibition butmay be related to binding to glyceraldehyde-3-phosphate dehydrogenase (Olanow et al., 1998).No apparent benefit in terms of slowing of diseaseprogression in PD patients has been found.

In other studies, dopamine agonists have beenproposed to be protective, on the basis of these

drugs reducing glutamatergic drive on the substantianigra. An extensive 5-year study using ropiniroland a 3-year study using pergolide comparing withlevodopa use have recently been concluded, andthe results will be published shortly. Both studieswere performed with clinical scales and longitudinalFDOPA PET scans as outcome measures. In theropinirol study, 45 patients were included atbaseline. After five years, seven patients were stillon ropinirole monotherapy and showed a declineof specific FDOPA putamen uptake of in total12%, whereas the levodopa monotherapy patients(n=4) showed a decline of 15% in 5 years. The 12patients with ropinirole and levodopa as rescuetherapy showed a decline of in total 36%. The 3-year pergolide study included 88 patients. Thepergolide monotherapy patients at 3 years showeda putamen FDOPA decline of in total 8% and thelevodopa patients 14%. The difference was notsignificant.

Thus, no clear-cut beneficial effect in terms ofprotection against dopaminergic decline has beenfound for either agonist. In fact, it can be said thatlevodopa appears to be not deleterious in terms ofprogression of the disease. Also a dopamine re-

uptake tracer measured with SPECT is used tostudy the effects of pramipexol, another dopamineD2 agonist used in everyday treatment of PDpatients. The preliminary data appear to becomparable with those of pergolide and ropinirole(personal communication).

Currently a glutamate antagonist, riluzole, is

being investigated in de novo PD patients in thecontext of neuroprotection. Here also, FDOPAPET scans are included in the evaluation of theresults. No results are available yet. The advantageof riluzole as compared with deprenyl or dopamineagonists is that the former has no direct clinical

symptomatic effect, whereas for the others a

combined effect was expected. To disentangle thetwo effects in multicenter large scale longitudinalstudies will be difficult.


Increased apoptosis has been suggested to bepresent in the substantia nigra and may betriggered by various mechanisms: oxidative stress,mitochondrial dysfunction, excitotoxicity, excessiveconcentration of iron (Jenner & Olanow, 1998).All these unfavorable factors have been demonstratedto be present in the substantia nigra. Selegiline hasbeen proposed (see above) to be a potentialcandidate to exert neuroprotection since not onlydoes it inhibit MAO-B to reduce oxidative stressbut also has it been shown to exert neuroprotectionin various cellular and animal models which areindependent of MAO-B inhibition but possiblyrelated to binding to glyceraldehyde-3-phosphatedehydrogenase. The activity of the latter enzyme istaken to be an indicator for apoptosis activity. Themajor problem of disentangling the neuroprotectiveeffect of a substance from its clinical effectivenessis demonstrated also in the case of selegiline. Thesituation is confounded by the metabolism ofselegiline: the desmethylated metabolite is supposedto be protective, whereas the metabolites ampheta-mine and metamphetamine were shown to beantagonistic to this effect. As a consequence ofthis TCH346 (formerly CGP 3466B), a propargyl-amine related to selegiline, has been selected as amore convenient candidate substance. TCH346 doesnot lead to MAO-B inhibition, does not metaboliteinto amphetamines, and is much more potent thanselegiline in inhibiting apoptosis. The applicationof TCH346 in mice mutant for motoneurondegeneration life span significantly increased, andin an animal model of ischemia, survival of CA1pyramidal neurons was shown (Andringa & Cools,2000). Our own group was involved in testingTCH346 in a group of 8 Rhesus monkeys (resultsto be published). Sequential bilateral carotid arteryapplication of the dopaminergic neurotoxin MPTPwas used as primate Parkinson model. Four hoursafter the second MPTP lesion, subcutaneousTCH346 administration was started for two weekstwice daily compared to vehicle. The four animals

receiving TCH346 did not show any reduction inFDOPA uptake in the corresponding striatum,whereas the vehicle treated animals did show theexpected significant decreases. The computerizedmotor responses of the animals were in completeagreement with the tracer findings.

Apoptosis inhibition is a new target to be triedin humans since in experimental conditions,effectivity against cell damage after toxins likeMPTP or after ischemia has been shown. Thequestion remains whether apoptosis is a key factorin the progressive decline of the nigral dopamin-ergic neurons or whether it is one of the stages inthe complex cascades of events once the lesion istaking effect. Most likely it needs to elucidatedwhich factors right in the beginning of the processare responsible for the impaired cell functionsbefore really effective protective or reparativeschemes can be tried with some outlook of success.

Restorative therapeutic designs like cerebralimplantation of viable possibly modified cells withor without concurrent neurotrophic factors is anoption which in the end may certainly bear fruits.Many encouraging experimental findings areavailable. The recent cell biological work withstem cells adds to the perspectives. However, thelevel of knowledge and the practical applicationsin this regard have to date not surpassed theexperimental level (Bjorklund & Svendsen, 2001;Dunnett et al., 2000; Peschanski et al., 1999).

