Functional imaging in relation to parkinsonian syndromes

Journal of the Neurological Sciences, 1l 5 (1993) 1-17 ~,;) 1993 Elsevier Science Publishers B.V. All rights reserved 0022-510X/93/$06.00

1

JNS 03942

Opinion and Review

Functional imaging in relation to parkinsonian syndromes David J. Brooks MRC Cyclotron Unit, Hammersmith Hospital, London, UK (Received 18 February, 1992) (Revision received 14 September, 1992) (Accepted 28 September. 1992)

Key words: Positron

emission tomography; Single photon emission tomography; Parkinson's disease; Activation; Metabolism: Receptors; Dopamine; Blood flow

Summary Parkinsonism is a feature not only of Parkinson's disease but also of many other diseases affecting basal ganglia function. Functional imaging (PET and SPECT) can demonstrate the various resting patterns of disruption of regional cerebral blood flow, metabolism, and neuropharmacology associated with different parkinsonian disorders. ~SF-dopa PET also has the potential to detect subclinical dysfunction of dopaminergic terminals in at-risk subjects. Finally, functional imaging can help us understand the nature of the networks involved in performing different motor tasks, and can reveal how these networks malfunction in the presence of bradykinesia or parkinsonian tremor.

Introduction Parkinsonism is characterised by slowness of movement (bradykinesia), rigidity that is constant throughout a full range of passive movement, and tremor. It can occur in association with nigral, striatal, and pallidal degeneration. As a consequence parkinsonism is a feature not only of Parkinson's disease (PD) but also of other degenerative, hereditary, and infective causes of basal ganglia dysfunction (see Table 1). Additionally, treatment with dopamine receptor antagonists (neuroleptics, vestibular sedatives, anti-emetics) can result in an akinetic-rigid syndrome. Functional imaging with either positron or single photon emission tomography can be used to demonstrate in vivo the regional changes in cerebral function associated with different parkinsonian disorders. Changes in neurotransmitter systems can be studied both in affected and at-risk subjects. To date, the dopaminergic system has been most extensively examined." The effect of basal ganglia degeneration on cortical metabolism and blood flow can also be investigated; patients can be scanned either at rest or while performing activating paradigms. If involuntary movements,

Correspondence to: Dr. D.J. Brooks, MRC Cyclotron Unit, Hammersmith Hospital, Du Cane Road, London WI2 0HS, UK,

such as parkinsonian tremor, are present, the abnormal cerebral activity associated with such movements can be detected. Positron emission tomography (PET) measurements are obtained by administering a tracer labelled with short-[Ned positron-emitting isotope (Phelps et al. 1982). These isotopes are usually generated by a cyclotron; examples include 150 (tl/, 2.03 rain), ~C (t~/2 20.4 rain), lSF (tl/2 110 min), and %Br (tl/2 16 h). The subject is scanned and tomographic maps of regional cerebral tracer uptake are generated. By comparing regional cerebral and arterial plasma activity of suitable tracers it is possible to determine regional cerebral blood flow, metabolism, dopa decarboxylase and monoamine oxidase activities, and receptor densities. Table 2 details some of the PET tracers in current use. State of the art P E T cameras can now provide a reconstructed resolution of 3 - 5 mm and have 3D reconstruction capabilities. Single photon emission tomography (SPECT) tracers are generally ~'~lTc or t2~l based and are longer lived than P E T tracers. They have the advantage that there is no need for an on-site cyclotron or chemistry facilities for their production. This makes SPECT cheaper and more available than PET. The disadvantages of S P E C T compared to P E T are that at present it is less versatile and there is no way of correcting for radiation scatter or directly measuring tissue attenua-

"3

TABLE 1 CONDITIONS ASSOCIATED WITH PARKINSONISM

(a) Subcortical degenerations

(b) Hereditary disorders

(c) Toxins

(d) Infective (e) Vascular

Condition

Pathological hallmark

Parkinson's disease (PD) Diffuse Lewy body disease (DLBD) Multiple system atrophy (MSA) Striatonigral degeneration (SND) Progressive supranuclear palsy (PSP) PD-ALS-dementia complex Progressive subcortical gliosis (PSG) Corticobasal degeneration (CBD) Hallevorden-Spatz syndrome (HVS) Primary pallidal atrophy Alzheimer's disease (AD) Huntington's disease (Westphal) Wilson's disease Dopa-rcsponsive dystonia Machado-Joseph disease manganese oxide MPTP (1-methyl-4-phenyltetrahydropyridine) carbon monoxide Encephalitis lethargica Creutzfelfdt-Jakob disease Cerebrovascular disease

Lewy bodies

tion of emitted radiation. As a consequence, the majority of SPECT studies are semi-quantitative. State of the art SPECT cameras with detector rings provide a reconstructed resolution of around 5 mm but rotating gamma cameras have lower resolution.

Parkinson's disease Parkinson's disease (PD) has a lifetime incidence of 2.5% (Kurland 1958) and is the most common of the neurodegenerative disorders that result in an akineticrigid syndrome. Pathologically it is characterised by

Glial inclusions Neurofibrillary tangles Neuronal achromasia Axonal spheroids Plaques, tangles Cystic degeneration

Neurofibrillary tangles Spongiform degeneration Lacunes

degeneration of dopaminergic cells in the substantia nigra compacta and midbrain tegmentum with the formation of intraneuronal eosinophilic inclusions (Lewy bodies) (Bethlem and Den Hartog Jager 1960; Jellinger 1986; Halliday et al. 1990). Nigro-striatal dopaminergic neurones are not uniformly affected in PD; greatest cell loss occurs in the less pigmented ventrolateral tier of the substantia nigra which sends projections t o posterior putamen (Fearnley and Lees 1991; German et al. 1989; Rinne et al. 1989; Mushiake et al. 1990). Although PD is generally regarded as a subcortical degeneration, in one series all patients were found to have occasional cortical Lewy bodies (Hughes et al. 1992).

TABLE 2 PET AND SPECT TRACERS IN CURRENT USE FOR STUDYING PARKINSONIAN SYNDROMES Biological application

Tracer

Blood flow Oxygen metabolism Glucose metabolism Dopa metabolism Dopamine reuptake sites Dopamine Dl-type sites Dopamine De-type sites

c I S o 2 , H21So, 99mTc-HMPAO

Monoamine oxidase B Opiate p~, r, ~ sites

~50 2 2-[ is F]Fluoro-2-deoxyglucose (Is FDG) 6-[ 18F]Fluorodopa ([lSF]dopa) [11C]Nomifensine ([ 11C]NMF) [11C]SCH 23390 [ I l C]Raclopride (RAC) [123I]Iodobenzamide (IBZM) [ 1t C]Methylspiperone (MSP) [lSF]Fluoroethylspiperone (FESP) [ 76Br]Bromospiperone (BSP) [ 11C]Deprenyl [11C]Diprenorphine

The pre-synaptic dopaminergic system

PET methodology The functional integrity of nigro-striatal dopaminergic terminals can be studied using 6-[18F]fluorodopa whose specific uptake reflects the activity of striatal aromatic amino acid decarboxylase (AADC) activity (Firnau et al. 1987; Melega et al. 1990). When given intravenously, lSF-dopa is transported across the blood-brain barrier by the large neutral amino acid carrier (Leenders et al. 1986d) and then decarboxylated to ~8F-dopamine in the striatum (Firnau et al. 1987; Melega et al. 1990). Striatal ~SF-dopamine is then metabolised to ~8F-dihydroxyphenylacetic acid (DOPAC) and 18F-homovanillic acid (HVA) by monoamine oxidase B (MAOB) and catechol-O-methyl transferase (COMT). There is a body of evidence suggesting that the striatum handles 18F-dopamine similarly to endogenous dopamine. Depletion of dopamine vesicles with reserpine, and inhibition of striatal AADC with NSD 1015, reduces striatal 18F-dopa and [llC]dopa storage (Firnau et al. 1976; Garnett et al. 1978; Tedroff et al. 1992). Pretreatment with an MAOB inhibitor, to block dopamine metabolism to dopac, increases striatal 18Fdopa retention (Garnett et al. 1983). The nigral poison MPTP renders monkeys parkinsonian and causes a parallel fall in striatal dopamine levels and 18F-dopa uptake (Chieuh et al. 1986). Because of its peripheral and central metabolism, modelling striatal uptake of lSF-dopa has proved a complex problem. Multiple compartment models have been designed to describe the metabolic fates of this tracer but, unless a number of assumptions are incorporated, these tend to generate values for individual rate constants that have high standard errors on their estimations (Huang et al. 1991; Kuwabara et al. 1993). A simpler modelling approach makes use of the fact that although 18F-dopa is metabolised to 18F-dopamine, 18F-dopac, and ~SF-HVA, these metabolites remain in the striatum during the 2 h of scanning. As a consequence, specific striatal lSF uptake can be regarded as being irreversible and can be described in terms of a single influx constant, K i (Patlak and Biasberg 1985; Martin et al. 1989). This influx constant represents the product of the volume of distribution of free ~8F dopa in the striatum and a rate constant describing its subsequent metabolism. Striatal 18F-dopa g i values provide information about the ability of the nigro-striatal dopaminergic terminals to store and decarboxylate exogenous dopa. They do not reflect the ability of these terminals to generate endogenous dopamine from tyrosine. Individual striatal K i values can be measured for normal subjects with a standard error of around 10%; serial

striatal ~SF-dopa K i measurements show a 5% variation (Sawle et al. 1992a). [11C]Nomifensine is a reversible dopamine and noradrenaline reuptake site inhibitor. Like ~8F-dopa, its uptake provides a measure of the functional integrity of nigro-striatal terminals (Salmon et al. 1990) and MPTP lesioned primates show reduced striatal uptake of this tracer (Leenders et al. 1988a). Striatal uptake of [l~C]nomifensine has been modelled using both twoand three-compartmental approaches (Salmon et al. 1990; Tedroff et al. 1990).

