Presynaptic and Postsynaptic Striatd Dopaminergic Function in Neuroacanthocytosis: A Positron Emission Tomographic Study ~
D. J. Brooks, MD,*? V. Ibanez, MD,* E. D. Playford, MRCP," G. V. Sawle, MD," P. N. Leigh, PhD,$ R. S. Kocen, FRCP,? A. E. Harding, MD,? and C. D. Marsden, DSct
Using [lBF}dopa,["C}raclopride, CI5O2,and positron emission tomography, we have assessed striatal dopamine storage capacity, dopamine D,-receptor integrity, and regional cerebral blood flow, respectively, of 6 patients with neuroacanthocytosis. The patients with neuroacanthocytosis all had chorea and variable combinations of seizures, dementia, axonal neuropathy, and orolingual self-mutilation. {"Fldopa positron emission tomographic findings were compared with 30 normal controls and 16 patients with sporadic, L-dopa-responsive, Parkinson's disease. Caudate and anterior putamen { "Fldopa uptake were normal in patients with neuroacanthocytosis, but mean posterior putamen {"FJdopa uptake was reduced to 42% of normal, similar to that in patients with Parkinson's disease. In patients with neuroacanthocytosis, mean equilibrium caudate :cerebellum and putamen: cerebellum {"CJraclopride uptake ratios were reduced to 54% and 62% of normal, compatible with a 65% and 53% loss of caudate and putamen D,-receptor-binding sites, respectively. Striatal and frontal blood flow was also depressed. The severe loss of D,-receptor-bearing striatal neurons, with concomitant loss of dopaminergic projections from the nigra to the posterior putamen, is consistent with both chorea and extrapyramidal rigidity being features of patients with neuroacanthocytosis. Brooks DJ, Ibanez V, Playford ED, Sawle GV, Leigh PN, Kocen RS, Harding AE, Marsden CD. Presynaptic and postsynaptic striatal dopaminergic function in neuroacanthocytosis: a positron emission tomographic study. Ann Neurol 1991;30:166-171
Neuroacanthocytosis (NA) is a condition characterized clinically by chorea, dystonia, tics, seizures, dementia, amyotrophy, areflexia, and orolingual self-mutilation { 1-41. Paradoxically, parkinsonian signs frequently accompany the chorea, particularly as the disease progresses 141. Acanthocytes are found on wet blood films, however, unlike Bassen-Kornzweig disease, serum lipoprotein electrophoresis and vitamin E levels are normal. The inheritance of NA is unclear because autosomal dominant, recessive, X-linked, and sporadic forms have all been reported [3}. Computed tomographic scanning (CT) may reveal caudate atrophy in these patients [4, 51, and magnetic resonance imaging (MIU) increased signal from the caudate and lentiform nuclei [4}. Two positron emission tomographic (PET) studies have reported low caudate glucose utilization [b, 7) in patients with neuroacanthocytosis, but because patients with Huntington's disease, benign fmilial chorea, and dentatorubropallidoluysianatrophy may also show low caudate metabolism, this PET finding is nonspecific E7-9).
Striatal ['8F1dopa and ["C)raclopride uptake reflect striatal dopamine storage capacity [lo} and the integrity of striatal dopamine D,-receptors [I 11, respectively. In view of the chorea and concomitant parkinsonian signs (rigidity and bradykinesia) that dominate the clinical syndrome of neuroacanthocytosis, we believed it would be noteworthy to examine the pre- and postsynaptic striatal dopaminergic system in patients with this condition. PET findings were compared with those of normal control subjects and patients with sporadic, L-dopa-responsive, Parkinson's disease (PD).
From *MRC Cyclotron Unit, Hammersmith Hospital, ?Institute of Neurology, Queen Square, and $Institute of Psychiatry, Denmark Hill, London, England.
Received Oct 19, 1990, and in revised form Jan 15, 1991.Accepted for publication Feb 5, 1991.
Methods
Patient Selection Six patients with NA, aged 31 to 46 years, had ["F)dopa PET scans. One patient had an affected father, brother, and two sisters; 2 patients had a single affected sibling; and 3
patients had apparent sporadic disease. All had chorea at the time of PET scanning, though 2 presented with epilepsy. Acanthocytes constituted 8 to 50% of red cells on wet blood films. Five of the 6 patients with NA had normal CT brain
Address correspondence to Dr Brooks, MRC Cyclotron Unit, Hammersmith Hospital, Du Cane Road, London W12 OHS, England.
166 Copyright 0 1991 by the American Neurological Association
Table 1. Neuroacanthocytosis Patient Details
Patient
Sex
Age (yr)
D.B.
F
37
E.B."
F
W.W."
F
M.T." M.F. K.H.
Duration (yr)
Acanthocytes
(%I
Clinical
9
50
46
6
30
15
M
34 31
3
21 8
F M
42 36
15 30
30 30
Chorea, Seizures, Dem, OLM, A N Chorea, Dep, Dem, A N Tics Seizures Chorea, Dem, Seitures, AN Chorea, A N Chorea, OLM, A N
Affected Relatives
Treatment (daily dose)
None
Sulpiride 200 mg
Father, 3 siblings
Trifluoperazine 4 mg
Brother Sister
None None
None None
Haloperidol 3 mg Benzhexol6 mg
"Raclopnde/CBFstudies.
Dem = dementia; OLM = orolingual mutilation; A N
=
axonal neuroparhy;Dep = depression; CBF = cerebral flood flow.
scans, whereas the sixth (M.T.) had evidence of enlarged lateral ventricles and mild frontal atrophy, but no striatal abnormalities. The details of patients with N A are shown in Table 1. Three of the 6 patients with NA also had ["Clraclopride scans, with concomitant measurement of regional cerebral blood ffow (rCBF) using steady-state inhalation of C150,. Suiatal [lBF]dopa uptake of the group of patients with NA was compared with that of 30 normal control subjects, aged 30 to 77 years, and with 16 patients aged 38 to 76 years who had L-dopa-responsive PD. Disability of the patients with PD ranged from 1 to 4 on the Hoehn and Yahr scale [l2] when assessed 12 hours after stopping treatment, and their clinical details have been presented previously [13]. The striatal ["Clraclopride uptake of 3 of the patients with NA was compared with that of 7 normal control subjects, and their striatal blood flow with 8 control Subjects.
Scanning Procedure PET scans were performed on a CTI 981/08/12 tomograph (CTI, Knoxville, TN) giving 15 simultaneous planes with an axial full width half maximum resolution of 7 mm, and an in-plane resolution of 8.5 X 8.5 mm [14]. Correction for tissue attenuation of 5 11 keV gamma-radiation was measured with an external 68Ge ring source. Three of the 6 patients ( 1 of whom had ["Clraclopride) were taking dopaminereceptor blocking agents and these were stopped the day before PET scanning. During the hour preceding (l8F1dopa scanning, subjects were given a 150-mg oral dose of carbidopa, a peripheral dopa decarboxylase blocker. All subjects were fasted for 12 hours before PET. ["F}dopa, 2 to 5 mCi (mean specific activity, 8 mBq/ pmol) in 10 ml of normal saline, was infused intravenously over 2 minutes. Scanning began at the start of tracer infusion with serial 1-minute, increasing to 5-minute, time frames over 90 minutes, providing a total of 25 time frames. f"C]raclopride, 5 to 8 mCi in 5 ml of normal saline, was infused intravenously over 2 minutes. Scanning began at the start of tracer infusion with serial 30-second, increasing to 5-minute, time frames over 60 minutes, providing a total of 2 1 time frames. Measurements of rCBF were performed before ["Clraclopride administration using steady-state tracer inhalation of Cl5O2,as previously described { 15).
