Striatal Function in Normal Aging: Implications for Pxkmson's Disease G. V. Sawle, MRCP," J. G. Colebatch, FRACP,f A. Shah, BSc,: D. J. Brooks, MD,*$ C . D. Marsden, FRS,f$ and R. S. J. Frackowiak, MD,"$ Central to several current theories of the etiology of Parkinson's disease is the premise that the nigrostriatal dopaminergic system degenerates with normal aging. Much of the evidence for this assertion has come frompostmortern neurochemical studies. We have used L-G{18F'ffluoro-Dopaand positron emission tomography in 26 healthy volunteers (age range, 27-76 years) to examine striatal and frontal cortical tracer uptake. Data have been analyzed by using a graphical approach to calculate an influx constant (Ki) for ~-6-['~FMh.1oro-Dopauptake into the caudate, putamen, and medial frontal cortex of each subject. In the population studied, there was no decline in Ki with age for any of these structures. A series of physiological measurements made on the older subjects also showed fewsignificant changes with age. The positron emission tomographic findings demonstrate preservation of nigrostriatal dopaminergic function in normal aging. The pathological process causing Parkinson's disease may operate closer to the time of presentation than has been suggested. Sawle GV, Colebatch JG, Shah A, Brooks DJ, Marsden CD, Frackowiak RSJ. Striatal function in normal aging: implications for Parkinson's disease. Ann Neurol 1990;28:799-804
Lewy body Parkinson's disease becomes clinically manifest when patients have lost approximately 50 to 80% of pigmented nigral neurones [l], and positron emission tomographic (PET) scans in affected patients show a 60% reduction of ~-6-{~~F)fluoro-Dopa ("F-Dopa) uptake into striatal tissue {2]. Several authors have correlated postmortem measurements of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AAAD) in subjects dying without neurological disease in life [ 3 , 41, and some have reported a fall in concentration with age, most pronounced in the first three decades. Patients dying without neurological disease may have incidental nigral Lewy bodies [ S ] . Including such patients, who should be regarded as patients with preclinical Parkinson's disease, among normal patients might have contributed to the finding of a fall in nigral cell numbers with age {C,-S]. The selective nigral neurotoxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), has provided a toxicological model for the development of Parkinson's disease {9],and PET studies have demonstrated a subclinical reduction of "F-Dopa in patients exposed to MPTP who have not developed clinical parkinsonism {lo]. It has been suggested that Parkinson's disease might be due to subclinical exposure to an MFTPlike agent in early or middle life, and that the
From the *MRC Cyclotron Unit, Clinical Sciences Section, and the TMRC Cyclotron LJnit, Chemistry Section, Hammersmith Hospital, the 8MRC Human Movement and Balance Unit' and the sity Department of Clinical Neurology, Institute of Neurology, National Hospitals for Nervous Diseases, London, UK.
subsequent "normal" effect of aging on the nigrostriatal system could then reduce cell numbers further, to the degree of depletion required for the appearance of overt clinical parkinsonism {ll]. Recent PET evidence in favor of an aging effect has come from Martin and colleagues [12] who measured total striatal 18FDopa uptake in asymptomatic individuals. The primary object of the present study was to measure in normal volunteers, particularly those over the age of 50 years, the effect of age on "F-Dopa uptake into caudate, putamen, and medial frontal cortex. Additionally, the older patients also underwent a series of physiological tests thought to be related to striatal function.
Methods All subjects were examined and found to have no clinical evidence of rigidity, bradykinesia, or tremor. None had any neurological history. All scored 30 of 30 on the mini mental test 1131.
PET Studies Twenty-six healthy volunteers between the ages of 27 and 76 years were studied with PET. Scans were performed on the CTI 981/12/8 scanner (CTI, Knoxville, TN) at the MRC Cyclotron Unit at the Hammersmith Hospital (London, England). The performance characteristics of this scanner are as described by Spinks and colleagues l14). The final effective
Received Dec 6, 1989, and in revised form Apr 6 and Jun 21, 1990. Accepted for publication Jun 25, 1990. Address correspondence lo Dr Sawle, MRC Cyclotron Unit, Clinical Sciences Section, Hammersmith Hospital, 150 DuCane Road, London W12 OHS. UK.
Copyright 0 1990 by the American Neurological Association
733
spatial resolution for 15 simultaneously acquired slices is 8.5 X 8.5 X 7.0 mm (at full width half maximum). Ethical permission for these studies and for studies on normal volunteers was obtained from the ethical committee of the Royal Postgraduate Medical School, Hammersmith Hospital. Approval to administer radiolabeled gases and ligands was obtained from the Administration of Radioactive Substances Advisory Committee of the United Kingdom (ARSAC). Written consent was obtained from all volunteers after a full explanation of the procedure. For all studies, subjects were positioned in the scanner with the orbitomeatal line parallel to the detector rings, the head being immobilized in an individually molded polyurethane support. A 22-gauge arterial cannula was inserted into the radial artery after subcutaneous infiltration with bupivacaine 1%. A 10-minute transmission scan was collected by using a retractable 68Ga/68Gering source. Subjects received 100 mg carbidopa 1 hour before the study to inhibit peripheral aromatic amino acid decarboxylase. A further 50 mg carbidopa was given immediately before scanning to maintain plasma levels of carbidopa throughout the length of the study. Each patient received approximately 140 MBq "F-Dopa (mean, 137 MBq; SD, 54) by intravenous infusion over 2 minutes. Dynamic emission scans were collected for the following 124 minutes divided into 28 time frames. I8F-Dopa scans were analyzed by using image-analysis software (Analyze version 2.0, Biodynamics Research Unit, Mayo Foundation, Rochester, MN) on SUN 3/60 Workstations (Sun Microsystems, Inc, Mountain View, CA). The position of striatal structures was determined by inspection, with reference to the stereotactic atlas of Talairach and Tourn o w [l5]. Regions of interest were defined for caudate (1 region each side of 4 x 4 pixels; 1 pixel, 2.05 mm), putamen (3 regions each side of 4 x 4 pixels, placed contiguously along the axis of the structure), medial frontal cortex (1 circular region of diameter 8 purels), occipital lobe (1 circular region each side of d m e t e r 16 pixels), and cerebellum (dimensions as for occipital regions). The medial frontal cortex, caudate, putamen, and occipital lobe regions were defined on the same planes. The cerebellar regions were defined on lower planes. The occipital and cerebellar regions were of sufficient size to include both Cortex and white matter. The posterior midline was avoided in each case to avoid sampling activity within venous sinuses. All regions of interest were defined on two adjacent planes, and appropriately weighted average values for each anatomical structure were calculated. Regional time activity curves were plotted (Fig l), demonstrating the initial entry of tracer into all regions with subsequent washout from cerebellum and occipital cortex, and irreversible trapping within strianun (see Fig 1). The data were further analyzed by using two adaptations of the multiple-time-graphical analysis (MTGA) as described by Patlak and co-workers [16, 171. In the MTGA approach, the irreversible uptake of tracer into a tissue compartment (in this case, the trapping of {'8Fffluorodopamine in terminal vesicles) is measured by a comparison of the rate of change of activity in the tissue of interest (striacum) against a uansformed and expanded time scale. In the first case, we have used an adaptation of this approach similar to that described by Tedroff and colleagues 1181 but using occipital activity in place of cerebellar activity as reference tissue [l9f. Occipital
c
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Fig 1. Regional decay-cowected time-activity data after injection of ~-b-{'~F}fltloro-Dopa ("F-Dopa). Uptakes into caudate and putamen were similar, greatly exceeding uptake into other regions. Uptake into medial frontal cortex exceeded uptake into cerebellum or occipital cortex.