PE T findings The initial reports on striatal 18F-dopa uptake in PD by Garnett et al. (1984) and Nahmias et al. (1985) concerned hemiparkinsonian subjects early into their disease. Normal caudate, but bilaterally reduced putamen, 18F-dopa uptake was observed, activity being most depressed in the putamen contralateral to the affected limbs. These studies were the first to demonstrate the selectivity of the nigral pathology for putamen projections in PD, and the first to reveal subclinical involvement of dopaminergic terminals in the ipsilateral putamen. The authors noted that reductions in putamen ~8F-dopa uptake were of a similar magnitude irrespective of whether patients had tremor or akinetic-rigid predominant PD. Other workers subsequently confirmed the above observations and went on to demonstrate that striatal 18F dopa uptake in PD falls with increasing disability (Leenders et al. 1986b, c; Brooks et al. 1990a; Martin et al. 1986; Otsuka et al. 1991). Patients with early disease and a sustained response to L-dopa therapy retain striatal 18F-dopa more effectively than those with long standing disease and a fluctuating response to therapy. On average, putamen ~8F-dopa K i values are reduced to 50%, and caudate values to 80%, of normal in PD (Brooks et al. 1990a). A 50% reduction in putamen 18F-dopa uptake is comparable with the 60% reduction in striatal dopa decarboxylase activity and 50-80% fall in nigra compacta cell counts reported at post-mortem in PD (German et al. 1989; Goto et al. 1989; Rinne et al. 1989; Nagatsu et al. 1979), but considerably less than the 90% reduction observed in putamen dopamine content (Bernheimer et al. 1973). This serves to emphasise that striatal 18F-dopa uptake does not provide a measure of endogenous dopamine levels, but reflects the ability of the striatum to decarboxylate exogenous dopa. Mean putamen uptake of [HC]nomifensine is also reduced by 50% in PD while caudate uptake of the tracer is less affected. Striatal uptake of [l~C]nomifensine and ~8F-dopa are highly correlated in PD patients (Leenders et al. 1990; Salmon et al. 1990; Tedroff et al. 1990) and putamen [llC]nomifensine binding falls with increasing disability. These findings suggest that mea-

sures of striatal dopamine reuptake site density and dopa decarboxylase activity can be used interchangeably to monitor dopamine terminal functional integrity in PD.

The post-synaptic dopaminergic system At least five different sub-types of dopamine receptors have now been described; broadly they fall into D 1 type (D1, D 5) which are adenyl cyclase dependent, and D2-type (D 2, D 3, D 4) which are not. The striatum contains D1 and D 2 receptors and these are present in equal density. D 1 receptors are expressed by intrinsic striatal neurones that project to internal pallidum and substantia nigra, while D 2 receptors are found on neurones projecting to external pallidum, and on terminals of nigrostriatal and corticostriatal fibres (Smith and Bolam 1990). The cerebellum contains few D 1 or D 2 sites and so cerebellar uptake of dopamine receptor tracers is often assumed to reflect their non-specific signal in the striatum. Table 2 shows that there are a n u m b e r of suitable P E T tracers for studying striatal D 2 receptor density. These tracers are antagonists which bind irreversibly ([11C]methylspiperone, [t8F]fluoroethylspiperone) or reversibly ([11C]raclopride, [123I]IBZM, [76Br]bromospiperone). The advantage of using reversible antagonists as tracers is that equilibrium striatal:cerebellar uptake ratios can be measured which directly reflect receptor binding potential, that is receptor density ( B m ~ ) / a f f i n i t y ( K d) (Salmon et al. 1990). Their affinity for D2 sites, however, is weaker than that of irre-

versibly bound antagonists, and their uptake may be influenced by changes in occupancy of D 2 sites by endogenous dopamine. Table 3 summarises the findings of seven functional imaging studies on striatal D 2 site status in untreated PD. Putamen D 2 binding potential ranges from normal to moderately upregulated; caudate D 2 binding potential is consistently normal. W h e r e side to side striatal [llC]raclopride uptake has been compared, tracer uptake has been 11-14% greater in the putamen contralateral to the more affected limbs. It is likely that raised putamen D 2 binding potential in untreated PD, when present, represents an adaptive response to loss of nigro-putamen dopaminergic afferents. This is supported by the finding that putamen [ltC]raclopride binding correlates inversely with 18F-dopa uptake in untreated PD patients (Sawle et al. 1990a). Animal studies also support this view: Leenders et al. (1988a) reported a 50% increase in striatal [llC]raclopride binding in a primate 9 days after it was lesioned with M P T P while Fuxe et al. (1981) found that rat striatal N-propylapomorphine (NPA) site density increased by 50% 2 months after lesioning the nigra with 6-hydroxydopamine. Interestingly, striatal D e site density subsequently normalised over the course of a year in both these studies (Tedroff 1990; Fuxe et al. 1981). Functional imaging studies on treated PD patients have reported normal or moderately reduced levels of striatal D 2 binding potential (see Table 3). Patients who have only received levodopa for a few months have normal striatal [11C]raclopride uptake (Leenders et al. 1992) but long standing PD cases, who have

TABLE 3 STRIATAL D 2 SITE STATUS IN PD Report (a) Untreatedpatients Leenders et al. 1985 Briicke et al. 1991 Schwarz et al. 1992 Brooks et al. 1992a

Tracer

Finding

[llC]MSP [123I]IBZM

Leenders et al. 1992

[1t C]RAC

Rinne et al. 1990b Sawle et al. 1990a

[nC]RAC [11C]RAC

Striatal uptake normal Striatal uptake normal Striatal uptake normal Putamen uptake up 11% Caudate uptake normal Putamen uptake up 20% Caudate uptake normal CL 11% > IP putamen CL 14% > IP putamen

(b) Treatedpatients Leenders et ai. 1985 Hagglund et al. 1987 Shinotoh et al. 1990 Wienhard et al. 1990 Leenders et al. 1992 Brooks et al. 1992a Briicke et al. 1991

[11C]RAC

[uC]MSP [ISF]FESP [11C]RAC [123I]IBZM

CL, contralateral to affected limbs; IP, ipsilateral to affected limbs.

Striatal uptake down 20% Striatal uptake normal Striatal uptake normal Caudate uptake down 18% Putamen uptake normal Caudate and putamen uptake down 30% Striatal uptake down 17%

developed a fluctuating response to therapy, show up to a 40% fall in striatal [11C]raclopride binding (Brooks et al. 1992a). It remains unclear whether loss of striatal D 2 sites in treated PD cases, when present, is a consequence of the disease itself or of prolonged treatment with dopaminergic agents. Animal studies suggest that chronic exposure to both c-dopa and dopamine agonists can result in down-regulation of striatal D e sites (Fuxe et al. 1981; Mishra et al. 1978). Longitudinal studies are currently in progress to try to answer this question. The above functional imaging findings on striatal D 2 receptor status in PD are broadly in agreement with pathological reports. In untreated PD three postmortem studies have reported upregulation of putamen D 2 sites (Guttman and Seeman 1985; Lee et al. 1978; Rinne 1991) while three other studies noted normal levels (Bokobza et al. 1984; Cortes et al. 1989; Quik et al. 1979). Treated PD patients have been variously reported to have normal (Bokobza et al. 1984; Guttman and Seeman, 1985) and reduced levels of striatal D 2 receptors (Quik et al. 1979; Lee et al. 1978; Reisene et al. 1977). Only one pathological study to date has classified PD patients in terms of their treatment response: Rinne et al. (1981) found that sustained responders had normal, and fluctuating responders decreased, numbers of striatal D 2 receptors. To date, there has only been one P E T report on striatal D 1 receptor binding potential in PD (Rinne et al. 1990a). [~C]SCH 23390 is a reversibly bound D 1 receptor antagonist and untreated hemiparkinsonian patients, later shown to be levodopa responsive, showed no side-to-side difference in striatal:cerebellar [11C] SCH 23390 uptake ratios. This contrasted with their [llC]raclopride uptake which was increased in the putamen contralateral to the affected limbs. The authors concluded that, unlike D 2 sites, there is no compensatory upregulation of striatal D 1 sites in untreated PD. This conclusion is in line with the majority of pathological studies which have reported normal striatal D~ site densities in both treated and untreated PD patients (Pierot et al. 1988; Cortes et al. 1989; Cash et al. 1987; Pimoule et al. 1985; Raisman et al. 1985). Metabofic and actiL,ation studies

P E T measurements of regional cerebral oxygen and glucose metabolism with the tracers 150 2 and ISFDG, respectively, primarily reflect the metabolism of synaptic vesicles in nerve terminals. Levels of basal ganglia metabolism, therefore, reflect the activity of afferent projections to these nuclei, and interneurones, rather than efferent activity of striato-pallidal projections. Autoradiographic 2-[laC]deoxyglucose studies have shown that unilateral destruction of the substantia nigra compacta in primates results in a selective increase in

external pallidal glucose utilisation (Crossman 1990). Striato-pallidal projections are gabaminergic and inhibitory in action. Increased external pallidal metabolism following nigral destruction suggests that nigro-striatal dopaminergic projections normally act to inhibit striato-external pallidal fibres. 150 2 and lSFDG P E T studies on PD patients with early, asymmetrical disease have reported relatively increased oxygen and glucose metabolism in the lentiform nucleus contralateral to the more affected limbs (Miletich et al. 1988; Wolfson et al. 1985). It is likely that this increased lentiform metabolism represents raised external pallidal activity. PD patients with more long-standing, bilateral disease have normal levels of striatal metabolism (Wolfson et al. 1985; Kuhl et al. 1984a; Otsuka et al. 1991) suggesting that any initial increase reverses as the disease progresses. Non-demented PD patients have normal or mildly reduced cortical metabolism, prefrontal cortex being most affected (Wolfson et al. 1985; Kuhl et al. 1984a; Otsuka et al. 1991). Levels of cortical glucose utilisation correlate with cognitive performance (Peppard et al. 1988; Kuhl et al. 1984b). Frankly demented PD patients show the typical metabolic appearances of Alzheimer's disease, parietal and frontal association areas severely underfunctioning while striatal, primary motor cortex, and primary visual cortex metabolism is preserved (Kuhl et al. 1985). Dementia in PD is thought to be associated with either the presence of cortical Lewy body disease or coincident Alzheimer pathology. Only one demented PD patient to date has had pathological and lSFDG P E T findings correlated (Schapiro et al. 1990). This patient showed bilateral hypometabolism of parietal association areas but no Alzheimer pathology or cortical Lewy bodies were found at post-mortem. The basis of the cortical association area hypometabolism in demented PD patients, therefore, remains unclear. It is unlikely to arise from loss of cholinergic projections as lesions of the nucleus basalis of Meynert in primates have been shown to result in short-lived diffuse cortical hypofunction (Kiyosawa et al. 1989). While non-demented PD patients generally have normal levels of striatal and cortical metabolism under resting conditions, they do not activate these structures appropriately. With P E T it can be shown that when normal subjects perform repetitive forward movements of a joystick there are associated increases in contralateral regional cerebral blood flow (rCBF) in the lentiform nucleus and sensorimotor cortex (SMC), and bilateral rCBF increases in the anterior cingulate area (ACA), supplementary motor area (SMA), and lateral premotor cortex (PMC) (Playford et al. 1992). If normal subjects are allowed to freely select the direction of joystick movement there is additional, more anterior, activation of ACA, SMA, PMC, and parietal

association areas, and activation of right dorsolateral prefrontal cortex (DLPFC). When PD patients perform the same stereotyped and freely selected joystick tasks they show impaired activation of the contralateral lentiform nucleus, anterior cingulate, SMA, and right DLPFC, that is those frontal areas that receive their main input from the basal ganglia. It is thought that the supplementary motor area and dorsolateral prefrontal cortex play a crucial role in generating volitional motor programmes while lateral premotor cortex is responsible for generating motor responses to external cues (Thaler and Passingham, 1989; Goldberg 1985; Mushiake et al. 1990; GoldmanRakic 1987). Impaired ability to activate SMA and DLPFC in PD could, therefore, explain the difficulty these patients experience in initiating volitional motor actions while remaining able to respond to visual cues. Recently, Jenkins et al. (1992) have demonstrated that when apomorphine, a combined D~ and D 2 agonist, is given subcutaneously to PD patients resolution of their bradykinesia is associated with a significant increase in SMA blood flow. This study provides further evidence that the SMA has a role in the generation of volitional movement. Similar findings have been obtained measuring rCBF with 133Xe SPECT (Rascol et al. 1992). In an elegant study Parker et al. (1992) have recently reported PET rCBF findings in seven patients with levodopa-resistant unilateral parkinsonian rest tremor. These patients had an electrode stereotactically placed in the contralateral ventral intermediate nucleus (Vim) of the thalamus. Electrical stimulation abolished the tremor and led to an associated bilateral fall in cerebellar, and ipsilateral fall in motor cortex, blood flow. In patients without tremor electrical stimulation was reported to have no effect on cerebellar function. These findings suggest that parkinsonian rest tremor is associated with cerebellar overactivity and that loss of dopaminergic fibres may lead to disinhibition of cerebello-thalamo-cortical connections.