Data Anabsis Region of interest (ROI) analysis was performed on SUN 31 60 workstations (SUN Microsystems Inc, Mountain View, CA) using image analysis software (ANALYZE 2.0, BRU, Mayo Foundation, Rochester, MN). In all subjects, the positions of striatal, occipital, and cerebellar structures were defined by summing time frames to create an integrated image representing activity collected 30 to 90 minutes after rJ8F]dopa or ["C]raclopride administration. Although all the patients with N A had chorea during PET scanning, this was only severe in 1 patient, and neither the integrated images of striatal l8F or "C activity nor the rCBF scans showed evidence of significant degradation due to movement artifact. Where both [18F]dopa and ["Clraclopride scans were performed, the ["Fldopa study always preceded the ["Clraclopride study by several weeks. ROIs were placed by inspection in a standard template arrangement; one circular region 8.2 mm in diameter was placed over the head of caudate and three contiguous circular regions 8.22 mm in diameter were lined along the a x i s of the putamen for each hemisphere in both normal subjects and patients 1131. One circular region 32.8 mm in diameter was placed over the occipital lobe and cerebellar lobe of each hemisphere. This array of ROIs was defined on the rCBF image or the integrated images, or both, of "F and "C activity of the two optimum contiguous 7-mm axial planes for each cerebral structure with reference to the stereotactic atlas of Talairach and Tournow [l6] and then superimposed on individual time frames. Averaged values for each structure (caudate, putamen, occiput, and cerebellum) over two planes were then calculated from the individual hemispheric ROI data. Positions of patient striatal ROJs were checked by superimposing by eye C T images at the appropriate axial level over PET images. None of the 6 subjects studied showed significant striatal atrophy on C T scan, and so partial volume effects were not a problem. After decay correction, regional time-activity curves were plotted for ['*F]dopa and {"Cfraclopride. Specific striatal ['*F)dopa uptake was determined by using a modlfied multiple time graphical analysis (MTGA) approach with an occipital nonspecific tissue rather than a plasma input function [13, 17, IS]. This MTGA approach causes the striatal '*F uptake
Brooks et al: Dopaminergic Function in Neuroacanthocytosis
167
Fig 1. (Left) Positron emission tomographic scans of striatal {l8F)dopauptake, collected 30 t o 90 minutes aftw tracer injec-
tion. for a normal control subject and a patient with neuroacanthocytosis (NAI. The NA scans show selective impairment of posterior putamen {'"F}dopa accumubtion. (Right) Positron curves to become linear over 30 to 90 minutes of real time, and the gradients of the plots obtained using this approach can be regarded as influx constants, K,, which reflect the rate of striatal uptake and decarboxylation of [lXF}dopa and its storage as ['*F)dopamine and its metabolites. Equilibrium striatal :cerebellar ["C)raclopride uptake ratios were the average of eight measurements taken 30 to 60 minutes after tracer administration, when tracer distribution had reached a secular equilibrium throughout brain compartments [ 191.
Results Figure 1 shows PET images of striatal E1sF]d~pa and {"C)raclopride uptake for a normal subject and a patient with NA. The patient with NA shows selective
emi.rsion tomographic scans of striatal {"C) raclopride, collected during the 60 minutes after tracer injection, for a n o m l control subject and a patient with neuroacanthocytosis (NA). The NA scans show low striatal tracer uptake, the caudate king the worrt aflected.
loss of posterior putamen { "Fldopa uptake, and a diffuse reduction in { "C}raclopride uptake, the caudate being more affected than the putamen. Table 2 details mean head of caudate and putamen (whole, anterior, and posterior) {"F)dopa influx constants (Ki) for the groups of control subjects and patients with NA and PD. Mean K, values for caudate and anterior putamen were normal in patients with NA, but posterior putamen {l8F}dopa uptake was reduced to parkinsonian levels. Figure 2A shows individual caudate and global putamen, and Figure 2B anterior and posterior putamen, ["Fldopa Ki values for the normal subjects and patients with NA and PD. They again emphasize selec-
Table 2. Regional Striatal [ I 8F)Dopa In&x Constants (K; Min- ') Subjects (n)
Caudate Head
Putamen Whole
Control (30) N A (6) P D (16)
0.0107 ? 0.0019 0.0098 f 0.0020 0.0090 0.0021"
0.0098 0.0011 0.0068 +- 0.0008" 0.0047 I O.OOlO*b
*
*
ap < 0.05, compared with normal, Bonferroni statistics. ' p < 0.05, compared with NA, Bonferroni statistics. NA = neuroacanthocytosis; PD = Parkinson's disease.
168 Annals of Neurology Vol 30 No 2 August 1991
Putamen Anterior
Putamen Posterior
0.0105 f 0.0021 0.0105 5 0.0014 0.0065 ? 0.0015"b
0.0086 +- 0.0017 0.0036 k 0.0014" 0.0039 ? 0.0013"
tive involvement of dopaminergic projections from the nigra to the posterior putamen in patients with NA. Table 3 details mean equilibrium striatal: cerebellar E1'C}raclopride uptake ratios and rCBF for the groups of normal subjects and patients with NA. Mean N A caudate and putamen {l 'C)raclopride uptake ratios were significantly reduced to 54% and 62% of normal levels. A5 specific striatal { llC}raclopride binding constitutes 70% of the total tracer uptake in normal subjects, our findings are compatible with a mean loss of 6S% and 53% of caudate and putamen D,-receptorbinding sites in our 3 patients with NA. Striatal and frontal blood flow of the patients with N A was also selectively reduced (see Table 3), caudate blood flow being most severely affected (68% of normal).
-1
Ki
0.016 7
Nor (30) Nor (30)
-
0.012
-
0.008
Q
-
0.004
o.Oo0
J
putamen
caudate
A KI min
-' 0.020
0.015
ant
0.010-
T
ant
post 0 005
-
0.000
J
-8* NA (6)
Normals (30)
PD (16)
B Fig 2. (A) A scatter diagram showing individual striatal {'8F}dopa injux constants (%) for control subjects, patients and patients with Parkinson's with neuroacanthocytosis (NA), disease (PO). Caudate tracer uptake is n o m l , but putamen uptake is reduced in patients with NA. (B) A scatter diagram shwing individual regional putamen {'sF)dopa injux constants (%) for control subjects, patients with NA, and patients with PD. Tracer uptake ir selectively impaired in postenor Putamen in patients with NA.