-
0
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Fig 2. Method of calculation of K, (occipital)by using the occipital cortex as a reference tissue. K, was given by the gradient of the linear regression t o the data points.
and cerebellar nonspecific input functions yield similar Ki values for striatal "F-Dopa uptake. The plot of region/ occipital activity versus integrated occipitalioccipital activity is linear for the data collected from 30 to 90 minutes from injection (Fig 2). The gradient of the linear regression to this data describes the rate of irreversible trapping of activity, the influx constant Ki (occipital) min- I. Although this analysis has the advantage of simplicity in that arterial cannulation is unnecessary, it may be criticized on the grounds that the peripherally formed metabolite ~-3-O-methyl-6-{'~F}fluoroDopa (OMFD) enters the brain but cannot be further metabolized to ["Flfluorodopamine. The net effect may be to underestimate the true rate of specific tracer uptake. This would be particularly important if the rate of peripheral metabolism changed as a function of age, and for this reason, our data have also been analyzed by using another adaptation of the MTGA approach, similar to that described by Martin and co-workers { 12}. Assuming the cerebellum contains only nonspecific background activity (including plasma-derived metabolites), we subtracted cerebellar activity from striatal activity to obtain specific striatal activity. The arterial plasma curve was corrected for the accumulation of OMFD, assuming a linear increase in the ratio of 0MFD:"F-Dopa with time. The rate of increase of the ratio OMFD:18F-Dopa with time varies according to age, and the gradient of this increase may be described by the following linear equation: 0.084 - (0.0004
800 Annals of Neurology Vol 28 No 6 December 1990
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,
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Fig 3. Method of calculation of K, (plasma} by using metabolitecorrected plasma as input function and subtracting cerebellar counts from regional counts. As with the occipital analysis, the value of Ki (plasma) was derived from the gradient of the linear regression t o the data. x age), R2 = 0.646 (W.R.W. Martin, personal communication, 1989). The plot of region cerebellar activity/plasma activity versus integrated plasma activity/plasma activity for the time 30 to 120 minutes from injection is shown in Figure 3. Again, the value ofKi (plasma) min-' was calculated from the gradient of the linear regression to this data.
Physiological Sttldies Physiological measurements were made on the 21 patients aged 55 years or older (11 women 66-77 years old [mean age, 63.6 years); 10 men 56-76 years old [mean age, 65.5 years)). All recordings were made on a separate occasion from the PET scan, all were made bilaterally, and the final results were averaged. Three types of test were performed, that is, stretch reflexes, movement times for simple and complex tasks, and rates of repetitive movement. The first two are known to show characteristic abnormalities in Parkinson's disease 120-231 and are thus probably dependent on normal striatal function. Stretch reflexes were recorded at both the thumb and the wrist; conventional methods were used [20). At the thumb, a series of servocontrolled linear stretches were applied; whereas, at the wrist, three different torque pulses were used, each level of stretch being presented pseudorandomly. Resting torques were 0.10 and 0.23 Nm, respectively. The long-latency stretch reflex was identified visually from the averaged records. The duration was measured and the size quantitated as a ratio to the level of resting electromyogram (EMG) immediately before the stretch. The durations of simple and sequential movements were recorded for the elbow (isotonic flexion) and handgrip (isometric squeeze) by using methods previously reported 121, 22). Ten trials were performed of each type of movement on both sides. All trials were measured and the results averaged. The rate of repetitive thumb abduction was recorded by using a manipulandum, which kept the fingers fixed while allowing thumb abduction. The subjects were instructed to repetitively abduct the thumb 3 cm as quickly as possible for 30 seconds. Only one recording was made on each side. The number of completed movements in the first and final 10 seconds were measured.
F i g 4. Images of striatal~-6-['~F}Jluoro-Dopa ("F-Dopa) uptake in 2 patients, aged 31 and 76 years, respectively. Similar tracer uptake is seen in the two studies, with clear separation of caudate and putamen signal.