Detection of preclinical Parkinson's disease At autopsy around 5-6% of normal subjects aged 40 or over have incidental Lewy bodies in their substantia nigra although only 0.3-0.4% of this population manifest clinical PD (Golbe 1990). Incidental Lewy body disease, like PD, targets the less pigmented ventrolateral tier of the substantia nigra (Fearnley and Lees 1991). It has, therefore, been suggested that incidental Lewy body disease represents preclinical PD, the onset of parkinsonian symptoms correlating with a 50% loss of pigmented nigral ceils and an 80% loss of dopamine from the putamen (German et al. 1989; Rinne et al. 1989; Bernheimer et al. 1973). Based on the above

figures it has been estimated that for every patient with overt PD there are 14 subjects in the community with preclinical disease (Golbe 1990). A recent PET series found that putamen 18F-dopa uptake was reduced by at least 35% below the normal mean in PD patients with early disease (Brooks et al. 1990a); lSF-dopa PET, therefore, provides a potential means of detecting sub-clinical nigral dysfunction in at-risk subjects. Calne et al. (1985) were the first to explore this potential, examining four asymptomatic subjects who had been exposed to the nigral toxin MPTP. These workers were able to demonstrate reduced striatal lSF-dopa uptake in two of these four subjects.

Family studies Relatives of PD patients may be at risk for the disease. Three kindreds with familial parkinsonism and nigral Lewy body disease have now been reported (Duvoisin 1991). Mj6nes (1949) was the first to suggest that PD might be a familial condition. He examined nine Swedish kindreds and concluded that PD was dominantly inherited with a 60% penetrance. His conclusions have been criticised, however, as he considered cases with isolated dementia or tremor as being affected. We now know, however, that diffuse Lewy body disease can present as isolated dementia (Byrne et al. 1989). Two kindreds with L-dopa responsive parkinsonism have been studied with ~SF-dopa PET, In the first kindred two brothers were affected, rigidity and tremor starting in the third decade (Mark et al. 1992). One of the two affected males became demented and died, aged 33, and a t autopsy diffuse Lewy body disease was present. The other affected male, aged 35, is cognitively intact. His PET scan showed reduced striatal ~8F-dopa uptake in the typical pattern of sporadic PD, putamen being more affected than caudate. Their three asymptomatic female siblings, aged 27-36 years, were also studied. The 36 year old showed subnormal putamen ~SF-dopa uptake, while the other two sisters had putamen tracer uptake in the normal range. The second pedigree consisted of ten Irish siblings, four of whom were clinically affected at the time of PET (Sawle et al. 1992b). Parkinsonism developed between the ages of 31 and 39 and the affected siblings (three male, one female) all showed severely reduced striatal 18F-dopa uptake, putamen uptake being more affected than caudate. Two asymptomatic siblings, aged 38 and 47, were scanned and both had reduced putamen lSF-dopa uptake. Six months after PET the 38year-old asymptomatic male sibling began to complain of inner tremulousness of his legs and on examination had bradykinetic left finger movements, The other asymptomatic sibling who was studied remains well.

The findings in these two pedigrees confirm that PET is capable of detecting subclinical nigral dysfunction in at-risk subjects, and that the pattern of reduced striatal 18F-dopa uptake in familial PD mirrors that of the sporadic disease, putamen being more affected than caudate. To date, however, not enough relatives have been PET scanned to determine the full extent of subclinical familial PD.

Twin studies Clinical surveys of the prevalence of PD in co-twins of affected patients have reported similar, low, 2-12% concordances in both monozygotic (MZ) and dizygotic (DZ) twin pairs (Johnson et al. 1990). If, as has been calculated, only one out of every 15 subjects who have nigral Lewy body disease actually manifests overt PD, clinical surveys are capable of missing a large number of affected co-twins. In order to determine whether the level of concordance for nigral dysfunction in PD twin pairs is higher than the level of clinical concordance Burn et al. (1992a) performed 18F-dopa PET on 16 asymptomatic co-twins of PD patients and one clinically concordant twin pair. Four out of ten asymptomatic monozygotic (MZ), and two out of seven asymptomatic dizygotic (DZ), co-twins had putamen tracer uptake reduced more than 2 SD below the normal mean. Interestingly, three of the four MZ co-twins with reduced putamen ISF-dopa uptake had isolated tremor (postural in two cases and resting in one case) which they had failed to notice. One of these co-twins has subsequently become akinetic over 3 years of follow-up. The concordance levels for nigral dysfunction in co-twins (36% MZ, 29% DZ at a 2 SD threshold), determined by ~SF-dopa PET, are far higher than the 2-12% concordance levels for PD reported by clinical surveys. The correlation of reduced putamen tracer uptake with the presence of isolated tremor in co-twins suggests that Mj6nes (1949) may well have been correct in considering postural and rest tremor as forme frustes of PD in his original familial survey. At present the numbers of co-twins that have had ~8F-dopa PET are too small to establish whether the concordances for nigral dysfunction in MZ and DZ co-twins are significantly different.

Drug-induced parkinsonism It has been suggested that patients who develop severe akinetic-rigid syndromes while taking conventional doses of dopamine receptor antagonists, such as neuroleptics and vestibular sedatives, may be having subclinical nigral pathology unmasked by dopamine receptor blockade. Nigral Lewy bodies were found at

post-mortem in two patients with drug-induced parkinsonism (DIP) (Rajput et al. 1982). Burn and Brooks (1992) performed [18F]dopa PET on 13 DIP patients suspected by their referring clinicians of having underlying Parkinson's disease. The drugs were subsequently stopped and patient recovery monitored over 2 years. Four out of the 13 DIP patients had reduced putamen 18F-dopa uptake. Three of these four deteriorated in spite of cessation of their dopamine blocking agents while one improved. Eight out of the nine DIP patients with normal levels of striatal 18F-dopa uptake significantly improved off dopamine antagonists; the ninth died before reassessment was possible. These authors concluded that the majority of patients with drug-induced parkinsonism had intact striatal dopaminergic terminal function; their parkinsonism probably reflected high levels of dopamine receptor blockade. Recovery from DIP correlated well with normal striatal lSF-dopa uptake but abnormal uptake did not necessarily indicate a poor prognosis. In summary, tSF-dopa PET is capable of detecting striatal dopaminergic terminal dysfunction in asymptomatic at-risk relatives of patients with familial PD, and in patients who become severely parkinsonian on conventional doses of dopamine receptor antagonists. The sensitivity of ~8F-dopa PET for detecting subclinical PD, however, has yet to be established.

Tremor and dopaminergic function

The relationship between isolated tremor and PD is unclear. Patients occasionally present with a 3-5 Hz rest tremor, indistinguishable from that seen in PD, but without significant bradykinesia or rigidity. There have been no pathological reports on such cases, and it is uncertain whether they represent a forme fruste of PD or some alternative condition. PD may also present as an isolated 4-9 Hz postural tremor of the arms, indistinguishable from essential tremor (ET), rigidity and bradykinesia only becoming evident some years later (Lance et al. 1963; Findley et al. 1981; Jankovic and Frost, 1981). This has led to the suggestion that there is an association between ET and PD. Clinical surveys on this question have produced conflicting resuits; some have reported no relationship (Cleeves et al. 1988) while others have found an increased incidence of PD in ET patients (Geraghty et al. 1985). Fourteen ET cases have come to autopsy to date. These have all shown non-specific histopathological changes, arguing against an association between ET and PD (Rajput et al. 1991a). lSF-dopa PET allows us to assess the integrity of the presynaptic dopaminergic system in tremor patients. Brooks et al. (1992b) measured striatal ~8F-dopa up-

take in 11 patients with isolated 3-5 Hz rest tremor. Four of these cases had cogwheel rigidity on synkinesis but none had evidence of bradykinesia. All 11 rest tremor patients had significantly reduced putamen 18F-dopa uptake contralateral to their more affected limbs. Mean putamen and caudate tracer uptake for the group was reduced to 50% and 80% of normal, a similar pattern of reduction to that seen in sporadic PD. In spite of this, under half of these patients showed a good response of their tremor to L-dopa. Seven of the 11 patients had focal or hemi limb tremor but showed evidence of subclinically reduced putamen 18F-dopa uptake ipsilateral to the affected limbs. The authors concluded that isolated rest tremor represents a phenotypic variant of PD. Brooks et al. (1992b) also studied eight patients with familial ET. Putamen and caudate lSF-dopa uptake were within the normal range in all cases, arguing against an association between ET and PD. Twelve patients with sporadic ET also had ~SF-dopa PET. Putamen 18F-dopa uptake was normal in ten, but reduced in two of these patients, one falling in the PD range. His postural arm tremor had been present for 2 years and over the following 18 months he developed frank PD with bradykinesia, cogwheel rigidity, and rest tremor. The authors concluded that while there was no evidence for an association between familial ET and PD, isolated postural tremor could on occasion be associated with nigral dysfunction. Past clinical surveys of the prevalence of familial PD may have been wrong to consider relatives with isolated tremor as unaffected, Subtle signs of parkinsonism in isolated tremor cases, such as the presence of low amplitude breakthrough rest tremor, reduced arm swing on walking, and the presence of sustained cogwheel rigidity on synkinesis, proved to be unreliable predictors of the presence of nigral dysfunction.

Parkinson-plus syndromes PD is usually diagnosed when a patient has bradykinesia, muscular rigidity, a n d / o r a 3-5 Hz rest tremor, and these features show a good response to levodopa. Recent pathological series have shown, however, that around 20% of patients diagnosed as having PD on these criteria prove to have other conditions (Hughes et .al. 1992; Rajput et al. 1991b; Fearnley and Lees 1990). The most common alternative pathologies are striatonigral degeneration (SND), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), and cerebrovascular disease (see Table 1). In this section functional imaging findings in some of the conditions associated with atypical parkinsonian syndromes are reviewed.