Discussion Striatal ["F)dopa uptake reflects efficiency of transport of L-dopa into nigrostriatal nerve terminals and its subsequent decarboxylation [lo}. As a consequence, striatal [18F]dopa uptake does not measure endogenous dopmaine levels, which are determined by striatal tyrosine hydroxylase activity, but provides a measure of the functional integrity of nigrostriatal nerve terminals and aromatic amino acid decarboxylase activity. Our patients with N A showed normal uptake of {18F]dopa into the head of caudate and anterior putamen, but a mean 58% reduction in posterior putamen tracer uptake. Even the least-affected patient with NA had posterior putamen ["F)dopa accumulation that fell below the normal range. This finding suggests that a selective degeneration of dopaminergic projections from the nigra compacta to the posterior putamen occurs in patients with NA. Such dopaminergic projections have been postulated to arise from the ventrolateral nigral area [ZO}. One postmortem study [4} has reported such a selective loss of pigmented cells from the ventrolateral nigra compacta in patients with NA, in addition to the severe loss of neurons from the caudate and more moderate loss from the lentiform nucleus that is a characteristic feature of this condition. TWOother studies [21, 221, however, noted preservation of nigral
Table 3. Striatal:Cerebellar {"CiRacloprtde Uptake Ratios, and Blood Flow in Patients with N A
Raclopride (n) Normal (7) Caudate
Putamen Frontal Occipital
Cerebellum
3.40 3.55 ... ...
2
0.49
t 0.52
...
rCBF (ml/ml/min) (n) NA ( 3 )
Normal (8)
NA (3)
1.85 5 0.75" 2 0.46"
0.38 t 0.07 0.42 r 0.07 0.46 2 0.10 0.40 0.07 0.40 2 0.07
0.26 0.33
2.20
... ...
*
...
? -t-
0.34
?
0.38 0.41
5
+-
0.03b 0.03 0.05 0.05 0.05
"p < 0.005, bp < 0.025, compared with normal, Student's t tesc. N A = neuroacanthocytosis;K B F
= regional cerebral
blood flow.
Brooks et
al:
Dopaminergic Function in Neuroacanthocytosis 169
pigmented cells, though no formal cell counts were performed in either of these cases. L e y bodies, said to be characteristic in patients with Parhnson's disease, are not found in patients with NA. One postmortem study measured caudate and putamen dopamine levels in their 2 patients with NA and reported a severe global reduction 12I]. This finding is surprising because the substantia nigra of the 2 patients concerned was said to be normally pigmented. The postmortem findings of these authors could only be explained if global degeneration of nigrostriatal terminals occurred with complete preservation of the dopaminergic nigral cell bodies. Our PET findings are against such global degeneration of nigrostriatal nerve terminals occurring, and agree with the findings of the postmortem study 141 reporting selective loss of ventrolateral nigral dopaminergic projections to the posterior putamen. Equilibrium striatal: cerebellar [l'Clraclopride uptake ratios reflect integrity of striatal dopamine D,-receptors [19]. Our PET findings are compatible with a mean 65% loss of caudate and 53% loss of putamen D,-receptor-binding sites in our 3 patients with NA, even the most mildly affected patient showing severe loss of striatal ["Clraclopride binding. Their mean levels of caudate, putamen, and medial frontal blood flow were reduced to 68%, 7996, and 74% of normal, respectively. Dubinsky and colleagues 161 reported up to 71% and 61% reductions in caudate and putamen glucose utilization, respectively, in 2 siblings with NA. Our findings and those of Dubinsky and colleagues 161 suggest that PET is a sensitive means of detecting the presence of striatal degeneration in vivo in patients with NA, either by measuring striatal metabolism or dopamine receptor integrity. They are also in line with pathological reports of more severe involvement of caudate than putamen in patients with NA [4, 21, 22). The presence of low striatal and frontal blood flow and metabolism is not specific for patients with NA. Other causes of chorea such as Huntington's disease (HD), benign familial chorea, and dentatorubropallidoluysian degeneration have also been reported to show this distribution of functional depression C7-91, as does the akinetic-rigid syndrome progressive supranuclear palsy 1231. Severely reduced striatal D,-receptor densiry is also a feature of patients with HD 124, 251. PET, therefore, cannot be used in isolation to diagnose NA, but is a useful means of quantitating the functional consequences of the condition and a potential means of detecting the disease in at-risk subjects. Our finding of reduced striatal D,-receptors in patients with NA, as evidenced by low ["C)raclopride uptake, is at variance to the pathological report of De Yebenes and co-workers 121). These authors measured postmortem putamen D,-receptor-binding Site density and affinity with [3H]spiperone in a single patient with N A and found an increased density and &170 Annals of Neurology Vol 30 No 2 August 1991
finity of binding sites for this tracer. Upregulation of putamen D,-receptor sites in patients with N A would be surprising because severe striatal degeneration similar to that found in patients with HD occurs. Loss of striatal D,-binding sites is a feature in patients with HD 124, 251, and a similar finding in patients with N A would be predicted. Receptor densities of De Yebenes and co-workers {2l] were assessed per unit weight of remaining striatal tissue and so do not correct for striatal neuronal loss, whereas our PET measurements are taken from a standard striatal volume in both patients and control subjects. Combining our PET findings with the pathological data of De Yebenes and colleagues 1213 suggests that in patients with NA, overall striatal density of D,-receptor sites is reduced, however, in those surviving striatal neurons, local D,-receptor upregulation may occur. Three of our patients with N A who had {l8F1dopa scans were takmg dopamine receptor blocking agents (DRBAs) to control their chorea. One of these 3 patients also had an ["C]raclopride study. All medication was stopped for 24 hours before PET, but the presence of these agents could have influenced our PET findings. It has been shown in mice that DRBAs act on striatal presynaptic dopamine receptors to upregulate striatal L-dopa accumulation [26]. It is conceivable, therefore, that our 3 patients with NA taking these agents may have shown a higher level of striatal rL8F]dopauptake than they would have if they were studied when drug naive. The effect of the DRBAs is likely to have been slight, however, since caudate ["Fldopa K, values for ail 6 patients with N A fell well within normal range. It is also conceivable that trifluoperazine therapy may have influenced the striatal I''C]raclopride uptake of 1 of our patients with NA. Short courses of neuroleptic medication lead to sustained striatal D,-receptor upregulation in rats 1271, whereas the presence of the neuroleptic itself could impar access of the { "C)raclopride to D,-receptor sites either by direct occupation of the sites or by inducing receptor internalization 1281. Because the trifluoperazine was stopped 24 hours before PET scanning, it is unlikely that it would still be present to directly block D,-receptor sites in OUT patient with NA. It is impossible to know whether this agent had already caused significant D,-receptor internalization or upregulation but, because our 2 drug-naive patients with N A showed levels of striatal {"Clraclopride uptake similar to our medicated patient, it is likely that the effect of the trifluoperazine was slight. In view of our PET findings, can the presence of both chorea and parkinsonian signs in patients with N A be explamed? The major functional lesion in patients with N A is severe loss of striatd Q-receptor sites, similar to that found in patients with HD {24, 251. It has been elegantly argued by Penney and Young P91 that if selective loss of striatal projections
to the external pallidum occurs, a choreiform disorder will result. Such a finding has been demonstrated in patients with HD with predominant chorea [30]. In patients with HD presenting with an akinetic-rigid syndrome, severe loss of striatointernal pallidal fibers is also present. It is likely that a similar phenomenon occurs in patients with NA. In the initial phase of the disease, D,-bearing striatal neurons projecting to external pallidum preferentially degenerate, resulting in predominantly choreiform syndrome. This is accompanied by slower loss of both striatointernal pallidal fibers and dopaminergic projections from the nigra to the posterior putamen, resulting in a progressive, concomitant, kinetic-rigid syndrome. In conclusion, patients with N A show a severe loss of striatal dopamine D-receptor-binding sites and a selective loss of dopaminergic projections from the nigra to the posterior putamen. Such pathology explains why chorea and parkinsonian signs may both be present in these patients. PET scanning provides a sensitive means of quantifying the degree of functional striatal degeneration present in these patients and may, as has been demonstrated in patients with HD 1311, provide a means of detecting subjects at risk for this condition. In this way, PET scanning may help in the future to establish the role of inheritance in NA.