Results Typical images of cumulative striatal 18F-Dopa uptake in 2 healthy subjects aged 31 and 76 years, respectively, are shown in Figure 4. Activity in caudate and putamen may clearly be distinguished in each case, and greatly exceeds activity in cortical and white matter regions. Within cortex, the greatest accumulation of activity is seen in medial frontal areas. Data from the first method of analysis, using the occipital reference tissue to calculate Ki (occipital) values for uptake into caudate and putamen in all subjects are shown in Figures 5A and 5B. The linear regressions for these data have an R * value close to zero, demonstrating no correlation between age and "FDopa uptake in any of these regions. Data from the second method of analysis (using a plasma curve with simulated metabolite correction and subtraction of cerebellar counts from striatal counts) were similar. The average Ki (plasma) values describing "F-Dopa uptake into striatal regions did not decline with advancing age (R2 for caudate Ki vs. age, 0.014; R 2 for putamen Ki vs. age, 0.039). A significant correlation was found between individual Ki values obtained by using the two methods of analysis @ < 0.01, Y = 0.495 for caudate; p < 0.05, r = 0.392 for putamen). Uptake into medial frontal cortex was more variable and at lower concentration than into striatal tissue but nevertheless exceeded uptake into other cortical regions by either analytical method. There was no significant decline in medial frontal cortex Ki calculated by using either an occipital or a plasma input function (R2,0.020 and 0.124, respectively). Physiological S t d i e s
The results of the physiological measures were correlated with age and the two measures of putaminal I*F-Dopa uptake. Many of the subjects had difficulty in
Sawle et al: Dopa Uptake in Normal Aging 801
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F i g 5 . (A)and (Bj show the values of K, (occipital)for caudate and pgctamen, respectively. The values for each patient have been plotted as a function of age. The R2values demonstrate no cowelation between age and Ki (occipital)for either region.
correctly performing the sequential movements rapidly but did the other tests well. The mean level of EMG required to hold the initial torques increased significantly with age at both the wrist and thumb (R2 = 0.35, p = 0.003 for the wrist; R 2 = 0.21, p = 0.017 for the thumb). The size of the stretch reflex at the wrist fell with age ( R 2 = 0.14,p = 0.046).There was no significant change in its duration, nor the size of the stretch reflex at the thumb. No other measure of movement performance showed a significant change with age, although trends for slower movement were present for flexion ( R 2 = 0.05), squeeze (Fig 6), and right-sided repetitive thumb abduction. None of the physiological parameters showed significant correlations with both methods of calculating putaminal "F-Dopa uptake.
Discussion The principal finding of this study is the absence of an aging effect on the uptake of "F-Dopa into caudate or putamen, as measured by PET in healthy adults aged 27 to 76 years. Additionally, physiological studies in the subjects older than 55 years showed no significant age-related change in any of several measures reported to be abnormal in Parkinson's disease. Striatal "F-Dopa accumulation represents uptake into nerve terminals, conversion into '8F-fluorodopamine by AAAD, and subsequent concentration and storage in terminal neurotransmitter vesicles f24). A 802
70
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Fig 6. The timefrom onset to peak of a rapid isometric hundgrip (squeeze) in the 21 oldest patients. R2 value indicates no sign$cant cowelation with age.
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reduction in 18F-Dopauptake represents a reduction in the number of functioning nigrostriatal dopaminergic neurons. We have used two similar analytical methods to derive quantitative data regarding the rate of "FDopa uptake into brain. Neither method can give absolute quantitation of endogenow dopamine formation because the principal substrate for AAAD comes from brain tyrosine and not from plasma Dopa. Martin and co-workers 112) reported "F-Dopa uptake data from 10 asymptomatic patients aged 22 to 80 years in whom they reported a linear reduction between influx of 18F-Dopa and age. These workers measured caudate and putamen together as a single "striatal" region of interest. Only 4 of their subjects were aged over 50 years, however, and in these subjects there is no decline with age (range, -50-80 years). Neither study, therefore, provides any evidence of an age-effect in the age group of 50+ years, which is the age at which Parkinson's disease most commonly presents. This argues against a normal aging effect precipitating Parkinson's disease in a patient who has suffered an acute but possibly subclinical illness causing nigral cell depletion in early life. There is no clear agreement between our study and that of Martin and co-workers [12) who found a significant effect of aging on nigral uptake of I8F-Dopa. We analyzed our data in a broadly similar way, except that we were not able to measure plasma metabolites in our volunteers, and we accordingly used a simulated metabolite correction based on the data of Martin and co-workers. We have assumed a fixed trend of change in the rate of conversion of "F-Dopa to OMFD with age. We believe this approach is justified by the coefficient of regression ( R 2 = 0.646) of the metabolite data of Martin and co-workers [12) (see previous personal communication). Clearly, any subtle nonlinearity of this age effect might affect the conclusions based on this form of analysis. Martin and co-workers [IZ} subtracted temporal cortex counts from striatal counts (to remove background nonspecific signal), whereas we subtracted cerebellar counts because cere-
No 6 December 11990
bellum contains fewer dopaminergic neurons. Martin and co-workers [l21 studied their patients at a lower scanner resolution and were unable to fractionate striatal counts into caudate and putamen. They calculated their influx constant per striatum (including all counts for a given structure), whereas we calculated ours per volume. We studied a larger number of subjects (26 vs. lo), although our youngest patient was older than in the report of Martin and co-workers [la] (27 vs. 22). These slight methodological differences seem insufficient, however, to explain our different conclusions over the broader age group. It is possible that PET studies with a tracer such as 4[‘*F)fluoro-L-m-tyrosine, which suffers very little peripheral metabolism, might provide data suitable for quantitative analysis without the complications of metabolite correction {25}, although it has yet to be demonstrated that striatal accumulation of this tracer represents vesicular storage. Most previous studies of aging of the nigrostriatal system have been neurochemical or histopathological. Carlsson and Winblad 1261 measured caudate and putamen dopamine levels in 30 brains, concluding that approximately half of the variation in log(dopamine + methoxytyramine) concentration could be explained by a combination of the subjects’ age and deathautopsy interval. Riederer and Wuketich 1271 reported a 12.8% loss of caudate dopamine per decade in 28 control patients without neurological disease who died at age 45 to 95 years. McGeer and McGeer [3} presented data for 22 patients meeting sudden and unexpected death, and 6 patients in the hospital, dying from nonneurological illnesses. There was a clear fall in caudate and putamen TH levels between groups of patients aged l to 18 and 19 to 38 years but little decline in the older age groups. AAAD similarly fell between the groups of patients aged 1 to 18 and 19 to 38 years with little further fall. No significant correlation was found between age and TH in the substantia nigra C6t6 and Kremzner [281 reported TH loss in the substantia nigra, whereas Grote and colleagues 141 found no decline in TH concentration with age in patients aged 30 years and older. Recently, Scherman and co-workers [291 reported the binding of [3H)a-dihydrotetrabenazine ([3H1T13ZOH), a specific ligand of the vesicular monoamine transporter, in the brains of normal patients and patients with Parkinson’s disease. They found a reduction in caudate but not putamen r3H)TBZOH binding with age in normal patients, and yet a rise in caudate L3H}TBZOH binding with age in brains of patients with Parkinson’s disease. The rate of decrease of E3H)TBZOH binding in patients with Parkinson’s disease was identical, whether the onset of Parhnson’s disease occurred before or after the age of 60 years, suggesting that age does not enhance the rate of progression of the dopaminergic lesions.