Multiple system atrophy (MSA) MSA, occasionally known as Shy-Drager syndrome, is characterised clinically by a poorly L-dopa responsive akinetic-rigid syndrome in association with autonomic failure and cerebellar ataxia. Its pathology is distinct from PD, neuronal loss occurring in caudate and putamen, globus pallidus (external more than internal), pigmented brainstem nuclei - in particular the substantia nigra, cerebeUar Purkinje cells, olives, and intermediolateral columns of the spinal cord, in the presence of neuronal and glial argyrophilic inclusion bodies (Spokes et al. 1979; Kobayashi et al. 1992). MSA, therefore, includes striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and pure autonomic failure (PAF) in its clinical spectrum.

Pre-synaptic dopaminergicfunction While nigral degeneration is a feature of both PD and MSA, the nigra tends to be more extensively involved in MSA (Goto et al. 1989; Fearnley and Lees, 1990). The ventrolateral nigral dopaminergic projections to putamen are targeted in both these conditions but there is greater involvement of the dorsomedial nigral tier in MSA. One might, therefore, predict that dopamine terminal function in the caudate would be more affected in MSA than PD. Brooks et al. (1990b) compared caudate and putamen uptake of both lSFdopa and the dopamine reuptake site inhibitor [nC]nomifensine in ten patients with MSA and eight equally disabled patients with probable PD. Mean putamen lSF-dopa uptake was reduced to a similar levels in the MSA and PD patients (41%/38% of normal) but mean caudate tracer uptake was significantly lower in MSA ( 5 6 % / 7 3 % of normal). [llC]Nomifensine gave similar findings. The putamen ~SF-dopa uptake of MSA patients fell with increasing locomotor disability and disease duration. Otsuka et al. (1991) compared striatal 18F-dopa uptake in six patients with poorly levodopa responsive parkinsonism, presumed to have striatonigral degeneration, with that of eight patients with PD. Again, putamen lSF-dopa was equally depressed in SND and PD but caudate tracer uptake was relatively spared in PD. While there is differential involvement of caudate dopaminergic terminal function in MSA and PD, individual ranges of caudate lSF-dopa uptake overlap in these conditions. This means, in practice, that [18F]dopa PET cannot consistently distinguish MSA from PD. Performing discriminant analysis on putamen and caudate ~SF-dopa influx constants led to correct assignment of patients to MSA as opposed to PD categories 70% of the time (D.J. Burns and D.J. Brooks, unpublished observations). Patients showing a similar depression in caudate and putamen tracer uptake invariably had MSA.

Striatal function Striatal degeneration is a feature of MSA, but not PD, and so functional imaging should be able to discriminate these conditions by demonstrating reduced striatal function in MSA. De Voider et al. 1989 have studied regional cerebral glucose utilisation (rCMRGIc) with 18FDG in seven cases of probable SND. Five had isolated levodopa-resistant parkinsonism, while two had additional autonomic failure and cerebellar ataxia and so had the full spectrum of MSA. The seven SND patients showed mean 46% and 36% reductions in putamen and caudate glucose utilisation, respectively. This contrasts with PD where striatal metabolism has been reported to be normal or raised (Miletich et al. 1988; Wolfson et al. 1985; Kuhl et al. 1984a; Otsuka et al. 1991). Cortical glucose utilisation was decreased by 20% SND, frontal cortex being most affected. Cerebellar metabolism was reduced in the two MSA, but not the other five SND patients. Two PET studies have examined striatal dopamine D 2 receptor binding potential in SND. Brooks et al. (1992a) performed [11C]raclopride PET on ten patients with L-dopa resistant parkinsonism. They found significant mean 10% and 11% reductions in equilibrium caudate and putamen : cerebellum tracer uptake ratios, respectively, compatible with a mean 15% loss of striatal D 2 sites. Only two of these ten SND patients, however, had significantly reduced striatal [HC]raclopride uptake. Shinotoh et al. (1990) have reported reduced levels of striatal [IIC]MSP binding in four SND cases, though individual levels of tracer uptake remained within the low normal range. [11C]MSP binding was lowest in posterior putamen. Using IBZM SPECT, Schwarz et al. (1992) studied striatal D e binding potential in de novo parkinsonian patients, subseqently categorised as apomorphine responsive and non-responsive. All 18 apomorphine responsive cases had normal levels of striatal IBZM binding. Twelve patients had a negative apomorphine response; eight of these had reduced and four normal striatal IBZM uptake. There are few pathological data on SND to compare with functional imaging findings. Quik et al. 1979 have reported a mean 26% loss of caudate O 2 receptors in four SND patients, while Cortes et al. 1989 found 40% and 25% losses of caudate and putamen O 2 receptors, respectively, in five patients with 'parkinsonism'. In summary, functional imaging studies suggest that, in contrast to PD, striatal glucose metabolism is impaired in SND. Prospective studies are still required, however, to determine the specificity of this finding. Striatal D 2 binding potential can be either normal or moderately reduced in SND. The resistance of SND patients to dopaminergic agents is, therefore, unlikely to be due to loss of striatal D 2 receptors alone, but probably reflects additional degeneration of pallidal or

brainstem projections. As striatal D 2 site density can be normal in both PD and SND its measurement is unlikely to provide a reliable means of discriminating these two conditions. A more discriminating tracer may prove to be [HC]diprenorphine, an opiate agonist that binds to /z, K, and ~ receptors. The striatum is rich in all three opiate receptors and preliminary studies suggest that striatal [HC]diprenorphine uptake is normal in PD, but usually reduced in SND (D.J. Burn and D.J. Brooks, unpublished observations).

The relationship between SND, OPCA and PAF As mentioned earlier in this section, striatonigral degeneration, olivopontocerebellar atrophy, and pure autonomic failure, all fall within the clinical spectrum of MSA. It remains unclear whether these conditions are simply part of a continuum or whether they exist as independent entities. At post-mortem, SND patients frequently show subclinical cerebellar, and OPCA patients subclinical striatonigral, degeneration (Adams et al. 1964; Berciano 1982). Those few PAF patients that have been autopsied have shown similar degeneration of the intermediolateral columns of the spinal cord to that found in MSA. Confusingly, Lewy bodies have also been reported in the substantia nigra and sympathetic ganglia raising the question of an overlap between PAF and PD (Vanderhaegen et al. 1970; Johnson et al. 1966). Fulham et al. (1991) examined 18FDG uptake in seven sporadic OPCA patients with autonomic failure. They found significantly reduced cerebellar and frontal, but normal striatal glucose utilisation. De Voider et al. (1989) noted normal levels of cerebellar glucose metabolism in their five SND cases without ataxia while Brooks (1992) has reported normal striatal FD uptake in three sporadic OPCA cases with autonomic failure. These three PET studies failed, therefore, to find evidence of subclinical multisystem involvement in their SND and OPCA cases suggesting that, on occasion, these conditions can exist independently. Normal levels of rCMRGlc and striatal 18F-dopa uptake have also been reported in PAF (Fulham et al. 1991; Brooks et al. 1990b) arguing against this condition being a forme fruste of MSA or PD.

Progressiue supranuclear palsy A number of neurodegenerative disorders are associated with supranuclear gaze problems including diffuse Lewy body disease, corticobasal degeneration, progressive subcortical gliosis, olivopontocerebellar atrophy, and Creutzfeldt-Jakob disease (Lees 1986). PSP is conventionally taken to refer to Steele-RichardsonOlszewski syndrome (Steele et al. 1964). Affected patients have associated rigidity and bradykinesia, axial dystonia, bulbar palsy, and dementia of frontal type. At

11 •r ~

C

~

,"

-.~

~

.-

-~

=

2:

-,

N~

.sz

"5

-=

",..n

~

©

,~

~

•-~ " ~

z

.,.

~5

e-,

:::3

Z

~,

"~

ez

=

r.,-~

E.

~

2 --=

=

~

±

,

~

F_

~

_~

'~ ~

~

.:

.:

~,.~

~

~

b-

~

[-"

[---

--

e,i

~

,4

-

post-mortem neuronal loss, with associated neurofibrillary tangle (NFT) inclusions and gliosis, is found in the basal ganglia, brainstem, and cerebellar nuclei. The cerebral and cerebellar cortices are usually spared but frontal lobe involvement may be present (De Bruin et al. 1992). In contrast to PD, where ventrolateral nigral dopaminergic projections to putamen are most affected, the nigra is uniformly involved in PSP resulting in similar reductions in caudate and putamen dopamine content (Jellinger et al. 1980; Fearnley and Lees 1991; Bokobza et al. 1984; Rubcrg et al. 1984; Kish et al. 1985). Leenders et al. (1988b) were the first to report reduced striatal ~SF-dopa uptake in PSP but the 1.7 cm resolution of the scanner used was unable to scpcrate caudate and putamen signals. With a higher resolution camera, Brooks et al. (1990a)were able to demonstrate similar reductions in putamen and caudatc ~SF-dopa uptake in PSP: a group of equivalently disabled PD patients showed a similar reduction in putamen tSFdopa uptake to the PSP group but significant sparing of caudate function. Individual ranges of PSP and PD caudate lSF-dopa influx constants overlap and so, as with MSA, I~F-dopa P E T cannot consistently distinguish PSP from PD. Performing discriminant analysis on putamen and caudate ~SF-dopa influx constants led to correct assignment of patients to PSP as opposed to PD categories 90% of the time (D.J. Burns and D.J. Brooks, unpublished observations). Levels of striata[ ISF-dopa uptake in PSP show no correlation with disability (Leenders et al. 1988b; Brooks et al. 1990a): indeed on occasion striatal ~SF-dopa uptake can be normal (Bhatt et al. 1991). This contrasts with PD and MSA, and suggests that it is primarily degeneration of pallidal and brain stem neurones rather than nigrostriatal dopaminergic projections that leads to impaired locomotor function in PSP. Like MSA, PSP is associated with striatal degeneration and so P E T should be able to discriminate this condition from PD by demonstrating reduced levels of striatal function. Table 4 summarises the findings of five different P E T studies on regional cerebral metabolism in PSP. All five found significant reductions of striatal, thalamic, cerebellar, and frontal metabolism, a similar pattern of hypofunction to that reported for MSA but distinct from that of PD where striatal and thalamic metabolism are preserved (De Voldcr et al. 1989; Kuh[ et al. 1984a). In the largest series (Blin et al. 1990a) cognitive function in PSP correlated with levels of cortical metabolism, and locomotor status with levels of caudatc and thalamie metabolism. Several P E T studies have examined the integrity of striatal D 2 receptors in PSP (see Table 4); moderate reductions in mean striatal binding of [Te'Br]bromospiperone (Baron et al. 1986), [lSF]fluoroethyl-

12 spiperone (Wienhard et al. 1990), and [llC]raclopride (Brooks et al. 1992a), have been reported. Two out of seven of Baron et al.'s L-dopa resistant PSP patients had normal striatal D 2 binding potential, as did four out of nine of Brooks et aI.'s patients. This suggests that, like SND, the resistance of some PSP patients to dopaminergic agents must reflect degeneration of pallidal and brain stem projections rather than loss of striatal dopamine receptors. PET findings on striatal D 2 site status in PSP are in reasonable agreement with autopsy reports: Bokobza et al. (1984) reported a 30% reduction in striatal D 2 receptors in five PSP patients while Ruberg et al. (1985) found a mean 40% loss in their follow up series of seven patients. As was concluded for MSA, measurement of striatal D 2 binding potential is unlikely to provide a useful means of discriminating PSP from PD as it can be normal, on occasion, in both of these conditions.