References 1 Critchley EMR, Clark DB, Wikler A. Acanchocytosis and neurological disorder without abetalipoproteinaemia. Arch Neurol 1968;18: 134-140 2 Levine IM, Estes JW, Looney JM. Hereditary neurological disorder with acanthocytosis. Arch Neurol 1968;19:403-409 3 Hardie RJ. Acanthocytosis and neurological impairment-a review. Q J Med 1989;264:291-306 4 Hardie RJ, Pullon HWH, Harding AE, et al. Neuroacanthocytosis. A clinical, haematological, and pathological study of 19 cases. Brain 1991;114:13-50 5 Serra S, Xerra A, Scribano E, et al. Computed tomography in amyotrophc chorea-acanthocytosis. Neuroradiology 1987:29: 480-482 6 Dubinsky RM, Hallett M, Levey R, Di Chiro G. Regional brain glucose metabolism in neuroacanthocytosis. Neurology 1989; 39: 1253- 1255 7. Hosokawa S, Ichiya Y, Kuwabara Y ,et al. Positron emission tomography in cases of chorea with different underlying diseases. J Neurol Neurosurg Psychiatry 1987;50:1284-1287 8. Kuhl DE, Phelps ME, Markham CH, et al. Cerebral metabolism and atrophy in Huntington’s disease determined by ‘*FDG and positron emission tomographic scans. Ann Neurol 1982;12: 425-434 9. Suchowersky 0, Hayden MR, Martin WRW, et al. Cerebral metabolism of glucose in benign hereditary chorea Move Disord 1986;1:3345 10. Firnau G, Sood S, Chirdkd R, et al. Cerebral metabolism of 6-(’XF)fluoro-~-3,4-dihydroxyphenylalanine in the primate. J Neurochem 1987;48:1077-1082 11. Farde L, Ehrin E, Eriksson L, et al. Substituted benzamides as liands for doparnine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA 1985; 82~3863-3867
12. Hoehn MM, Y,&r MD. Parkinsonism: onser, progression, and mortality. Neurology (Minneapolis) 1967;17:427-445 13. Brooks DJ, Ibanez V, Sawle GV, et al. Differing patterns of striatal 18F-dopa uptake io Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990;28:547-555 14. Spinks TJ,Jones T, Gilardi MC, Heather JD. Physical performance of the latest generation of commercial positron scanners. IEEE Trans Neurol Sci 1988;35:721-725 15 Frackowiak RSJ, Lenzi G, Jones T, Heather JD. Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using ”0and positron emission tomography: procedure and normal values. J Comput Assist Tomogr 1980; 4727-1 36 16 Talairach J, Tournoux P. Co-planar stereotavic atlas of the human brain. Stuttgart: Thieme, 1988 17. Brooks DJ, Salmon EP, Mathias CJ, et al. The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatd dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson‘s disease, studied with PET. Brain 1990;113:1539-1552 18. Tedroff J, Aquilonius S-M, Laihinen A, et al. Striatal kinetics of [”C]-( )-nomifensine and 6-[’8F]Auorodopa in Parkinson’s disease measured with positron emission tomography. Acta Neurol Scand 1990;81:24-30 19. Farde L, Hall H, Ehrin E, Sedvall G. Quantitative analysis of dopamine-D, receptor binding in the living brain by positron emission tomography. Science 1986;231:258-261 20. Bernheimer H, Birkmayer W, Hornykiewicz 0, et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological, and neurochemical correlations. J Neurol Sci 1973;20:415-455 21. De Yebenes JG, Brin MF, Mena MA, et al. Neurochemical findings in neuroacanthocytosis. Move Disord 1988;3:300-3 12 22. Bird TD, Ccdarbaum S, Valpey RW, Stahl WL. Familial degeneration of the basal gangha with acanthocytosis: a clinical, pathological, and neurochemical study. Ann Neurol 1978:3:253258 23. Blin J, Baron JC, Dubois B, et al. Positron emission tomography in progressive supranuclear palsy. Brain hypometabolic pattern and clinicometabolic correlations. Arch Neurol 1990;47:747752 24. Leenders KL, Frackowiak RSJ, Quinn N, Marsden CD. Brain energy metabolism and dopaminergic function in Huntington’s disease measured in vivo using positron emission tomography. Move Disord 1986;1:69-77 25. Hagglund J, Aquilonius S-M, Eckernas SA, et al. Dopamine receptor properties in Parkinson’s disease and Huntington’s chorea evaluated using positron emission tomography and ”Cmethylspiperone. Acta Neurol Scand 1987;75:87-94 26. Reches A, Rosenthal J. Lisuride interaction with presynaptic dopamine receptors in the mouse striatum. J Neurol 1990; 23756 27. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 1977;196:326-328 28. Chugani DC, Ackerman RF, Phelps ME. [3H]Spiperone and [‘*F]2-fluoro-2-deoxyglucose studies in nigrostriatal stimulation in rats, J Cereb Blood Flow Metab 1985;5:S161-S162 29. Penney JB, Young AB. Striatal inhomogeneities and basal ganglia function. Move Disord 1986;1:3-15 30. Albin RL, Reiner A, Anderson KD, et al. Striatal and n i g d neuron subpopulations in rigid Huntington’s disease: implications for the functional anatomy of chorea and rigidity-akinesia Ann Neurol 1990;27:357-365 31. Maztiorta JC.Phelps ME, Pahl JJ, et al. Reduced cerebral glucose metabolism in asyrnptomacic subjects at risk for Huntington’s disease. N Engl J Med 1987;316:357-362
+
Brooks et al: Dopaminergic Function in Neuroacanthocvtosis 17 1
D. J. Brooks, MD,*? V. Ibanez, MD,* E. D. Playford, MRCP," G. V. Sawle, MD," P. N. Leigh, PhD,$ R. S. Kocen, FRCP,? A. E. Harding, MD,? and C. D. Marsden, DSct
Using [lBF}dopa,["C}raclopride, CI5O2,and positron emission tomography, we have assessed striatal dopamine storage capacity, dopamine D,-receptor integrity, and regional cerebral blood flow, respectively, of 6 patients with neuroacanthocytosis. The patients with neuroacanthocytosis all had chorea and variable combinations of seizures, dementia, axonal neuropathy, and orolingual self-mutilation. {"Fldopa positron emission tomographic findings were compared with 30 normal controls and 16 patients with sporadic, L-dopa-responsive, Parkinson's disease. Caudate and anterior putamen { "Fldopa uptake were normal in patients with neuroacanthocytosis, but mean posterior putamen {"FJdopa uptake was reduced to 42% of normal, similar to that in patients with Parkinson's disease. In patients with neuroacanthocytosis, mean equilibrium caudate :cerebellum and putamen: cerebellum {"CJraclopride uptake ratios were reduced to 54% and 62% of normal, compatible with a 65% and 53% loss of caudate and putamen D,-receptor-binding sites, respectively. Striatal and frontal blood flow was also depressed. The severe loss of D,-receptor-bearing striatal neurons, with concomitant loss of dopaminergic projections from the nigra to the posterior putamen, is consistent with both chorea and extrapyramidal rigidity being features of patients with neuroacanthocytosis. Brooks DJ, Ibanez V, Playford ED, Sawle GV, Leigh PN, Kocen RS, Harding AE, Marsden CD. Presynaptic and postsynaptic striatal dopaminergic function in neuroacanthocytosis: a positron emission tomographic study. Ann Neurol 1991;30:166-171