There have been very few reports of cell counts in the substantia nigra of patients dying without neurological illness. McGeer and colleagues [61 reported counts for the substantia nigra of 13 brains that were not screened for Lewy bodes. Gibb and Lees I51 found that up to 12.8% of apparently healthy elderly people have incidental Lewy bodies, so studies of “clinically normal” elderly people may include individuals with nigral k w y bodies and hence preclinical Parkinson’s disease. Of the patients of McGeer and colleagues [6] who were aged 30 years or older, all had similar cell counts except for a single patient aged more than 80 years, in whom the count was within the range seen in 4 parkinsonian patients. Mann and co-workers {7] reported nigral cell counts from 67 control patients dying without neurological disease. Nigral cell numbers declined in the groups of patients aged 65 years and older, although some of these patients had incidental Lewy bodies and we would therefore regard them as preclinical parkinsonian patients. More recently, Morris and colleagues {8] counted nigral cells in 8 Lewybody-free, normal control subjects aged 55 to 85 years, finding no correlation between cell numbers and age. Recent postmortem studies of the pars compacta of parkinsonian substantia nigra have demonstrated numerous reactive microglia or macrophages phagocytizing dopaminergic cells [30). This implies an active pathological process at the time of death, which concurs with our assertion that aging does not have a major role in the etiology of Parkinson’s disease. Although ‘*F-Dopa uptake is an indirect measure of nigrostriatal function, it has a major advantage over the other chemical and pathological techniques previously described, in that measurements can be made during life in healthy patients (as well as in early and untreated disease), and such measurements may be repeated in the same individual. The physiological data generally showed only modest change with age. Mortimer and Webster [31), who studied 74 normal subjects, found no significant change in their measures of rigidity or tremor with increasing age but did find a significant fall in tests of speed of movement. In our study, the duration of isometric squeeze and isotonic flexion both showed trends indicative of slowing with increasing age, and the rate of repetitive thumb movement on the right also showed a decline. More powerful, however, was the significant increase in baseline EMG with age, occurring at both the thumb and wrist. This is not a simple consequence of the well-documented fall in strength with age [32] but indicates a systematic change in the relation between force and surface EMG with age. This might reflect changes in motor unit composition with age [3 11 or an alteration in the force production per motor unit, although changes in dermal thickness may contribute. This effect was probably reSawle et al: Dopa Uptake in Normal Aging 803
sponsible for the apparent decline with age in (the normalized value of) stretch reflexes at the wrist. The findings of this study can only be extrapolated to the general population if the patients studied are representative of that population. Our older subjects were recruited from the Parkinson’s Disease Society of Great Britain and were mostly close relatives of patients with Parkinson’s disease. Their educational background and social class varied but all were in good health and showed an active interest in the welfare of their affected relative. We plan to rescan our subjects in 2 to 3 years to assess the effect of age on a longitudinal rather than cross-sectional basis. It will be very interesting if those individuals with the lowest uptake show a decrement of uptake that is greater than any measured for the remainder of the population. G.V.S. is supported by the Parkinson’s Disease Society of Great Britain. We thank colleagues at the MRC Cyclotron Unit, Chemistry and Physics sections, whose expertise made these studies possible. We also thank Ms C.J.V. Taylor and Mr G.C. Lewington for their considerable help with scanning.
References 1. Jellinger K. The pathology of parkinsonism. In: Marsden CD, Fahn S, eds. Movement disorders 2. London: Butterworths, 1987:124-165 2. Leenders KL,Palmer AJ, Quinn N , et al. Brain dopamine metabolism in patients with Parkinson’s disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry 1986;49:853-860 3. McGeer PL, McGeer EG. Enzymes associated with the metabolism of catecholamines, acetylcholine and GABA in human controls and patients with Parkinson’s disease and Huntington’s chorea. J Neurochem 1976;26:65-76 4. Grote SS, Moses SG, Robins E, et al. A study of selective catecholamine metabolizing enzymes: a comparison of depressive suicides and alcoholic suicides with controls. J Neurochem 1974;23:791-802 5. Gibb WRG, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;51:745-752 6. McGeer PL, McGeer EG, Suzuki JS. Aging and extrapyramidal function. Arch Neurol 1977;34:33-35 7. Mann DMA, Yates PO, Marcyniuk B. Monoaminergic neurotransmitter systems in presenile Alzheimer’s disease and in senile dementia of Alzheimer type. Clin Neuropathol 1984;3: 199-205 8. Morris JC, Drazner M, Fulling K, et al. Clinical and pathological aspects of parkinsonism in Alzheimer’s disease. A role for extranigral factors? Arch Neurol 1989;46:651-657 9. Ballard PA, Tetrud JW, Iangston JW. Permanent human parkinsonism due to 1-1nethyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MI“): seven cases. Neurology 1985;35:949-956 LO. Calne DB, Langston JW, Martin WRW, et al. Positron emission tomography after MPTP: observations relating to the cause of Parkinson’s disease. Nature 1985;317:246-248 11. Calne DB, Eisen A, McGeer EG, Spencer P. Alzheimer’s disease, Parkinson’s disease and motoneurone disease: abiotrophic interaction between aging and environment. Lancet 1986;l: 1067-1070