Corticobasal degeneration (CBD) This syndrome is also known as corticodentatonigral degeneration and neuronal achromasia. Patients characteristically present with a dyspraxic, akinetic-rigid limb which may show cortical sensory loss. Myoclonus, supranuclear gaze problems, and bulbar dysfunction are also features. The intellect is generally spared though dysphasia may occur. The condition is usually poorly L-dopa responsive and tends to generalise to all four limbs (Riley et al. 1990). The pathology consists of collections of swollen, achromatic "Pick" cells which have a predilection for posterior frontal, inferior parietal, and superior temporal cortex, the cerebellar dentate nuclei, and the substantia nigra. This contrasts with Pick's disease which targets the inferior frontal and temporal areas resulting in personality change and cognitive decline. Argyrophilic neuronal inclusion Pick bodies are not found in CBD (Gibb et al. 1989).

Sawle et al. (1991a) studied six patients with clinically probable CBD. Striatal ~SF-dopa uptake was strikingly asymmetrical, being most depressed contralateral to the more affected limbs. Caudate and putamen tracer uptake were equally severely depressed in CBD, contrasting with PD where caudate 18F-dopa uptake is relatively spared. These workers also measured regional cerebral oxygen metabolism (rCMRO 2) with ~50 2. Like striatal ~8F-dopa uptake, rCMRO 2 was asymmetrically affected and was most reduced in those areas known to be targeted by the pathology: posterior frontal, inferior parietal, and superior temporal cortex, and thalamus. The authors concluded that the asymmetry and pattern of metabolic and dopaminergic system dysfunction distinguished CBD from other parkinsonian syndromes. Eidelberg et al. (1991) studied five patients with probable CBD. They found relative depression of inferior parietal, hippocampal, and thalamic glucose metabolism, and of striatal LSF-dopa uptake, contralateral to the more affected limbs. By contrast, PD patients showed symmetrical cortical and thalamic glucose metabolism. Blin et al. (1990b) have also reported asymmetrical reductions of inferior parietal and thalamic FDG uptake in CBD. To date no PET studies on the integrity of dopaminergic receptors in this condition have been reported.

Other causes of parkinsonism

Dopa-responsive dystonia (DRD) This familial condition typically presents in childhood with dystonic posturing of the legs which fluctuates diurnally and responds dramatically to L-dopa. With time the dystonia generalises and background parkinsonism becomes evident. Occasionally, adult rel-

TABLE 4 REGIONAL

CEREBRAL

D ' A n t o n a et al. 1985 L e e n d e r s et al. 1988b F o s t e r et al. 1988 G o f f i n e t et al. 1989 Blin et al. 1 9 9 0 a STRIATAL

DOPAMINE

B a r o n et al. 1986 (7) W i e n h a r d et al. 1990 (2) B r o o k s et al. 1 9 9 2 a (9)

METABOLISM

IN PSP (% OF NORMAL)

No.

Wholecortex

(%)

(%)

(%)

(%)

Striatal

Thalamic

(%)

(%)

6 4 14 9 41

83 81 85 -

73 78 75 75 78

93 89 86 83

78 79 79 81

84 69 73

91 76 79

D 2 RECEPTOR

Frontal

Occipital

STATUS IN PSP

[76 B r ] B S P [18F]FESP [11C]RAC

Striatum Caudate Caudate Putamen

: cerebellum ratio down 24% binding potential down 17% : cerebellum ratio down 24% : cerebellum ratio down 9%

Cerebeltar

13 TABLE 5 P E T F I N D I N G S IN P A R K I N S O N I A N S Y N D R O M E S PD

PD (demented)

MSA

PSP

CBD

HD

DRD

Mn

FDG uptake

normal

low parietal temporal

low striatal, frontal, and cerebellar

low striatal, frontal, thalamic, and cerebellar

low striatal, thalamic, and inf. parietal

low striatal, thalamic

'~

?

F-dopa

putamen < caudate

putamen < caudate

putamen _< caudate

low p u t a m e n - caudate

low p u t a m e n = caudate

normal

normal

normal

Striatal D 2 sites

normal or raised normal or low

(untreated) (treated)

normal or low

normal or low

?

low

normal

':'

Opiate sites

normal

normal

low striatal

low striatal

?

9

?

9

atives of D R D patients present with a levodopa-responsive parkinsonian syndrome indistinguishable from PD. Unlike PD, however, striatal lSF-dopa uptake is normal or only mildly reduced in D R D (Snow et al. 1992; Sawle et al. 1991b). This P E T finding suggests that in D R D there may be a problem with the tyrosine hydroxylase complex which converts endogenous tyrosine to dopa. This is effectively overcome by administering exogenous levodopa which is then decarboxylated normally to form dopamine.

Manganese-associated parkinsonism Manganese miners in Chile are at risk of developing an akinetic-rigid syndrome due to ingestion of manganese dioxide dust. The condition is poorly levodopa responsive. In contrast to most parkinson-plus syndromes striatal 18F-dopa uptake is normal in these patients (Wolters et al. 1989) suggesting that manganese ore does not act as a nigral toxin. It is likely that these miners have striatal or pallidal necrosis.

Akinetic-rigid Huntington's disease (HD) Young onset H D tends to present as the akineticrigid Westphal variant. This is usually poorly levodopa responsive. Unlike PD, striatal metabolism and dopamine D 2 receptor densities are severely reduced in these patients (Kuhl et al. 1984b; Young et al. 1986; Hagglund et al. 1987; Leenders et al. 1986a) while striatal 18F-dopa uptake remains preserved. At pathology extensive striatal degeneration is found with loss of G A B A projections to both internal and external pallidum (Albin et al. 1990). Choreic H D patients show little involvement of striatal projections to internal pallidum and so it is probably loss of these that is responsible for the rigidity in young-onset HD. In the same way that subclinical nigral dysfunction can be demonstrated with lSF-dopa P E T it has proved possible to detect subclinical reductions in striatal glucose utilisation in some at-risk relatives of H D patients with 18FDG P E T (Grafton et al. 1990; Hayden et al. 1987).

Conclusions

In this review the ways in which functional imaging can be used to demonstrate the patterns of derangement of regional cerebral metabolism and the dopaminergic system associated with different parkinsonian syndromes have been presented. These patterns have distinguishing features, which are summarised in Table 5, and can help to seperate PD from atypical parkinsonian disorders when clinical doubt exists. PET can also detect subclinical nigral and striatal dysfunction. This is enabling us to re-examine the role of inheritance in PD and with the advent of neuroprotcctive agents may have important therapeutic implications. Functional imaging has revealed that PD patients fail to activate their striatum and mesial frontal structures normally. P E T and SPECT provide a potential means of monitoring the ability of striatal engraftment, nerve growth factors, and stereotactic lesioning to reverse these functional deficits in parkinsonian disorders. The majority of pharmacological studies with PET and SPECT have involved the use of antagonist tracers which are unable to distinguish high and low agonist affinity receptor subclasses. There are now suitable dopamine agonist tracers on the horizon which may prove to be of greater value for distinguishing different parkinsonian disorders and help to throw light on the mechanisms underlying on-off therapeutic fluctuations and drug-induced dyskinesias. In the future tracers for studying serotonergic, glutamatergic, and peptidergic systems in parkinsonian disorders are likely to come available further increasing the potential of functional imaging.

References Adams, R., L. Van Bogaert and E.H. Van Der (1964) Striatonigral degeneration. J. Neuropathol. Exp. Neurol., 23:219 259. Albin, R.L., A. Reiner, K.D. Anderson, J.B. Penney and A.B. Young

14 (1990) Striatal and nigral neuron subpopulations in rigid Huntington's disease: implications for the functional anatomy of chorea and rigidity-akinesia, Ann. Neurol., 27: 357-365. Baron, J.C., B. Maziere, C. koc'h, H. Cambon, P. Sgouropoulos, M. Bonnet and Y. Agid (1986) Loss of striatal (76Br)bromospiperone binding sites demonstrated by positron tomography in progressive supranuclear palsy, J. Cereb. Blood. Flow. Metabol., 6: 131-136. Berciano, J. (1982) Olivopontocerebellar atrophy, J. Neurol. Sci., 53: 253 272. Bernheimer, H., W. Birkmayer, O. Hornykiewicz, K. Jellinger and F. Seitelberger (1973) Brain dopaTnine and the syndromes of Parkinson and Huntington. Clinical, morphological, and neurochemical correlations, J. Neurol. Sci., 20: 415-455. Bethlem, J. and W.A. Den Hartog Jager (1960) The incidence and characteristics of Lewy bodies in idiopathic paralysis agitans (Parkinson's disease), J. Neurol Neurosurg. Psychiat., 23: 74-80. Bhatt, M.H., B.J. Snow, W.R.W. Martin, R. Peppard and D.B. Calne (199l) Positron emission tomography in progressive supranuclear palsy, Arch. Neurol., 48: 389-391. Blin, J., J.C. Baron, P. Dubois, B. Pillon, H. Cambon, J. Cambier and Y. Agid (1990a) Positron emission tomography study in progressive supranuclear palsy, Arch. Neurol., 47: 747-752. Blin, J., M. Vidhailhet, A.M. Bonnet, P. Dubois, P. Pillon, A. Syrota and Y. Agid (1990b) PET study in corticobasal degeneration, Mov. Dis., 5 (Suppl. 1): 19. Bokobza, B., M. Ruberg, B. Scatton, F. Javoy-Agid and Y. Agid (1984) 3H-spiperone binding, dopamine and HVA concentrations in Parkinson's disease and supranuclear palsy, Eur. J. Pharmacol., 99: 167-175. Brooks, D.J. (1992) Special investigations in multiple system atrophy. A. Positron emission tomography (PET) studies, In: R. Bannister and C.J. Mathias (Eds.), Autonomic Failure, 3rd Edn., Oxford University Press, Oxford, pp. 548-552. Brooks, D.J., V. Ibafiez, G.V. Sawle, N. Quinn, A.J. Lees, C.J. Mathias, R. Bannister, C.D. Marsden and R.S.J. Frackowiak (1990a) Differing patterns of striatal 18F-dopa uptake in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy, Ann. Neurol., 28: 547-555. Brooks, D.J., E.P. Salmon, C.J. Mathias, N. Quinn, K.L. Leenders, R. Bannister, C.D. Marsden and R.S.J. Frackowiak (1990b) The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system, in patients with multiple system atrophy, pure autonomic failure, and Parkinson's disease, studied with PET, Brain, 113: 1539-1552. Brooks, D.J., V. Ibanez, G.V. Sawle, E.D. Playford, N. Quinn, C.J. Mathias, A.J. Lees, C.D. Marsden, R. Bannister and R.S.J. Frackowiak (1992a) Striatal D 2 receptor status in Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with llC-raclopride and PET, Ann. Neurol., 31: 184-192. Brooks, D.J., E.D. Playford, V. Ibanez, G.V. Sawle, P.D. Thompson, L.J. Findley and C.D. Marsden (1992b) Isolated tremor and disruption of the nigrostriatal dopaminergic system: An tSF-dopa PET study, Neurology, 42: 1554-1560. Brucke, T., I. Podreka, P. Angelberger, S. Wenger, A. Topitz, B. Kufferle, C. Muller and L. Deeeke (1991) Dopamine D 2 receptor imaging with SPECT: studies in different neuropsychiatric disorders, J. Cereb. Blood Flow Metab. 11: 220-228. Burn, D.J. and D.J. Brooks (1993) Nigral dysfunction in drug-induced parkinsonism: An ISF-dopa PET study, Neurology, in press. Burn, D.J., M.H. Mark, E.D. Playford, D.M. Maraganore, T.R. Zimmerman, Jr, R.C. Duvoisin, A.E. Harding, C.D. Marsden and D.J. Brooks (1992a) Parkinson's disease in twins studied with tSF-dopa and positron emission tomography, Neurology, 42: 1894-1900. Byrne, E., G. Lennox, J. Lowe and R.B. Godwin-Austin (1989)