Neuroacanthocytosis (NA) is a condition characterized clinically by chorea, dystonia, tics, seizures, dementia, amyotrophy, areflexia, and orolingual self-mutilation { 1-41. Paradoxically, parkinsonian signs frequently accompany the chorea, particularly as the disease progresses 141. Acanthocytes are found on wet blood films, however, unlike Bassen-Kornzweig disease, serum lipoprotein electrophoresis and vitamin E levels are normal. The inheritance of NA is unclear because autosomal dominant, recessive, X-linked, and sporadic forms have all been reported [3}. Computed tomographic scanning (CT) may reveal caudate atrophy in these patients [4, 51, and magnetic resonance imaging (MIU) increased signal from the caudate and lentiform nuclei [4}. Two positron emission tomographic (PET) studies have reported low caudate glucose utilization [b, 7) in patients with neuroacanthocytosis, but because patients with Huntington's disease, benign fmilial chorea, and dentatorubropallidoluysianatrophy may also show low caudate metabolism, this PET finding is nonspecific E7-9).
Striatal ['8F1dopa and ["C)raclopride uptake reflect striatal dopamine storage capacity [lo} and the integrity of striatal dopamine D,-receptors [I 11, respectively. In view of the chorea and concomitant parkinsonian signs (rigidity and bradykinesia) that dominate the clinical syndrome of neuroacanthocytosis, we believed it would be noteworthy to examine the pre- and postsynaptic striatal dopaminergic system in patients with this condition. PET findings were compared with those of normal control subjects and patients with sporadic, L-dopa-responsive, Parkinson's disease (PD).
From *MRC Cyclotron Unit, Hammersmith Hospital, ?Institute of Neurology, Queen Square, and $Institute of Psychiatry, Denmark Hill, London, England.
Received Oct 19, 1990, and in revised form Jan 15, 1991.Accepted for publication Feb 5, 1991.
Methods
Patient Selection Six patients with NA, aged 31 to 46 years, had ["F)dopa PET scans. One patient had an affected father, brother, and two sisters; 2 patients had a single affected sibling; and 3
patients had apparent sporadic disease. All had chorea at the time of PET scanning, though 2 presented with epilepsy. Acanthocytes constituted 8 to 50% of red cells on wet blood films. Five of the 6 patients with NA had normal CT brain
Address correspondence to Dr Brooks, MRC Cyclotron Unit, Hammersmith Hospital, Du Cane Road, London W12 OHS, England.
166 Copyright 0 1991 by the American Neurological Association
Table 1. Neuroacanthocytosis Patient Details
Patient
Sex
Age (yr)
D.B.
F
37
E.B."
F
W.W."
F
M.T." M.F. K.H.
Duration (yr)
Acanthocytes
(%I
Clinical
9
50
46
6
30
15
M
34 31
3
21 8
F M
42 36
15 30
30 30
Chorea, Seizures, Dem, OLM, A N Chorea, Dep, Dem, A N Tics Seizures Chorea, Dem, Seitures, AN Chorea, A N Chorea, OLM, A N
Affected Relatives
Treatment (daily dose)
None
Sulpiride 200 mg
Father, 3 siblings
Trifluoperazine 4 mg
Brother Sister
None None
None None
Haloperidol 3 mg Benzhexol6 mg
"Raclopnde/CBFstudies.
Dem = dementia; OLM = orolingual mutilation; A N
=
axonal neuroparhy;Dep = depression; CBF = cerebral flood flow.
scans, whereas the sixth (M.T.) had evidence of enlarged lateral ventricles and mild frontal atrophy, but no striatal abnormalities. The details of patients with N A are shown in Table 1. Three of the 6 patients with NA also had ["Clraclopride scans, with concomitant measurement of regional cerebral blood ffow (rCBF) using steady-state inhalation of C150,. Suiatal [lBF]dopa uptake of the group of patients with NA was compared with that of 30 normal control subjects, aged 30 to 77 years, and with 16 patients aged 38 to 76 years who had L-dopa-responsive PD. Disability of the patients with PD ranged from 1 to 4 on the Hoehn and Yahr scale [l2] when assessed 12 hours after stopping treatment, and their clinical details have been presented previously [13]. The striatal ["Clraclopride uptake of 3 of the patients with NA was compared with that of 7 normal control subjects, and their striatal blood flow with 8 control Subjects.
Scanning Procedure PET scans were performed on a CTI 981/08/12 tomograph (CTI, Knoxville, TN) giving 15 simultaneous planes with an axial full width half maximum resolution of 7 mm, and an in-plane resolution of 8.5 X 8.5 mm [14]. Correction for tissue attenuation of 5 11 keV gamma-radiation was measured with an external 68Ge ring source. Three of the 6 patients ( 1 of whom had ["Clraclopride) were taking dopaminereceptor blocking agents and these were stopped the day before PET scanning. During the hour preceding (l8F1dopa scanning, subjects were given a 150-mg oral dose of carbidopa, a peripheral dopa decarboxylase blocker. All subjects were fasted for 12 hours before PET. ["F}dopa, 2 to 5 mCi (mean specific activity, 8 mBq/ pmol) in 10 ml of normal saline, was infused intravenously over 2 minutes. Scanning began at the start of tracer infusion with serial 1-minute, increasing to 5-minute, time frames over 90 minutes, providing a total of 25 time frames. f"C]raclopride, 5 to 8 mCi in 5 ml of normal saline, was infused intravenously over 2 minutes. Scanning began at the start of tracer infusion with serial 30-second, increasing to 5-minute, time frames over 60 minutes, providing a total of 2 1 time frames. Measurements of rCBF were performed before ["Clraclopride administration using steady-state tracer inhalation of Cl5O2,as previously described { 15).