REFERENCES

Andringa G, Cools AR. 2000. The neuroprotectiveeffects ofCGP 3466B in the best in vivo model ofParkinson’s disease, the bilaterally MPTP-treatedrhesus monkey. J Neural Transm Supp160:215-225.

Benamer HT, Patterson J, Wyper DJ, Hadley DM,Macphee GJ, Grosset DG. 2000. Correlation ofParkinson’s disease severity and duration witht23I-FP-CIT SPECT striatal uptake. Mov Disord15: 692-698.


Bergman H, Feingold A, Nini A, Raz A, Slovin H,Abeles M, Vaadia E. 1998. Physiological aspectsof information processing in the basal ganglia ofnormal and parkinsonian primates. TrendsNeurosci 21" 32-38.

Bjorklund A, Svendsen CN. 2000. Chimeric stemcells. Trends Mol Med 7: 1444-1446.

Brooks DJ. 1993. Functional imaging in relation toparkinsonian syndromes. J Neurol Sci 115" 1-17.

Broussolle E, Lucking CB, Ginovart N, Pollak P,Remy P, Durr A. 2000. [lSF]-dopa PET study inpatients with juvenile-onset PD and parkin genemutations. Neurology 55: 877-879.

Dunnett SB, Nathwani F, Bjorklund A. 2000. Theintegration and function of striatal grafts. ProgBrain Res 127: 345-380.

Hirsch EC. 2000. Glial cells and Parkinson’s disease.J Neurol Suppl II 247: I158-I162.

Hirsch EC, Hunot S, Hartmann A. 2000. Mechanismof cell death in experimental models of Parkin-son’s disease. Funct Neurol 15" 229-237.

Jenner P, Olanow CW. 1998. Understanding celldeath in Parkinson’s disease. Ann Neurol Suppl44: $72-$84.

Klein C, Pramstaller PP, Kis B, Page CC, Kann M,Leung J, et al. 2000. Parkin deletions in a familywith adult-onset, tremor-dominant parkinsonism:expanding the phenotype. Ann Neuro148:65-71.

Kruger R, Kuhn W, Leenders KL, Sprengelmeyer R,Muller T, Woitalla D, et al. 2001. Familialparkin-sonism with synuclein pathology: Clinicaland PET studies of A30P mutation carriers.Neurology 56: 1355-1362.

Leenders KL, Salmon EP, Tyrrell P, Perani D, BrooksDJ, Sager H, et al. 1990. The nigrostriatal dopa-minergic system assessed in vivo by positronemission tomography in healthy volunteersubjects and patients with Parkinson’s disease.Arch Neuro147: 1290-1298.

Leenders KL. 1997. Pathophysiology of movementdisorders studied using PET. J Neural Transm

Suppl 50: 39-46.Levy ML, Cummings JL. 1999. Parkinson’s disease

and Parkinsonism. In: Joseph AB, Young RR,eds, Movement Disorders in Neurology andNeuropsychiatry. Malden: Blackwell Science,Inc.; 171-179.

Melega WP, Grafton ST, Huang SC, Satyamurthy N,Phelps ME, Barrio JR. 1991. L-6-[lSF]-fluorodopa metabolism in monkeys and humans:Biochemical parameters for the formulation oftracer kinetic models with positron emissiontomography. J Cereb Blood Flow Metab 11: 890-897.

Olanow CW, Mytilineou C, Tatton W. 1998. Currentstatus of selegiline as a neuroprotective agent inParkinson’s disease. Mov Disord Suppl 13: 55-58.

Peschanski M, Defer GL, Dethy S, Hantraye PM,Levivier M, Nguyen JP, Cesaro P. 1999. Theneed for phase III studies in experimental surgicaltreatments of Parkinson’s disease. Adv Neurol 80"651-653.

Piccini P, Bum DJ, Ceravolo R, Maraganore D,Brooks DJ. 1999. The role of inheritance insporadic Parkinson’s disease: Evidence from alongitudinal study of dopaminergic function intwins. Ann Neuro145: 577-582.

Portman AT, Giladi N, Leenders KL, Maguire P,Veenma-Van Der Duin L, Swart J, et al. 2001.The nigrostriatal dopaminergic system in familialearly onset parkinsonism with parkin mutations.Neurology 56:1759-1762.

Raz A, Frechter-Mazar V, Feingold A, Abeles M,Vaadia E, Bergman H. 2001. Activity of pallidaland striatal tonically active neurons is correlatedin mptp-treated monkeys but not in normalmonkeys. J Neurosci 21" RC128.

Tanner CM, Ottman R, Goldman SM, Ellenberg J,Chan P, Mayeux R, et al. Parkinson’s disease intwins: An etiologic study. J Am Med Assoc 1999.281: 341-346.

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