Diffuse Lewy body disease: clinical features in [5 cases. J. Nenrol. Neurosurg. Psychiat., 52: 709-717. Calne, D.B., J.W. Langston, W R . Martin, A.J. Stoessl, T.J. Ruth. M.J. Adam, B.D. Pate and M. Schulzer (1985) Positron emission tomography after MPTP: observations relating to the cause of Parkinson's disease, Nature, 317: 246-248. Calne, D.B., A. Eisen, E.G. McGeer and P. Spencer (19861 Alzheimer's disease, Parkinson's disease and motoneurone disease: abiotrophic interaction between aging and environment, Lancet, i: 1067-1070. Cash, R., R. Raisman, A. PIoska and Y. Agid (1987) Dopamine DI receptor and cyclic AMP-dependent phosphorylation in Parkinsons's disease, J. Neurochem., 49: 1075-1083. Chieuh, C.C., R.S. Burns, I.J. Kopin, K.L. Kirk, G. Firnau, C. Nahmias, R. Chirakal and E.S. Garnett (1986) 6-1SF-Dopa/ Positron emission tomography visualized degree of damage to brain dopamine in basal ganglia of monkeys with MPTP-induced parkinsonism. In: S.P. Markey, N. Castagno|i, A.J. Trevor and I.J. Kopin (Eds.), MPTP: a Neurotoxin Producing a Parkinsonian Syndrome, Academic Press, Orlando, FL, pp. 327-338. Cleeves, L., L.J. Findley and W. Koller (1988) Lack of association between essential tremor and Parkinson's disease, Ann. Neurol., 24: 23-26. Cortes, R., M. Camps, B. Gueye, A. Probst and J.M. Palacios (1989) Dopamine receptors in the human brain: autoradiographic distribution of D l and D z sites in Parkinson syndrome of different etiology, Brain Res., 483: 30-38. Crossman, A.R (1990) A hypothesis on the pathophysiologicat mechanisms that underlie levodopa- or dopamine agonist-induced dyskinesia in Parkinson's disease: implications for future strategies in treatment, Mov. Dis., 5: 100-108, D'Antona, R., J.C. Baron, Y. Samson, M. Serdaru, F. Viader, Y. Agid and J. Cambier (1985) Subcortical dementia. Frontal cortex hypometabolism detected by positron emission tornography in patients with progressive supranuclear palsy, Brain, 108: 785-799. De Bruin, V.M.S., A.J. Lees and S.E. Daniel (1992) Involvement of the cerebral cortex in Steele-Richardson-Olszewski syndrome, Mov. Dis., 7 (Suppl. 1): 80. De Voider, A.G., J. Francard, C. Laterre, G. Dooms, A. Bol, C. Michel and A.M. Goffinet (1989) Decreased glucose utilisation in the striatum and frontal lobe in probable striatonigral degeneration, Ann. Neurol., 26: 239-247. Duvoisin, R.C. (1991) The genetics of Parkinson's disease: a review, In: U.K. Rinne, T. Nagatsu and R. Horowski (Eds.), International Workshop Berlin Parkinson's Disease, Medicom, Netherlands, pp. 38-57. Eidelberg, D., V. Dhawan, J.R. Moeller, J.J. Sidtis, J.Z. Ginos, S.C. Strother, J. Cederbaum, P. Greene, S. Fahn, J.M. Powers and D.A. Rottenberg (1991) The metabolic landscape of cortico-basal ganglionic degeneration: regional asymmetries studied with positron emission tomography, J. Neurol. Neurosurg. Psychiat., 54: 856-862. Fearnley, J.M. and A.J. Lees (1990) Striatonigral degeneration: A clinicopathological study, Brain, 113: 1823-1842. Fearnley, J.M. and A.J. Lees (1991) Ageing and Parkinson's disease: Substantia nigra regional selectivity, Brain, 114: 2283-2301. Findley, LJ., M.A, Gresty and G.M. Halmagyi (1981) Tremor, the cogwheel phenomenon and clonus in Parkinson's disease, J. Neurol. Neurosurg. Psychiat., 44: 534-546. Firnau, G., E.S. Garnett, P.K. Chan and L.W. Belbeck (1976) Intracerebral dopamine metabolism studied by a novel radioisotope technique, J. Pharm. Pharmacol., 30: 584-585. Firnau, G., S. Sood, R. Chirakal, C. Nahmias and E.S. Garnett (1987) Cerebral metabolism of 6-[ 18F]fluoro~L_3;4_dihydroxyphen ylalanine in the primate, J. Neurochem., 48: 1077-1082. Foster, N.L., S. Gilman, S. Berent, E.M. Morin, M:B. Brown and R.A. Koeppe (1988) Cerebral hypometanolism in progressive

15 supranuclear palsy studied with positron emission tomography, Ann. Neurol., 24: 399-406. Fulham, M.J., R.M. Dubinsky, R.J. Polinsky, R.A. Brooks, R.T. Brown, M.T. Curras, S.M. Baser, M. Hallett and G. Di Chiro (1991) Computed tomography, magnetic resonance imaging, and positron emission tomography with [18F]fluorodeoxyglucose in multiple system atrophy and pure autonomic failure, Clin. Auton. Res., 1: 27-36. Fuxe, K., L.F. Agnati, C. Kohler, D. Kuonen, S.O. Ogren, K. Andersson and T. Hokfelt (19811 Characterisation of normal and supersensitive dopamine recetors: effects of ergot drugs and neuropeptides, J. Neural Transm., 51: 3-37. Garnett, E.S., G. Firnau, P.K. Chan, S. Sood and C.K. Belbeck (1978) [lSF]Fluoro-dopa, an analogue of dopa and its use in direct external measurements of storage, degradation and turnover of intracerebral dopa, Proc Natl. Acad. Sci. USA., 75: 464-467. Garnett, E.S., C. Nahmias and G. Firnau (1984) Central dopaminergic pathways in hemiparkinsonism examined by positron emission tomography, Can. J. Neurol. Sci., 11: 174-179. Garnett, S., G. Firnau, C. Nahmias and R. Chirakal (1983) Striatal dopamine metabolism in living monkeys examined by positron emission tomography, Brain Res., 280: 169-171. Geraghty, J.J., J. Jankovic and W.J. Zetusky (1985) Association between essential tremor and Parkinson's disease, Ann. Neurol., 17: 329-333. German, D.C., K. Manaye, W.K. Smith, D.J. Woodward and C.B. Saper (19891 Midbrain dopaminergic cell loss in Parkinson s disease. Computer visualization, Ann. Neurol., 26: 507-514. Gibb, W.R.G., P. Luthert and C.D. Marsden (1989) Corticobasal degeneration, Brain, 112:1171-1192. Goffinet, A.M., A.G. De Voider, C. Gillain, D. Rectem, A. Bol, C. Michel, M. Cogneau, D. Labar and C. Laterre (19891 Positron tomography demonstrates frontal lobe hypometabolism in progressive supranuclear palsy, Ann. Neurol., 25: 131-139. Golbe, L.I (1990) The genetics of Parkinson's disease: A reconsideration, Neurology, 40 Suppl. 3: 7-16. Goldberg, G (19851 Supplementary motor area structure and function: Review and hypotheses, Behav. Brain Sci., 8: 567-616. Goldman-Rakic, P.S., (1987) Circuitry of primate prefrontal cortex and regulation of behaviour by representational memory. In: F. Plum (Ed.), The Nervous System: Higher Functions of the Brain, American Physiology Society, Bethesda, MD, pp. 373-417. Goto, S., A. Hirano and S. Matsumoto (1989) Subdivisional involvement of nigrostriatal loop in idiopathic Parkinson's disease and striatonigral degeneration, Ann. Neurol., 26: 766-770. Grafton, S.T., J.C. Mazziotta, J.J. Pahl, P. St.George-Hyslop, J.L. Haines, J. Gusella, J.M. Hoffman, L.R. Baxter and M.E. Phelps (199/)) A comparison of neurological, metabolic, structural, and genetic evaluations in persons at risk for Huntington's disease, Ann. Neurol., 28: 614-621. Guttman, M. and P. Seeman (1985) L-DOPA reverses the elevated density of the D2 dopamine receptors in Parkinson's diseased striatum, J. Neural. Transm., 64: 93-103. Hagglund, J., S.M. Aquilonius, S.A. Eckernas, P. Hartvig, H. Lundquist, P. Gullberg and B. Langstrom (1987) Dopamine receptor properties in Parkinson's disease and Huntington's chorea evaluated by positron emission tomography using lJC-N-methylspiperone, Acta Neurol, Scand., 75: 87-94. Halliday, G.M., Y.W. El, P.C. Blumbergs, T.H. Job, R.G.H. Cotton, P.R.C. Howe, W.W. Blessing and L.B. Geffen (1990) Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease, Ann. Neurol., 27: 373-385. Hayden, M.R., J. Hewitt, W.R.W. Martin, C. Clark and A. Amman (1987) Studies in persons at risk for Huntington's disease, New Engl. J, Med., 317: 382-383. Huang, S.C., D.-C. Yu, J.R. Barrio, S. Grafton, W.P. Melega, J.M.