Data Anabsis Region of interest (ROI) analysis was performed on SUN 31 60 workstations (SUN Microsystems Inc, Mountain View, CA) using image analysis software (ANALYZE 2.0, BRU, Mayo Foundation, Rochester, MN). In all subjects, the positions of striatal, occipital, and cerebellar structures were defined by summing time frames to create an integrated image representing activity collected 30 to 90 minutes after rJ8F]dopa or ["C]raclopride administration. Although all the patients with N A had chorea during PET scanning, this was only severe in 1 patient, and neither the integrated images of striatal l8F or "C activity nor the rCBF scans showed evidence of significant degradation due to movement artifact. Where both [18F]dopa and ["Clraclopride scans were performed, the ["Fldopa study always preceded the ["Clraclopride study by several weeks. ROIs were placed by inspection in a standard template arrangement; one circular region 8.2 mm in diameter was placed over the head of caudate and three contiguous circular regions 8.22 mm in diameter were lined along the a x i s of the putamen for each hemisphere in both normal subjects and patients 1131. One circular region 32.8 mm in diameter was placed over the occipital lobe and cerebellar lobe of each hemisphere. This array of ROIs was defined on the rCBF image or the integrated images, or both, of "F and "C activity of the two optimum contiguous 7-mm axial planes for each cerebral structure with reference to the stereotactic atlas of Talairach and Tournow [l6] and then superimposed on individual time frames. Averaged values for each structure (caudate, putamen, occiput, and cerebellum) over two planes were then calculated from the individual hemispheric ROI data. Positions of patient striatal ROJs were checked by superimposing by eye C T images at the appropriate axial level over PET images. None of the 6 subjects studied showed significant striatal atrophy on C T scan, and so partial volume effects were not a problem. After decay correction, regional time-activity curves were plotted for ['*F]dopa and {"Cfraclopride. Specific striatal ['*F)dopa uptake was determined by using a modlfied multiple time graphical analysis (MTGA) approach with an occipital nonspecific tissue rather than a plasma input function [13, 17, IS]. This MTGA approach causes the striatal '*F uptake
Brooks et al: Dopaminergic Function in Neuroacanthocytosis
167
Fig 1. (Left) Positron emission tomographic scans of striatal {l8F)dopauptake, collected 30 t o 90 minutes aftw tracer injec-
tion. for a normal control subject and a patient with neuroacanthocytosis (NAI. The NA scans show selective impairment of posterior putamen {'"F}dopa accumubtion. (Right) Positron curves to become linear over 30 to 90 minutes of real time, and the gradients of the plots obtained using this approach can be regarded as influx constants, K,, which reflect the rate of striatal uptake and decarboxylation of [lXF}dopa and its storage as ['*F)dopamine and its metabolites. Equilibrium striatal :cerebellar ["C)raclopride uptake ratios were the average of eight measurements taken 30 to 60 minutes after tracer administration, when tracer distribution had reached a secular equilibrium throughout brain compartments [ 191.
Results Figure 1 shows PET images of striatal E1sF]d~pa and {"C)raclopride uptake for a normal subject and a patient with NA. The patient with NA shows selective
emi.rsion tomographic scans of striatal {"C) raclopride, collected during the 60 minutes after tracer injection, for a n o m l control subject and a patient with neuroacanthocytosis (NA). The NA scans show low striatal tracer uptake, the caudate king the worrt aflected.
loss of posterior putamen { "Fldopa uptake, and a diffuse reduction in { "C}raclopride uptake, the caudate being more affected than the putamen. Table 2 details mean head of caudate and putamen (whole, anterior, and posterior) {"F)dopa influx constants (Ki) for the groups of control subjects and patients with NA and PD. Mean K, values for caudate and anterior putamen were normal in patients with NA, but posterior putamen {l8F}dopa uptake was reduced to parkinsonian levels. Figure 2A shows individual caudate and global putamen, and Figure 2B anterior and posterior putamen, ["Fldopa Ki values for the normal subjects and patients with NA and PD. They again emphasize selec-
Table 2. Regional Striatal [ I 8F)Dopa In&x Constants (K; Min- ') Subjects (n)
Caudate Head
Putamen Whole
Control (30) N A (6) P D (16)
0.0107 ? 0.0019 0.0098 f 0.0020 0.0090 0.0021"
0.0098 0.0011 0.0068 +- 0.0008" 0.0047 I O.OOlO*b
*
*
ap < 0.05, compared with normal, Bonferroni statistics. ' p < 0.05, compared with NA, Bonferroni statistics. NA = neuroacanthocytosis; PD = Parkinson's disease.
168 Annals of Neurology Vol 30 No 2 August 1991
Putamen Anterior
Putamen Posterior
0.0105 f 0.0021 0.0105 5 0.0014 0.0065 ? 0.0015"b
0.0086 +- 0.0017 0.0036 k 0.0014" 0.0039 ? 0.0013"
tive involvement of dopaminergic projections from the nigra to the posterior putamen in patients with NA. Table 3 details mean equilibrium striatal: cerebellar E1'C}raclopride uptake ratios and rCBF for the groups of normal subjects and patients with NA. Mean N A caudate and putamen {l 'C)raclopride uptake ratios were significantly reduced to 54% and 62% of normal levels. A5 specific striatal { llC}raclopride binding constitutes 70% of the total tracer uptake in normal subjects, our findings are compatible with a mean loss of 6S% and 53% of caudate and putamen D,-receptorbinding sites in our 3 patients with NA. Striatal and frontal blood flow of the patients with N A was also selectively reduced (see Table 3), caudate blood flow being most severely affected (68% of normal).
-1
Ki
0.016 7
Nor (30) Nor (30)
-
0.012
-
0.008
Q
-
0.004
o.Oo0
J
putamen
caudate
A KI min
-' 0.020
0.015
ant
0.010-
T
ant
post 0 005
-
0.000
J
-8* NA (6)
Normals (30)
PD (16)
B Fig 2. (A) A scatter diagram showing individual striatal {'8F}dopa injux constants (%) for control subjects, patients and patients with Parkinson's with neuroacanthocytosis (NA), disease (PO). Caudate tracer uptake is n o m l , but putamen uptake is reduced in patients with NA. (B) A scatter diagram shwing individual regional putamen {'sF)dopa injux constants (%) for control subjects, patients with NA, and patients with PD. Tracer uptake ir selectively impaired in postenor Putamen in patients with NA.