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2. Martin WRW, Palmer MR, Patlak CS, Calne DB. Nigrostriatal function in humans studied with positron emission tomography. Ann Neurol 1989;26:535-542 3. Folstein MF, Folstein SE, and McHugh PR. “Mini-mental state” a practical method for graduating the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198 4. Spinks TJ, Jones T, Gilardi MC, Heather JD. Physical performance of the latest generation of commercial positron scanner. IEEE Trans Nucl Sci 1988;35:721-725 15. Talairach J, Tournoux P. Coplanar stereotaxic atlas of the human brain. New York: Georg Thieme Verlag, 1988 16. Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Plow Metab 1983;3:1-7 17. Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 1985;5:584-590 18. Tedroff J, Aquilonius S-M, Laihmen A, et al. Striatal kinetics of [‘‘]C-( + )-nomifensine and 6-[’8F]fluoro-L-dopa in Parlunson’s disease measured with positron emission tomography. Acta Neurol Scand 1990;81:24-30 19. Brooks DJ, Salmon EP, Mathias CJ. et al. 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 1990 (in press) 20. Tatton WG, Lee RG. Evidence for abnormal long-loop reflexes in rigid Parkinsonian patients. Brain Res 1975;100:671-676 21. Rothwell JC,Obeso JA, Traub MM, et al. The behaviour of the long-latency stretch reflex in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1983;46:35-44 22. Benecke R, Rothwell JC, Dick JPR, et al. Performance of simultaneous movements in patients with Parkinson’s disease. Brain 1986;1091739-7 57 23. Benecke R, Rothwell JC, Dick JPR, et al. Disturbance of sequential movements in patients with Parkinson’s disease. Brain 1987;110:361-379 24. Firnau G, Sood S, Chirakal R, et al. Cerebral metabolism of 6-f1*F]fluoro-L3,4-dihydroxyphenylalanine in the primate. J Neurochem 1987;48:1077- 1082 25. Barrio JR, Melaga WP, Grafton S, et al. 4-[’sF)Fluoro-~-mtyrosine: A biochemical probe of striatal dopaminergic function with PET. J Cereb Blood Flow Metab 1989;9:S193 26. Carlsson A, Winblad B. Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm 1976;38:271276 27. Lederer P, Wuketich St. Time course of nigrostriatal degeneration in Parkinson’s disease. J Neural Transm 1976;38:277-301 28. CBti LJ, Kremzner LT. Changes in neurotransmitter systems with increasing age in human brain. Trans Am SOCNeurochem 1974;5:83 29. Scherman D, Desnos C, Darchen F, et al. Striatal dopamine deficiency in Parkinson’s disease: Role of aging. Ann Neurol 1989;26:551-557 30. McGeer PL, Itagaki S, Akiyama H, McGeer EG. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 1988;24:574-576 31. Mortimer JA, Webster DD. Comparison of extrapyramidal motor function in normal aging and Parlunson’s disease. In: Mortimer JA, Pirozzolo FJ, Maletta GJ, eds. The aging motor system, advances in neurogerontology, vol3. New York: Praeger, 1982:217-241 32. Larsson L. Aging in mammalian skeletal muscle. In: Mortimer JA, Pirozzolo FJ, Maletta GJ, eds. The aging motor system, advances in neurogerontology, vol 3 New York: Praeger, 1982:60-97
Vol 28 No 6 December 1990
Lewy body Parkinson's disease becomes clinically manifest when patients have lost approximately 50 to 80% of pigmented nigral neurones [l], and positron emission tomographic (PET) scans in affected patients show a 60% reduction of ~-6-{~~F)fluoro-Dopa ("F-Dopa) uptake into striatal tissue {2]. Several authors have correlated postmortem measurements of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AAAD) in subjects dying without neurological disease in life [ 3 , 41, and some have reported a fall in concentration with age, most pronounced in the first three decades. Patients dying without neurological disease may have incidental nigral Lewy bodies [ S ] . Including such patients, who should be regarded as patients with preclinical Parkinson's disease, among normal patients might have contributed to the finding of a fall in nigral cell numbers with age {C,-S]. The selective nigral neurotoxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), has provided a toxicological model for the development of Parkinson's disease {9],and PET studies have demonstrated a subclinical reduction of "F-Dopa in patients exposed to MPTP who have not developed clinical parkinsonism {lo]. It has been suggested that Parkinson's disease might be due to subclinical exposure to an MFTPlike agent in early or middle life, and that the
From the *MRC Cyclotron Unit, Clinical Sciences Section, and the TMRC Cyclotron LJnit, Chemistry Section, Hammersmith Hospital, the 8MRC Human Movement and Balance Unit' and the sity Department of Clinical Neurology, Institute of Neurology, National Hospitals for Nervous Diseases, London, UK.
subsequent "normal" effect of aging on the nigrostriatal system could then reduce cell numbers further, to the degree of depletion required for the appearance of overt clinical parkinsonism {ll]. Recent PET evidence in favor of an aging effect has come from Martin and colleagues [12] who measured total striatal 18FDopa uptake in asymptomatic individuals. The primary object of the present study was to measure in normal volunteers, particularly those over the age of 50 years, the effect of age on "F-Dopa uptake into caudate, putamen, and medial frontal cortex. Additionally, the older patients also underwent a series of physiological tests thought to be related to striatal function.
Methods All subjects were examined and found to have no clinical evidence of rigidity, bradykinesia, or tremor. None had any neurological history. All scored 30 of 30 on the mini mental test 1131.
PET Studies Twenty-six healthy volunteers between the ages of 27 and 76 years were studied with PET. Scans were performed on the CTI 981/12/8 scanner (CTI, Knoxville, TN) at the MRC Cyclotron Unit at the Hammersmith Hospital (London, England). The performance characteristics of this scanner are as described by Spinks and colleagues l14). The final effective
Received Dec 6, 1989, and in revised form Apr 6 and Jun 21, 1990. Accepted for publication Jun 25, 1990. Address correspondence lo Dr Sawle, MRC Cyclotron Unit, Clinical Sciences Section, Hammersmith Hospital, 150 DuCane Road, London W12 OHS. UK.