Hoffman, N. Satyamurthy, J.C. Mazziotta and M.E. Phelps (1991) Kinetics and modelling of L-6-[~SF]fluorodopa in human positron emission tomography sludies, J. Cereb. Blood Flow Metab., 11: 898-913. Hughes, A.J., 8.E Daniel, L. Kilford and A.J. Lees (1992) The accuracy of the clinical diagnosis of Parkinson's disease: a clmicopathological study of 100 cases. J. Neurol. Neurosurg. Psychiatr., 55: 181-184. Jankovic, J. and J.D. Frost (1981) Quantitative assessment of parkinsonian and essential tremor: clinical application of triaxial accelerometry, Neurology, 31 : 1235-124(I. Jellinger, K. (1986) Pathology of parkinsonism, In: S. Fahn, ('.l). Marsden and R. Duvoisin (Eds.), Recent Developments in Parkinsonism, Raven Press, New York, pp. 33-66. Jellinger, K., P. Riederer and M. Tomananga (1980) Progressive supranuclear palsy: Clinico-pathological and biochemical studies, J. Neural. Transm., Suppl. 16: 111-128. Jenkins, I.H., W. Fernandez, E.D. Playtk)rd, A.,I. Lees, R.S.J. Frackowiak, R.E. Passingham and D.J. Brooks (lt.~421 Akinesia and Parkinson's disease: Impaired activation of the supplementary motor area is reversed by apomorphine, Ann. Neurol., in press. Johnson, R.H., G. de J. Lee, D.R. Oppenheimer and J.M.K. Spalding (1966) Autonomic failure with orthostatic hypotension due to intermediolateral column degeneration: a rep~rt of two cases with autopsies, O. J. Med., 35: 276-292. Johnson, W.G., S.E. Hodge and R.C. Duvoisin (1090) Twin studies and the genetics of Parkinson's disease - a re-appraisal, Mov. Dis., 5: 187-194. Kish, S.J., L.J. Chang, L.J. Mirchandani, K. Shannak and O. Hornykiewicz (19851 Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers, Ann, Neurol., 18:530 536. Kish, S.J., K, Shannak, A. Rajput, J.tI.N. Deck and O. Itornykiewicz (1992) Aging produces a specific pattern of striatal dopamine loss: Implications for the etiology of idiopathic Parkinson's disease, J. Neurochem., 58:642 648. Kiyosawa, M., J.C. Baron, E. Hamel, S. Pappata, D. Duverger. I), Riche, B. Mazoyer, R. Naquet and E.T. MacKenzie (19891 Time course of effects of unilateral lesions of the nucleus basalis of Meynert on glucose utilisation by the cerebral cortex. Positron emission tomography in baboons, Brain, 112: 435-455. Kobayashi, K., K. Miyazu, K. Katsukawa et al. (19921 Cytoskeletal protein abnormalities in patients with olivopontocerebellar atrophy - an immunocytochemical and Gallyas silver impregnation study. Neuropath. Appl. Neurobiot., 18: 237-249. Kuhl, D.E., E.J. Metter and W.H. Riege (1984a) Patterns of local cerebral glucose utilisation determined in Parkinson's disease by the ISF-fluorodeoxyglucose method, Ann. Neurol., 15: 419-424. Kuhl, D.E., E.J. Metter, W.H. Riege and C.ti. Markham (1984b) Patterns of cerebral glucose utilisation in Parkinson's disease and Huntington's disease, Ann. Neurol., 15 (Suppl.): S119 S125. Kuhl, D.E., E.J. Metter, D.F. Benson, J.W. Ashford, W.H. Ricge, D.G. Fujikawa, C.H. Markham, J.C. Mazziotta, A. Maltese and D.A. Dorsey (1985) Similarities of cerebral glucose metabolism in Alzheimer's and Parkinsonian dementia, J. Cereb. Blood Flow Metab., 5: S169-S170. Kurland, L.T. (19581 Epidemiology: incidence, geographic distribution, and genetic considerations, In: W.S. Fields, (Ed.), pp. 5 49. Pathogenesis and Treatment of Parkinsonism. Charles C. Thomas, Springfield, IL. Kuwabara, H., P. Cunning, J. Reith. G. Ldger, M. Diksic, A.C. Evans and A. Gjedde. (1993) Human striatal l-dopa decarboxylase activity estimated in vivo using 6-[lSF]fluoro-DOPA and positron emission topography: error analysis and application to normal subjects. J. Cerebr. Blood Flow Metab., 13: 43--56. Lance, J.W., R.S. Schwab and E.A. Peterson (19631 Action tremor

16 and the cogwheel phenomenon in Parkinson's disease, Brain, 86: 95-110. Lee. T., P. Seeman, A. Rajput, l.J. Farley and O. ttornykiewicz (1978) Receptor basis for dopaminergic supersensitivity in Parkinson disease, Nature, 273: 59-60. Leenders, K.L., S. Herold, A.J. Palmer, N. Turton, N. Quinn, T. Jones, R.S.J. Frackowiak and C.D. Marsden (1985) Human cerebral dopamine system measured in vivo using PET, J. Cereb. Blood. Flow. Metab., 5 (Suppl.): S157-S158. Leenders, K.L., R.S.J. Frackowiak, N. Quinn and C.D. Marsden (1986a) Brain energy metabolism and dopaminergic function in Huntington's disease measured in vivo using positron emission tomography, Mov. Dis., 1: 69-77. Leenders, K.L., A. Palmer, D. Turton, N. Quinn, G. Firnau, S. Garnett, C. Nahmias, T. Jones and C.D. Marsden, (1986b) DOPA uptake and dopamine receptor binding visualized in the human brain in vivo. In: S. Fahn, C.D. Marsden, P. Jenner and P. Teychenne (Eds.), Recent Developments in Parkinson's Disease, Raven Press, New York, pp. 103-113. Leenders, K.L., A.J. Palmer, N. Quinn, J.C. Clark, G. Firnau, E.S. Garnett, C. Nahmias, T. Jones and C.D. Marsden (1986c) Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography, J. Neurol. Neurosurg. Psychiat., 49: 853-860. Leenders, K.L., W.H. Poewe, A.J. Palmer, D.P. Brenton and R.S. Frackowiak (1986d) Inhibition of L-[lSF]Fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography, Ann. Neurol., 20: 258-262. Leenders, K.L., S.M. Aquilonius, K. Bergstrom, P. Bjurling, A.R. Crossman, S.A. Eckernas, A.G. Gee, P. Hartvig, H. Lundqvist, B. Langstrom, A. Rimland and J. Tedroff (1988a) Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET using various novel tracers, Brain. Res., 445: 61-67. Leenders, K.L., R.S. Frackowiak and A.J. Lees (1988b) SteeleRichardson-Olszewski syndrome. Brain energy metabolism, blood flow and fluorodopa uptake measured by positron emission tomography, Brain, 111: 615-630. Leenders, K.L., E.P. Salmon, P. Tyrrell, D. Perani, D.J. Brooks, H. Sagar, T. Jones, C.D. Marsden and R.S.J. Frackowiak (1990) The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease, Arch. Neurol., 47: 1290-1298. Leenders, K.L., A. Antonini, J. Schwarz, K. Hess, A. Weindl and W. Oertel (1992) Brain dopamine D 2 receptors in ~"de novo" drugnaive parkinsonian patients measured using PET and 11Craclopride, Mov. Dis., 7 (Suppl. 1): 141. Lees, A.J., (1986) The Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy), In: (C.D. Marsden and S. Fahn (Eds.), Movement Disorders, Vol. 2, Butterworth, London, pp. 273-287. Mark, M.H., D.J. Burn, M. Bergen, R.C. Duvoisin and D.J. Brooks, (1992) Familial diffuse Lewy body disease: An lSF-dopa PET study. In: B. Conrad (Ed.), Second International Congress of Movement Disorders, Munich. Martin, W.R.W., M.J. Adam, M. Bergstrom, W. Ammann, R. Harrop, A. Laihinen, J. Rogers, T. Ruth, C. Sayre, J. Stoessl, B.D. Pate and D.B. Calne (1986) In vivo study of DOPA metabolism in Parkinson's disease, In: S. Fahn, P. Jenner, C.D. Marsden and P. Teychenne (Eds.), Recent Developments in Parknson's Disease, Raven Press, New York, pp. 97-102. Martin, W.R: W., M.R. Palmer, C.S. Patlak and D.B. Calne (1989) Nigrostriatal function in humans studied with positron emission tomography, Ann. Neurol., 26: 535-542. McGeer, P.L., S. Itagaki, H. Akiyama and E.G. McGeer (1988) Rate of cell death in Parkinsonism indicates active neuropathological process, Ann. Neurol., 24:574 576.

Melega, W.P., A. Luxen, M.M.. Perlmutter, C.H.K. Nissenson, M.E. Phelps and J.R. Barrio (1990) Comparative in vivo metabolism of 6-[lSF]fluoro-L-dopa and [3H]L-dopa in rats, Biochem. Pharmacol., 39: 1853-1860. Miletich, R.S., T. Chan, M. Gillespie, G. Di Chiro and S. Stein (1988) Contralateral basal ganglia metabolism is abnormal in hemiparkinsonian patients. An FDG-PET study, Neurology, 38: $260. Mishra, R.K., Y.W. Wong, S.L. Varmuze and L. Tuff (1978) Chemical lesion and drug-induced supersensitivity and subsensitivity of caudate dopamine receptors, Life Sci., 23: 443-446. Mj6nes, H (1949) Paralysis agitans. A clinical genetic study, Acta Psychiat. Neurol. Scand., 25 (Suppl. 54): 1-195. Mushiake, H., M. Inase and J. Tanji (1990) Selective coding of motor sequence in the supplementary motor area of the monkey cerebral cortex, Exp. Brain Res., 82: 208-210. Nagatsu, T., T. Kato, I. Nagatsu et al. (1979) Catecholamine-related enzymes in the brains of patients with parkinsonism and Wilson's disease, Adv. Neurol., 24: 283-292. Nahmias, C., E.S. Garnett, G. Firnau and A. Lang (1985) Striatal dopamine distribution in Parkinsonian patients during life, J. Neurol. Sci., 69: 223-230. Otsuka, M., Y. Ichiya, S. Hosokawa, Y. Kuwabara, T. Tahara, T. Fukumura, M. Kato, K. Masuda and I. Goto (1991) Striatal blood flow, glucose metabolism, and 18F-dopa uptake: difference in Parkinson's disease and atypical parkinsonism, J. Neurol. Neurosurg. Psychiat., 54: 898-904. Parker, F., N. Tzourio, S. Blond, H. Petit and B. Mazoyer (1992) Evidence for a common network of brain structures involved in parkinsonian tremor and voluntary repetitive movement, Brain Res., 584: 11-17. Patlak, C.S. and R.G. Blasberg (1985) Graphical evaluation of bloodto-brain transfer constants from multiple-time uptake data. Generalizations, J. Cereb. Blood Flow Metab., 5: 584-590. Peppard, R.F., W.R.W. Martin, M. Guttman, P.L. McGeer, E.M. Walsh, G.D. Carr, A.G. Phillips, E. Grochowski, J. Okada, J.K:C. Tsui, E. Mak, T. Ruth, M.J. Adam and D.B. Calne (1988) The relationship of cerebral glucose metabolism to cognitive deficits in Parkinson's disease, Neurology, 38 (Suppl. 1): 364. Phelps, M.E., J.C. Mazziotta and S.C. Huang (1982) Study of cerebral function with positron computed tomography, J. Cereb. Blood Flow Metab., 2: 113-162. Pierot, L., C. Desnos, J. Blin, R. Raisman, D. Scherman, F. JavoyAgid, M. Ruberg and Y. Agid (1988) D1 and D2-type dopamine receptors in patients with Parkinson's disease and progressive supranuclear palsy, J. Neurol. Sci., 86: 291-306. Pimoule, C., H. Schoemaker, G.P. Reynolds and S.Z. Langer (1985) [3H]SCH 23390 labeled D1 dopamine receptors are unchanged in schizophrenia and Parkinson's disease, Eur. J. Pharmacol., 114: 235-237. Playford, E.D., I.H. Jenkins, R.E. Passingham, J. Nutt, R.S.J. Frackowiak and D.J. Brooks (1992) Impaired mesial frontal and putamen activation in Parkinson's disease: a PET study, Ann. Neurol., 32: 151-161. Quik, M., E. Spokes, A. MacKay and R. Bannister (1979) Alterations in 3H-spiperone binding in human caudate, nucleus, substantia nigra and frontal cortex in the Shy Drager syndrome and Parkinson's disease, J. Neurol. Sci., 43: 429-437. Raisman, R., R. Cash, M. Ruberg, F. Javoy-Agid and Y. Agid (1985) Binding of [3H]SCH 23390 to D1 receptors in the putamen of controls and parkinsonian subjects, Eur. J. Pharmacol., 113: 467468. Rajput, A.H., B. Rozdilsky, O. Hornykiewicz, K. Shannak, T. Lee and P. Seeman (1982) Reversible drug-induced parkinsoaism. Clinicopathologic study of two cases, Arch. Neurol., 39: 644-646. Rajput, A.H., B. Rozdilsky, L. Ang and A. Rajput (1991a) Clinico-