Discussion Striatal ["F)dopa uptake reflects efficiency of transport of L-dopa into nigrostriatal nerve terminals and its subsequent decarboxylation [lo}. As a consequence, striatal [18F]dopa uptake does not measure endogenous dopmaine levels, which are determined by striatal tyrosine hydroxylase activity, but provides a measure of the functional integrity of nigrostriatal nerve terminals and aromatic amino acid decarboxylase activity. Our patients with N A showed normal uptake of {18F]dopa into the head of caudate and anterior putamen, but a mean 58% reduction in posterior putamen tracer uptake. Even the least-affected patient with NA had posterior putamen ["F)dopa accumulation that fell below the normal range. This finding suggests that a selective degeneration of dopaminergic projections from the nigra compacta to the posterior putamen occurs in patients with NA. Such dopaminergic projections have been postulated to arise from the ventrolateral nigral area [ZO}. One postmortem study [4} has reported such a selective loss of pigmented cells from the ventrolateral nigra compacta in patients with NA, in addition to the severe loss of neurons from the caudate and more moderate loss from the lentiform nucleus that is a characteristic feature of this condition. TWOother studies [21, 221, however, noted preservation of nigral
Table 3. Striatal:Cerebellar {"CiRacloprtde Uptake Ratios, and Blood Flow in Patients with N A
Raclopride (n) Normal (7) Caudate
Putamen Frontal Occipital
Cerebellum
3.40 3.55 ... ...
2
0.49
t 0.52
...
rCBF (ml/ml/min) (n) NA ( 3 )
Normal (8)
NA (3)
1.85 5 0.75" 2 0.46"
0.38 t 0.07 0.42 r 0.07 0.46 2 0.10 0.40 0.07 0.40 2 0.07
0.26 0.33
2.20
... ...
*
...
? -t-
0.34
?
0.38 0.41
5
+-
0.03b 0.03 0.05 0.05 0.05
"p < 0.005, bp < 0.025, compared with normal, Student's t tesc. N A = neuroacanthocytosis;K B F
= regional cerebral
blood flow.
Brooks et
al:
Dopaminergic Function in Neuroacanthocytosis 169
pigmented cells, though no formal cell counts were performed in either of these cases. L e y bodies, said to be characteristic in patients with Parhnson's disease, are not found in patients with NA. One postmortem study measured caudate and putamen dopamine levels in their 2 patients with NA and reported a severe global reduction 12I]. This finding is surprising because the substantia nigra of the 2 patients concerned was said to be normally pigmented. The postmortem findings of these authors could only be explained if global degeneration of nigrostriatal terminals occurred with complete preservation of the dopaminergic nigral cell bodies. Our PET findings are against such global degeneration of nigrostriatal nerve terminals occurring, and agree with the findings of the postmortem study 141 reporting selective loss of ventrolateral nigral dopaminergic projections to the posterior putamen. Equilibrium striatal: cerebellar [l'Clraclopride uptake ratios reflect integrity of striatal dopamine D,-receptors [19]. Our PET findings are compatible with a mean 65% loss of caudate and 53% loss of putamen D,-receptor-binding sites in our 3 patients with NA, even the most mildly affected patient showing severe loss of striatal ["Clraclopride binding. Their mean levels of caudate, putamen, and medial frontal blood flow were reduced to 68%, 7996, and 74% of normal, respectively. Dubinsky and colleagues 161 reported up to 71% and 61% reductions in caudate and putamen glucose utilization, respectively, in 2 siblings with NA. Our findings and those of Dubinsky and colleagues 161 suggest that PET is a sensitive means of detecting the presence of striatal degeneration in vivo in patients with NA, either by measuring striatal metabolism or dopamine receptor integrity. They are also in line with pathological reports of more severe involvement of caudate than putamen in patients with NA [4, 21, 22). The presence of low striatal and frontal blood flow and metabolism is not specific for patients with NA. Other causes of chorea such as Huntington's disease (HD), benign familial chorea, and dentatorubropallidoluysian degeneration have also been reported to show this distribution of functional depression C7-91, as does the akinetic-rigid syndrome progressive supranuclear palsy 1231. Severely reduced striatal D,-receptor densiry is also a feature of patients with HD 124, 251. PET, therefore, cannot be used in isolation to diagnose NA, but is a useful means of quantitating the functional consequences of the condition and a potential means of detecting the disease in at-risk subjects. Our finding of reduced striatal D,-receptors in patients with NA, as evidenced by low ["C)raclopride uptake, is at variance to the pathological report of De Yebenes and co-workers 121). These authors measured postmortem putamen D,-receptor-binding Site density and affinity with [3H]spiperone in a single patient with N A and found an increased density and &170 Annals of Neurology Vol 30 No 2 August 1991
finity of binding sites for this tracer. Upregulation of putamen D,-receptor sites in patients with N A would be surprising because severe striatal degeneration similar to that found in patients with HD occurs. Loss of striatal D,-binding sites is a feature in patients with HD 124, 251, and a similar finding in patients with N A would be predicted. Receptor densities of De Yebenes and co-workers {2l] were assessed per unit weight of remaining striatal tissue and so do not correct for striatal neuronal loss, whereas our PET measurements are taken from a standard striatal volume in both patients and control subjects. Combining our PET findings with the pathological data of De Yebenes and colleagues 1213 suggests that in patients with NA, overall striatal density of D,-receptor sites is reduced, however, in those surviving striatal neurons, local D,-receptor upregulation may occur. Three of our patients with N A who had {l8F1dopa scans were takmg dopamine receptor blocking agents (DRBAs) to control their chorea. One of these 3 patients also had an ["C]raclopride study. All medication was stopped for 24 hours before PET, but the presence of these agents could have influenced our PET findings. It has been shown in mice that DRBAs act on striatal presynaptic dopamine receptors to upregulate striatal L-dopa accumulation [26]. It is conceivable, therefore, that our 3 patients with NA taking these agents may have shown a higher level of striatal rL8F]dopauptake than they would have if they were studied when drug naive. The effect of the DRBAs is likely to have been slight, however, since caudate ["Fldopa K, values for ail 6 patients with N A fell well within normal range. It is also conceivable that trifluoperazine therapy may have influenced the striatal I''C]raclopride uptake of 1 of our patients with NA. Short courses of neuroleptic medication lead to sustained striatal D,-receptor upregulation in rats 1271, whereas the presence of the neuroleptic itself could impar access of the { "C)raclopride to D,-receptor sites either by direct occupation of the sites or by inducing receptor internalization 1281. Because the trifluoperazine was stopped 24 hours before PET scanning, it is unlikely that it would still be present to directly block D,-receptor sites in OUT patient with NA. It is impossible to know whether this agent had already caused significant D,-receptor internalization or upregulation but, because our 2 drug-naive patients with N A showed levels of striatal {"Clraclopride uptake similar to our medicated patient, it is likely that the effect of the trifluoperazine was slight. In view of our PET findings, can the presence of both chorea and parkinsonian signs in patients with N A be explamed? The major functional lesion in patients with N A is severe loss of striatd Q-receptor sites, similar to that found in patients with HD {24, 251. It has been elegantly argued by Penney and Young P91 that if selective loss of striatal projections
to the external pallidum occurs, a choreiform disorder will result. Such a finding has been demonstrated in patients with HD with predominant chorea [30]. In patients with HD presenting with an akinetic-rigid syndrome, severe loss of striatointernal pallidal fibers is also present. It is likely that a similar phenomenon occurs in patients with NA. In the initial phase of the disease, D,-bearing striatal neurons projecting to external pallidum preferentially degenerate, resulting in predominantly choreiform syndrome. This is accompanied by slower loss of both striatointernal pallidal fibers and dopaminergic projections from the nigra to the posterior putamen, resulting in a progressive, concomitant, kinetic-rigid syndrome. In conclusion, patients with N A show a severe loss of striatal dopamine D-receptor-binding sites and a selective loss of dopaminergic projections from the nigra to the posterior putamen. Such pathology explains why chorea and parkinsonian signs may both be present in these patients. PET scanning provides a sensitive means of quantifying the degree of functional striatal degeneration present in these patients and may, as has been demonstrated in patients with HD 1311, provide a means of detecting subjects at risk for this condition. In this way, PET scanning may help in the future to establish the role of inheritance in NA.