Copyright 0 1990 by the American Neurological Association
733
spatial resolution for 15 simultaneously acquired slices is 8.5 X 8.5 X 7.0 mm (at full width half maximum). Ethical permission for these studies and for studies on normal volunteers was obtained from the ethical committee of the Royal Postgraduate Medical School, Hammersmith Hospital. Approval to administer radiolabeled gases and ligands was obtained from the Administration of Radioactive Substances Advisory Committee of the United Kingdom (ARSAC). Written consent was obtained from all volunteers after a full explanation of the procedure. For all studies, subjects were positioned in the scanner with the orbitomeatal line parallel to the detector rings, the head being immobilized in an individually molded polyurethane support. A 22-gauge arterial cannula was inserted into the radial artery after subcutaneous infiltration with bupivacaine 1%. A 10-minute transmission scan was collected by using a retractable 68Ga/68Gering source. Subjects received 100 mg carbidopa 1 hour before the study to inhibit peripheral aromatic amino acid decarboxylase. A further 50 mg carbidopa was given immediately before scanning to maintain plasma levels of carbidopa throughout the length of the study. Each patient received approximately 140 MBq "F-Dopa (mean, 137 MBq; SD, 54) by intravenous infusion over 2 minutes. Dynamic emission scans were collected for the following 124 minutes divided into 28 time frames. I8F-Dopa scans were analyzed by using image-analysis software (Analyze version 2.0, Biodynamics Research Unit, Mayo Foundation, Rochester, MN) on SUN 3/60 Workstations (Sun Microsystems, Inc, Mountain View, CA). The position of striatal structures was determined by inspection, with reference to the stereotactic atlas of Talairach and Tourn o w [l5]. Regions of interest were defined for caudate (1 region each side of 4 x 4 pixels; 1 pixel, 2.05 mm), putamen (3 regions each side of 4 x 4 pixels, placed contiguously along the axis of the structure), medial frontal cortex (1 circular region of diameter 8 purels), occipital lobe (1 circular region each side of d m e t e r 16 pixels), and cerebellum (dimensions as for occipital regions). The medial frontal cortex, caudate, putamen, and occipital lobe regions were defined on the same planes. The cerebellar regions were defined on lower planes. The occipital and cerebellar regions were of sufficient size to include both Cortex and white matter. The posterior midline was avoided in each case to avoid sampling activity within venous sinuses. All regions of interest were defined on two adjacent planes, and appropriately weighted average values for each anatomical structure were calculated. Regional time activity curves were plotted (Fig l), demonstrating the initial entry of tracer into all regions with subsequent washout from cerebellum and occipital cortex, and irreversible trapping within strianun (see Fig 1). The data were further analyzed by using two adaptations of the multiple-time-graphical analysis (MTGA) as described by Patlak and co-workers [16, 171. In the MTGA approach, the irreversible uptake of tracer into a tissue compartment (in this case, the trapping of {'8Fffluorodopamine in terminal vesicles) is measured by a comparison of the rate of change of activity in the tissue of interest (striacum) against a uansformed and expanded time scale. In the first case, we have used an adaptation of this approach similar to that described by Tedroff and colleagues 1181 but using occipital activity in place of cerebellar activity as reference tissue [l9f. Occipital
c
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Fig 1. Regional decay-cowected time-activity data after injection of ~-b-{'~F}fltloro-Dopa ("F-Dopa). Uptakes into caudate and putamen were similar, greatly exceeding uptake into other regions. Uptake into medial frontal cortex exceeded uptake into cerebellum or occipital cortex.
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Fig 2. Method of calculation of K, (occipital)by using the occipital cortex as a reference tissue. K, was given by the gradient of the linear regression t o the data points.
and cerebellar nonspecific input functions yield similar Ki values for striatal "F-Dopa uptake. The plot of region/ occipital activity versus integrated occipitalioccipital activity is linear for the data collected from 30 to 90 minutes from injection (Fig 2). The gradient of the linear regression to this data describes the rate of irreversible trapping of activity, the influx constant Ki (occipital) min- I. Although this analysis has the advantage of simplicity in that arterial cannulation is unnecessary, it may be criticized on the grounds that the peripherally formed metabolite ~-3-O-methyl-6-{'~F}fluoroDopa (OMFD) enters the brain but cannot be further metabolized to ["Flfluorodopamine. The net effect may be to underestimate the true rate of specific tracer uptake. This would be particularly important if the rate of peripheral metabolism changed as a function of age, and for this reason, our data have also been analyzed by using another adaptation of the MTGA approach, similar to that described by Martin and co-workers { 12}. Assuming the cerebellum contains only nonspecific background activity (including plasma-derived metabolites), we subtracted cerebellar activity from striatal activity to obtain specific striatal activity. The arterial plasma curve was corrected for the accumulation of OMFD, assuming a linear increase in the ratio of 0MFD:"F-Dopa with time. The rate of increase of the ratio OMFD:18F-Dopa with time varies according to age, and the gradient of this increase may be described by the following linear equation: 0.084 - (0.0004
800 Annals of Neurology Vol 28 No 6 December 1990
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Fig 3. Method of calculation of K, (plasma} by using metabolitecorrected plasma as input function and subtracting cerebellar counts from regional counts. As with the occipital analysis, the value of Ki (plasma) was derived from the gradient of the linear regression t o the data. x age), R2 = 0.646 (W.R.W. Martin, personal communication, 1989). The plot of region cerebellar activity/plasma activity versus integrated plasma activity/plasma activity for the time 30 to 120 minutes from injection is shown in Figure 3. Again, the value ofKi (plasma) min-' was calculated from the gradient of the linear regression to this data.