17 pathologic observations in essential tremor: Report of six cases, Neurology, 41: 1422-1424. Rajput, A.H., B. Rozdilsky and A. Rajput (1991b) Accuracy of clinical diagnosis in Parkinsonism - a prospective study, Can. J, Neurol. Sci., 18: 275-278. Rascol, O., U. Sabatini, F. Chollet, P, Celsis, J.-L. Montastruc, J.-P. Marc-Vergnes and A. Rascol (1992) Supplementary and primary sensory motor area activity in Parkinson's disease. Regional cerebral blood flow changes during finger movements and effects of apomorphine, Arch. Neurol., 49: 144-148. Reisene, T.D., J.Z. Fields, H,I. Yamamura, E.D. Bird, E. Spokes, P.S. Schreiner and S.J.Enna (19771 Neurotransmitter receptor alterations in Parkinson's disease, Life Sci., 21: 335-344. Riley, D.E., A.E. Lang, A. Lewis, L. Resch, P. Ashby, O. Hornykiewicz and S. Black 11990) Cortical-basal ganglionic degeneration, Neurology, 40: 1203-1212. Rinne, J.O., J. Rummukainen, M. Lic, L. Paljarvi and U.K. Rinne (1989) Dementia in Parkinson's disease is related to neuronal loss in the medial substantia nigra, Ann. Neurol., 26: 47-50. Rinne, J.O., A. Laihinen, K. Nagren, J. Bergman, O. Solin, M. Haapparanta, U.Ruotsalainen and U.K. Rinne (1990a) PET demonstrates different behaviour of striatal dopamine DI and D2 receptors in early Parkinson's disease, J. Neurosci. Res., 27: 494-499. Rinne, U.K., P. L6nnberg and V. Koskinen (1981) Dopamine receptors in the parkinsonian brain. J. Neural Transm., 51: 97-106. Rinne, U.K., A. Laihinen, J.O. Rinne, K. Nagren, J. Bergman and U. Ruotsalainen (1990b) Positron emission tomography demonstrates dopamine D 2 receptor supersensitivity in the striatum of patients with early Parkinson's disease, Mov. Dis., 5: 55-59. Ruberg, M., B. Bokobza, F. Javoy-Agid, J.C. Montfort and Y. Agid (1984) 3H-spiperone binding in the nigro-striatal system in human brain, Eur. J. Pharmacol., 99: 159-165. Ruberg, M., F. Javoy-Agid, E. Hirsch, B. Scatton, R. L'Heureux, J.-J. Hauw, C. Duyckaerts, F. Gray, A. Morel-Maroger, A. Rascol, M. Serdaru and Y. Agid (1985) Dopaminergic and cholinergic lesions in progressive supranuclear palsy, Ann. Neurol., 18: 523-529. Salmon, E.P., D.J. Brooks, K.L. Leenders, D.R. Turton, S.P. Hume, J.E. Cremer, T. Jones and R.S.J. Frackowiak (1990) A two-compartment description and kinetic procedure for measuring regional cerebral [l~C]nomifensine uptake using positron emission tomography, J. Cereb. Blood Flow Metab., 10: 307-316. Sawle, G.V., D,J. Brooks, V. Ibafiez and R.S.J. Frackowiak (1990) Striatal D 2 receptor density is inversely proportional to dopa uptake in untreated hemi-Parkinson's disease, J. Neurol. Neurosurg. Psychiat., 53: 177-170. Sawle, G.V., D.J. Brooks, C.D. Marsden and R.S.J. Frackowiak (1991a) Corticobasal degeneration: a unique pattern of regional cortical oxygen metabolism and striatal fluorodopa uptake demonstrated by positron emission tomography, Brain, 114: 541556. Sawle, G.V., K.L. Leenders, D.J. Brooks, G. Harwood, A.J. Lees, R.S.J. Frackowiak and C.D. Marsden (1991b) Dopa-responsive dystonia: [lSF]dopa positron emission tomography, Ann. Neurol., 30: 24-30. Sawle, G.V., N. Turjanski, D.J. Brooks and R.S.J. Frackowiak (1992a) The rate of disease progression in Parkinson's disease: PET findings in patients receiving medical treatment or following foetal mesencephalic transplantation, Neurology, 42 (Suppl. 3): 295. Sawle, G.V., S.J. Wroe, A.J. Lees, D.J. Brooks and R.S.J. Frackowiak (1992b) The identification of presymptomatic parkinsonism: Clinical and [~SF]dopa PET studies in an Irish kindred, Ann. Neurol., 32: 609-617. Schapiro, M.B., C. Grady, M.J. Ball, C. DeCarli and S.I. Rapoport (1990) Reductions in parietal/temporal cerebral glucose metabo-

lism are not specific for Alzheimer's disease, Neurology, 40 (Suppl. 1): 152. Schwarz, J., K. Tatsch, G. Arnold, T. Gasser, C. Trenkwalder, C.M. Kirsch and W. Oertel. (1992) n231-iodobenzamide-SPECT predicts dopaminergic resporlsiveness in patients with de-novo parkinsonism, Neurology, in press. Shinotoh, H., A. Aotsuka, H. Yonezawa, H. Fukuda, O. lnoue, T. Yamasaki, Y. Tateno and K. Hirayama, (1990) Striatal dopamine D 2 receptors in Parkinson's disease and striato-nigral degeneration determined by positron emission tomography. In: T. Nagatsu et al. (Eds,), Basic, Clinical, and Therapeutic Advances of Alzheimer's and Parkinson's Diseases, Vol. 2, Plenum Press, New York, pp. 107-110. Smith, A.D. and J.P. Bolam (1990) The neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurones, Trends Neurosci., 13:259 265. Snow, B., A. Okada, W.R.W. Martin, R.C. Duvoisin and D.B. Calne (1992) PET scanning in dopa-responsive dystonia, parkinsonismdystonia, and young-onset parkinsonism. In: M. Segawa (Ed.). Proceedings of the Hereditary Progressive Dystonia Symposium, Tokyo, 19911, Parthenon Publishing, London, in press. Spokes, E.G.S., R. Bannister and D.R. Oppenheimer (1979) Multiple system atrophy with autonomic failure. Clinical, histological, and neurochemical observations on four cases, J. Neurol. Sci, 43: 59-62. Steele, J.C., J.C. Richardson and J. Olszewski 119641 Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia, and cerebellum, with vertical gaze and pseudobulbar palsy, Arch. Neurol., 10: 333-359. Tedroff, J. (1990) Parkinson's Disease - Pathophysiology and PET, PhD Thesis, Uppsala University, Uppsala. Tedroff, J., S.-M. Aquilonius, A. Laihinen, U. Rinne, P. Hartvig, J. Andersson, H. Lundqvist, M. Haarparanta, O. Solin, G. Antoni, A.D. Gee, J. Ulin and B. L~ngstrom (19911) Striatal kinetics of [l~C],(+)_nomifensine and 6-[ISF]fluoro-L-dopa in Parkinson's disease measured with positrom emission tomography, Acta Neurol. Scand., 81: 24-31/. Tedroff, J., S.-M. Aquilonius, P. Hartvig, H. Lundqvist, P. Bjurling and B. Langstrom (1992) Estimation of regional cerebral utilisation of [laC]-L-3,4-dihydroxy-phenylalanine (DOPA) in the primate by positron emission tomography, Acta Neurol. Scand., 85: 166-173. Thaler, D.E. and R.E. Passingham (19891 The supplementary motor cortex and internally directed movement. In: Crossman, A.R. and M. Sambrook (Eds.), Neural Mecfianisms in Disorders of Movement, Libby, London, pp. 175-181. Vanderhaegen, J.J., O. Perier and J.E. Sternon 1197//) Pathological findings in idiopathic orthostatic hypotension: its relationship with Parkinson's disease, Arch. Neurol., 22: 207-214. Wienhard, K., H.H. Coenen, G. Pawlik, J. Rudolf, P. Laufer, S. Jovkar, G. Stocklin and W.D. Heiss (1990) PET studies of dopamine receptor distribution using [ISFJfluoroethylspiperone: findings in disorders related to the dopaminergic system, J. Neural Transm., 81: 195-213. Wolfson, L.I., K.L. Leenders, L.L. Brown and T. Jones (1985) Alterations of regional cerebral blood flow and oxygen metabolism in Parkinson's disease, Neurology, 35: 1399-14/15. Wolters, E.Ch., C.C. Huang, C. Clark, R.F. Peppard, J. Okada, N.S. Chu, M.J. Adam, T.J. Ruth, D. Li and D.B. Calne (1989) Positron emission tomography in manganese intoxication, Ann. Neurol., 26: 647-651. Young, A.B., J.B. Penney, S. Starosta-Rubinstein, D.S. Markel, S. Berent, B. Giordani and R. Ehrenkaufer (19861 PET scan investigations of Huntington's disease: cerebral metabolic correlates of neurological features and functional decline, Ann. Neurol., 20: 296-303.