References 1 Critchley EMR, Clark DB, Wikler A. Acanchocytosis and neurological disorder without abetalipoproteinaemia. Arch Neurol 1968;18: 134-140 2 Levine IM, Estes JW, Looney JM. Hereditary neurological disorder with acanthocytosis. Arch Neurol 1968;19:403-409 3 Hardie RJ. Acanthocytosis and neurological impairment-a review. Q J Med 1989;264:291-306 4 Hardie RJ, Pullon HWH, Harding AE, et al. Neuroacanthocytosis. A clinical, haematological, and pathological study of 19 cases. Brain 1991;114:13-50 5 Serra S, Xerra A, Scribano E, et al. Computed tomography in amyotrophc chorea-acanthocytosis. Neuroradiology 1987:29: 480-482 6 Dubinsky RM, Hallett M, Levey R, Di Chiro G. Regional brain glucose metabolism in neuroacanthocytosis. Neurology 1989; 39: 1253- 1255 7. Hosokawa S, Ichiya Y, Kuwabara Y ,et al. Positron emission tomography in cases of chorea with different underlying diseases. J Neurol Neurosurg Psychiatry 1987;50:1284-1287 8. Kuhl DE, Phelps ME, Markham CH, et al. Cerebral metabolism and atrophy in Huntington’s disease determined by ‘*FDG and positron emission tomographic scans. Ann Neurol 1982;12: 425-434 9. Suchowersky 0, Hayden MR, Martin WRW, et al. Cerebral metabolism of glucose in benign hereditary chorea Move Disord 1986;1:3345 10. Firnau G, Sood S, Chirdkd R, et al. Cerebral metabolism of 6-(’XF)fluoro-~-3,4-dihydroxyphenylalanine in the primate. J Neurochem 1987;48:1077-1082 11. Farde L, Ehrin E, Eriksson L, et al. Substituted benzamides as liands for doparnine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA 1985; 82~3863-3867
12. Hoehn MM, Y,&r MD. Parkinsonism: onser, progression, and mortality. Neurology (Minneapolis) 1967;17:427-445 13. Brooks DJ, Ibanez V, Sawle GV, et al. Differing patterns of striatal 18F-dopa uptake io Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990;28:547-555 14. Spinks TJ,Jones T, Gilardi MC, Heather JD. Physical performance of the latest generation of commercial positron scanners. IEEE Trans Neurol Sci 1988;35:721-725 15 Frackowiak RSJ, Lenzi G, Jones T, Heather JD. Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using ”0and positron emission tomography: procedure and normal values. J Comput Assist Tomogr 1980; 4727-1 36 16 Talairach J, Tournoux P. Co-planar stereotavic atlas of the human brain. Stuttgart: Thieme, 1988 17. Brooks DJ, Salmon EP, Mathias CJ, et al. The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatd dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson‘s disease, studied with PET. Brain 1990;113:1539-1552 18. Tedroff J, Aquilonius S-M, Laihinen A, et al. Striatal kinetics of [”C]-( )-nomifensine and 6-[’8F]Auorodopa in Parkinson’s disease measured with positron emission tomography. Acta Neurol Scand 1990;81:24-30 19. Farde L, Hall H, Ehrin E, Sedvall G. Quantitative analysis of dopamine-D, receptor binding in the living brain by positron emission tomography. Science 1986;231:258-261 20. Bernheimer H, Birkmayer W, Hornykiewicz 0, et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological, and neurochemical correlations. J Neurol Sci 1973;20:415-455 21. De Yebenes JG, Brin MF, Mena MA, et al. Neurochemical findings in neuroacanthocytosis. Move Disord 1988;3:300-3 12 22. Bird TD, Ccdarbaum S, Valpey RW, Stahl WL. Familial degeneration of the basal gangha with acanthocytosis: a clinical, pathological, and neurochemical study. Ann Neurol 1978:3:253258 23. Blin J, Baron JC, Dubois B, et al. Positron emission tomography in progressive supranuclear palsy. Brain hypometabolic pattern and clinicometabolic correlations. Arch Neurol 1990;47:747752 24. Leenders KL, Frackowiak RSJ, Quinn N, Marsden CD. Brain energy metabolism and dopaminergic function in Huntington’s disease measured in vivo using positron emission tomography. Move Disord 1986;1:69-77 25. Hagglund J, Aquilonius S-M, Eckernas SA, et al. Dopamine receptor properties in Parkinson’s disease and Huntington’s chorea evaluated using positron emission tomography and ”Cmethylspiperone. Acta Neurol Scand 1987;75:87-94 26. Reches A, Rosenthal J. Lisuride interaction with presynaptic dopamine receptors in the mouse striatum. J Neurol 1990; 23756 27. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 1977;196:326-328 28. Chugani DC, Ackerman RF, Phelps ME. [3H]Spiperone and [‘*F]2-fluoro-2-deoxyglucose studies in nigrostriatal stimulation in rats, J Cereb Blood Flow Metab 1985;5:S161-S162 29. Penney JB, Young AB. Striatal inhomogeneities and basal ganglia function. Move Disord 1986;1:3-15 30. Albin RL, Reiner A, Anderson KD, et al. Striatal and n i g d neuron subpopulations in rigid Huntington’s disease: implications for the functional anatomy of chorea and rigidity-akinesia Ann Neurol 1990;27:357-365 31. Maztiorta JC.Phelps ME, Pahl JJ, et al. Reduced cerebral glucose metabolism in asyrnptomacic subjects at risk for Huntington’s disease. N Engl J Med 1987;316:357-362
+
Brooks et al: Dopaminergic Function in Neuroacanthocvtosis 17 1
![Striatal D2 dopaminergic receptors assessed with positron emission tomography and [76Br]bromospiperone in untreated schizophrenic patients.](/assets/img/hold.png)