Physiological Sttldies Physiological measurements were made on the 21 patients aged 55 years or older (11 women 66-77 years old [mean age, 63.6 years); 10 men 56-76 years old [mean age, 65.5 years)). All recordings were made on a separate occasion from the PET scan, all were made bilaterally, and the final results were averaged. Three types of test were performed, that is, stretch reflexes, movement times for simple and complex tasks, and rates of repetitive movement. The first two are known to show characteristic abnormalities in Parkinson's disease 120-231 and are thus probably dependent on normal striatal function. Stretch reflexes were recorded at both the thumb and the wrist; conventional methods were used [20). At the thumb, a series of servocontrolled linear stretches were applied; whereas, at the wrist, three different torque pulses were used, each level of stretch being presented pseudorandomly. Resting torques were 0.10 and 0.23 Nm, respectively. The long-latency stretch reflex was identified visually from the averaged records. The duration was measured and the size quantitated as a ratio to the level of resting electromyogram (EMG) immediately before the stretch. The durations of simple and sequential movements were recorded for the elbow (isotonic flexion) and handgrip (isometric squeeze) by using methods previously reported 121, 22). Ten trials were performed of each type of movement on both sides. All trials were measured and the results averaged. The rate of repetitive thumb abduction was recorded by using a manipulandum, which kept the fingers fixed while allowing thumb abduction. The subjects were instructed to repetitively abduct the thumb 3 cm as quickly as possible for 30 seconds. Only one recording was made on each side. The number of completed movements in the first and final 10 seconds were measured.
F i g 4. Images of striatal~-6-['~F}Jluoro-Dopa ("F-Dopa) uptake in 2 patients, aged 31 and 76 years, respectively. Similar tracer uptake is seen in the two studies, with clear separation of caudate and putamen signal.
Results Typical images of cumulative striatal 18F-Dopa uptake in 2 healthy subjects aged 31 and 76 years, respectively, are shown in Figure 4. Activity in caudate and putamen may clearly be distinguished in each case, and greatly exceeds activity in cortical and white matter regions. Within cortex, the greatest accumulation of activity is seen in medial frontal areas. Data from the first method of analysis, using the occipital reference tissue to calculate Ki (occipital) values for uptake into caudate and putamen in all subjects are shown in Figures 5A and 5B. The linear regressions for these data have an R * value close to zero, demonstrating no correlation between age and "FDopa uptake in any of these regions. Data from the second method of analysis (using a plasma curve with simulated metabolite correction and subtraction of cerebellar counts from striatal counts) were similar. The average Ki (plasma) values describing "F-Dopa uptake into striatal regions did not decline with advancing age (R2 for caudate Ki vs. age, 0.014; R 2 for putamen Ki vs. age, 0.039). A significant correlation was found between individual Ki values obtained by using the two methods of analysis @ < 0.01, Y = 0.495 for caudate; p < 0.05, r = 0.392 for putamen). Uptake into medial frontal cortex was more variable and at lower concentration than into striatal tissue but nevertheless exceeded uptake into other cortical regions by either analytical method. There was no significant decline in medial frontal cortex Ki calculated by using either an occipital or a plasma input function (R2,0.020 and 0.124, respectively). Physiological S t d i e s
The results of the physiological measures were correlated with age and the two measures of putaminal I*F-Dopa uptake. Many of the subjects had difficulty in
Sawle et al: Dopa Uptake in Normal Aging 801
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F i g 5 . (A)and (Bj show the values of K, (occipital)for caudate and pgctamen, respectively. The values for each patient have been plotted as a function of age. The R2values demonstrate no cowelation between age and Ki (occipital)for either region.
correctly performing the sequential movements rapidly but did the other tests well. The mean level of EMG required to hold the initial torques increased significantly with age at both the wrist and thumb (R2 = 0.35, p = 0.003 for the wrist; R 2 = 0.21, p = 0.017 for the thumb). The size of the stretch reflex at the wrist fell with age ( R 2 = 0.14,p = 0.046).There was no significant change in its duration, nor the size of the stretch reflex at the thumb. No other measure of movement performance showed a significant change with age, although trends for slower movement were present for flexion ( R 2 = 0.05), squeeze (Fig 6), and right-sided repetitive thumb abduction. None of the physiological parameters showed significant correlations with both methods of calculating putaminal "F-Dopa uptake.
Discussion The principal finding of this study is the absence of an aging effect on the uptake of "F-Dopa into caudate or putamen, as measured by PET in healthy adults aged 27 to 76 years. Additionally, physiological studies in the subjects older than 55 years showed no significant age-related change in any of several measures reported to be abnormal in Parkinson's disease. Striatal "F-Dopa accumulation represents uptake into nerve terminals, conversion into '8F-fluorodopamine by AAAD, and subsequent concentration and storage in terminal neurotransmitter vesicles f24). A 802
70
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Fig 6. The timefrom onset to peak of a rapid isometric hundgrip (squeeze) in the 21 oldest patients. R2 value indicates no sign$cant cowelation with age.
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reduction in 18F-Dopauptake represents a reduction in the number of functioning nigrostriatal dopaminergic neurons. We have used two similar analytical methods to derive quantitative data regarding the rate of "FDopa uptake into brain. Neither method can give absolute quantitation of endogenow dopamine formation because the principal substrate for AAAD comes from brain tyrosine and not from plasma Dopa. Martin and co-workers 112) reported "F-Dopa uptake data from 10 asymptomatic patients aged 22 to 80 years in whom they reported a linear reduction between influx of 18F-Dopa and age. These workers measured caudate and putamen together as a single "striatal" region of interest. Only 4 of their subjects were aged over 50 years, however, and in these subjects there is no decline with age (range, -50-80 years). Neither study, therefore, provides any evidence of an age-effect in the age group of 50+ years, which is the age at which Parkinson's disease most commonly presents. This argues against a normal aging effect precipitating Parkinson's disease in a patient who has suffered an acute but possibly subclinical illness causing nigral cell depletion in early life. There is no clear agreement between our study and that of Martin and co-workers [12) who found a significant effect of aging on nigral uptake of I8F-Dopa. We analyzed our data in a broadly similar way, except that we were not able to measure plasma metabolites in our volunteers, and we accordingly used a simulated metabolite correction based on the data of Martin and co-workers. We have assumed a fixed trend of change in the rate of conversion of "F-Dopa to OMFD with age. We believe this approach is justified by the coefficient of regression ( R 2 = 0.646) of the metabolite data of Martin and co-workers [12) (see previous personal communication). Clearly, any subtle nonlinearity of this age effect might affect the conclusions based on this form of analysis. Martin and co-workers [IZ} subtracted temporal cortex counts from striatal counts (to remove background nonspecific signal), whereas we subtracted cerebellar counts because cere-
No 6 December 11990
bellum contains fewer dopaminergic neurons. Martin and co-workers [l21 studied their patients at a lower scanner resolution and were unable to fractionate striatal counts into caudate and putamen. They calculated their influx constant per striatum (including all counts for a given structure), whereas we calculated ours per volume. We studied a larger number of subjects (26 vs. lo), although our youngest patient was older than in the report of Martin and co-workers [la] (27 vs. 22). These slight methodological differences seem insufficient, however, to explain our different conclusions over the broader age group. It is possible that PET studies with a tracer such as 4[‘*F)fluoro-L-m-tyrosine, which suffers very little peripheral metabolism, might provide data suitable for quantitative analysis without the complications of metabolite correction {25}, although it has yet to be demonstrated that striatal accumulation of this tracer represents vesicular storage. Most previous studies of aging of the nigrostriatal system have been neurochemical or histopathological. Carlsson and Winblad 1261 measured caudate and putamen dopamine levels in 30 brains, concluding that approximately half of the variation in log(dopamine + methoxytyramine) concentration could be explained by a combination of the subjects’ age and deathautopsy interval. Riederer and Wuketich 1271 reported a 12.8% loss of caudate dopamine per decade in 28 control patients without neurological disease who died at age 45 to 95 years. McGeer and McGeer [3} presented data for 22 patients meeting sudden and unexpected death, and 6 patients in the hospital, dying from nonneurological illnesses. There was a clear fall in caudate and putamen TH levels between groups of patients aged l to 18 and 19 to 38 years but little decline in the older age groups. AAAD similarly fell between the groups of patients aged 1 to 18 and 19 to 38 years with little further fall. No significant correlation was found between age and TH in the substantia nigra C6t6 and Kremzner [281 reported TH loss in the substantia nigra, whereas Grote and colleagues 141 found no decline in TH concentration with age in patients aged 30 years and older. Recently, Scherman and co-workers [291 reported the binding of [3H)a-dihydrotetrabenazine ([3H1T13ZOH), a specific ligand of the vesicular monoamine transporter, in the brains of normal patients and patients with Parkinson’s disease. They found a reduction in caudate but not putamen r3H)TBZOH binding with age in normal patients, and yet a rise in caudate L3H}TBZOH binding with age in brains of patients with Parkinson’s disease. The rate of decrease of E3H)TBZOH binding in patients with Parkinson’s disease was identical, whether the onset of Parhnson’s disease occurred before or after the age of 60 years, suggesting that age does not enhance the rate of progression of the dopaminergic lesions.
There have been very few reports of cell counts in the substantia nigra of patients dying without neurological illness. McGeer and colleagues [61 reported counts for the substantia nigra of 13 brains that were not screened for Lewy bodes. Gibb and Lees I51 found that up to 12.8% of apparently healthy elderly people have incidental Lewy bodies, so studies of “clinically normal” elderly people may include individuals with nigral k w y bodies and hence preclinical Parkinson’s disease. Of the patients of McGeer and colleagues [6] who were aged 30 years or older, all had similar cell counts except for a single patient aged more than 80 years, in whom the count was within the range seen in 4 parkinsonian patients. Mann and co-workers {7] reported nigral cell counts from 67 control patients dying without neurological disease. Nigral cell numbers declined in the groups of patients aged 65 years and older, although some of these patients had incidental Lewy bodies and we would therefore regard them as preclinical parkinsonian patients. More recently, Morris and colleagues {8] counted nigral cells in 8 Lewybody-free, normal control subjects aged 55 to 85 years, finding no correlation between cell numbers and age. Recent postmortem studies of the pars compacta of parkinsonian substantia nigra have demonstrated numerous reactive microglia or macrophages phagocytizing dopaminergic cells [30). This implies an active pathological process at the time of death, which concurs with our assertion that aging does not have a major role in the etiology of Parkinson’s disease. Although ‘*F-Dopa uptake is an indirect measure of nigrostriatal function, it has a major advantage over the other chemical and pathological techniques previously described, in that measurements can be made during life in healthy patients (as well as in early and untreated disease), and such measurements may be repeated in the same individual. The physiological data generally showed only modest change with age. Mortimer and Webster [31), who studied 74 normal subjects, found no significant change in their measures of rigidity or tremor with increasing age but did find a significant fall in tests of speed of movement. In our study, the duration of isometric squeeze and isotonic flexion both showed trends indicative of slowing with increasing age, and the rate of repetitive thumb movement on the right also showed a decline. More powerful, however, was the significant increase in baseline EMG with age, occurring at both the thumb and wrist. This is not a simple consequence of the well-documented fall in strength with age [32] but indicates a systematic change in the relation between force and surface EMG with age. This might reflect changes in motor unit composition with age [3 11 or an alteration in the force production per motor unit, although changes in dermal thickness may contribute. This effect was probably reSawle et al: Dopa Uptake in Normal Aging 803
sponsible for the apparent decline with age in (the normalized value of) stretch reflexes at the wrist. The findings of this study can only be extrapolated to the general population if the patients studied are representative of that population. Our older subjects were recruited from the Parkinson’s Disease Society of Great Britain and were mostly close relatives of patients with Parkinson’s disease. Their educational background and social class varied but all were in good health and showed an active interest in the welfare of their affected relative. We plan to rescan our subjects in 2 to 3 years to assess the effect of age on a longitudinal rather than cross-sectional basis. It will be very interesting if those individuals with the lowest uptake show a decrement of uptake that is greater than any measured for the remainder of the population. G.V.S. is supported by the Parkinson’s Disease Society of Great Britain. We thank colleagues at the MRC Cyclotron Unit, Chemistry and Physics sections, whose expertise made these studies possible. We also thank Ms C.J.V. Taylor and Mr G.C. Lewington for their considerable help with scanning.
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