Functional neuroimaging in multiple sclerosis with radiolabelled glia markers: preliminary comparative PET studies with [11C]vinpocetine and [11C]PK11195 in patients.

Abstract

With the purpose of demonstrating the use of positron emission tomography (PET) and radiolabelled glia markers to indicate regional cerebral damage, we measured with PET in four young multiplex sclerosis (MS) patients in two consecutive measurements the global and regional brain uptake as well as regional distribution and binding potential (BP) of [(11)C]vinpocetine and [(11)C]PK11195. Both ligands showed increased uptake and BP in the regions of local brain damage. However, regional BP values for [(11)C]vinpocetine were markedly higher than those for [(11)C]PK11195. This feature of the former radioligand may be related to its high brain uptake and marked affinity to the peripheral benzodiazepine receptor binding sites (PBBS), characteristic for glia cells. As local brain traumas entail reactive glia accumulation in and around the site of the damage, the present findings may indicate that [(11)C]vinpocetine marks the place or boundaries of local brain damage by binding to the PBBS present in glia cells, which, in turn, accumulate in the region of the damage. The present findings (i) confirm earlier observations with [(11)C]PK11195 as a potential glia marker in PET studies and (ii) support the working hypothesis that [(11)C]vinpocetine is a potentially useful PET marker of regional and global brain damage resulting in glia accumulation locally or globally in the human brain. The comparative analysis of the two ligands indicate that [(11)C]vinpocetine shows a number of characteristics favourable in comparison with [(11)C]PK11195.

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Functional neuroimaging in multiple sclerosis with radiolabelled glia
markers: Preliminary comparative PET studies with
[11C]vinpocetine and [11C]PK11195 in patients
Ádám Vasa,⁎, Yevgeni Shchukinb, Virginija D. Karrenbauerc, Zsolt Cselényib,
Kosta Kostulasc, Jan Hillertc, Ivanka Savicc, Akihiro Takanob,
Christer Halldinb, Balázs Gulyásb
aChemical Works of Gedeon Richter Ltd., Gyomroi ut 19/21, H-1103 Budapest, Hungary
bKarolinska Institute, Psychiatry Section, Department of Clinical Neuroscience, S-17176 Stockholm, Sweden
cNeurotec, Section for Neurology, Huddinge University Hospital, Karolinska Institute, S-14186 Huddinge, Sweden
Received 12 October 2006; received in revised form 5 July 2007; accepted 9 July 2007
Available online 28 August 2007
Abstract
With the purpose of demonstrating the use of positron emission tomography (PET) and radiolabelled glia markers to indicate regional
cerebral damage, we measured with PET in four young multiplex sclerosis (MS) patients in two consecutive measurements the global and
regional brain uptake as well as regional distribution and binding potential (BP) of [11C]vinpocetine and [11C]PK11195. Both ligands showed
increased uptake and BP in the regions of local brain damage.
However, regional BP values for [11C]vinpocetine were markedly higher than those for [11C]PK11195. This feature of the former
radioligand may be related to its high brain uptake and marked affinity to the peripheral benzodiazepine receptor binding sites (PBBS),
characteristic for glia cells. As local brain traumas entail reactive glia accumulation in and around the site of the damage, the present findings
may indicate that [11C]vinpocetine marks the place or boundaries of local brain damage by binding to the PBBS present in glia cells, which,
in turn, accumulate in the region of the damage.
The present findings (i) confirm earlier observations with [11C]PK11195 as a potential glia marker in PET studies and (ii) support the
working hypothesis that [11C]vinpocetine is a potentially useful PET marker of regional and global brain damage resulting in glia
accumulation locally or globally in the human brain. The comparative analysis of the two ligands indicate that [11C]vinpocetine shows a
number of characteristics favourable in comparison with [11C]PK11195.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Vinpocetine; PK11195; Peripheral benzodiazepine binding site; Glia; Positron emission tomography; Sclerosis multiplex
1. Introduction
The search for an optimal glia tracer, usable in positron
emission tomography (PET) investigations in humans, has
been a long time objective of several research groups in the
field. An optimal glia PET tracer may serve as a diagnostic
marker in several central nervous system (CNS) diseases
accompanied by regional or global glia accumulation in the
brain, including stroke, multiple sclerosis (MS), epilepsy or
Alzheimer disease (AD).
The peripheral benzodiazepine binding site (PBBS) is one
of those binding sites of glia cells which may serve as a
preferred target site of PET radioligands. In recent years a
number of PET ligands with affinity to the PBBS have been
developed and tested. These include Ro5-4864, PK11195,
DAA1106 and, as recently demonstrated, vinpocetine [1–3].
The visualisation of the PBBS is of high importance in
various neurological diseases, since it can mainly be found in
glia cells. There is a reactive gliosis in the brain in global or
Journal of the Neurological Sciences 264 (2008) 9–17
www.elsevier.com/locate/jns
⁎Corresponding author. Tel.: +36 1 431 4200.
E-mail address: a.vas@richter.hu (Á. Vas).
0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2007.07.018

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local brain damage, such as degenerative CNS diseases (e.g.
AD) or local brain tissue damage (e.g. in stroke or multiple
sclerosis). The more, in these cases there is also a reactive
up-regulation of the PBBS,resulting in an ideal targetsystem
for a PBBS-radioligand which, in turn, can be an optimal
diagnostic marker of these diseases. With regard to MS this
holds true both for the experimental animal model, experi-
mental autoimmune encephalomyelitis [4] and the human
disease form [5].
TheselectivePBBSradioligand,[11C]-PK11195(Fig.1A),
has low brain penetration feature [6]. This fact solicits for
PBBS tracers with higher brain penetration.
Vinpocetine (ethyl-apovincaminate) is a synthetic com-
pound, structurally related to the Vinca minor alkaloid
vincamine (Fig. 1B). Since 1978 vinpocetine (Cavinton®,
Gedeon Richter Ltd., Budapest, Hungary) has been widely
used in the world as a neuroprotective agent in the prevention
and treatment of various diseases of cerebrovascular origin
[7,8].
In earlier studies using positron emission tomography we
have shown in both monkeys [9] and humans [10] that [11C]-
vinpocetine rapidly enters the brain after intravenous
injection, the maximal uptake being approximately 4% of
the total injected radioactivity at 2 min after injection. The
distribution pattern of vinpocetine in the brain was
heterogenous, with the highest uptake in the thalamus,
basal ganglia and visual cortex. We have shown also that
[11C]vinpocetine, orally administered, shows a similar
regional distribution pattern, albeit with less maximal uptake
(0.7% at 100 min after administration) in the human brain
[11]. It is worth here to note that the uptake reached the plato
after approximately 100 min and still lasted at 120 min
(endpoint of detection) after oral administration in the brain
of the healthy young volunteers.
The ex vivo receptogram of vinpocetine showed that in
tissue homogenisates the drug has the highest binding
affinity (with the only sub-micromolar IC50 value, as
compared to all other investigated receptor types) to the
peripheral benzodiazepine binding sites with an IC50value
of 0.2 μM (quoted in Ref. [3]). In a recent PET study in
cynomolgous monkeys we have demonstrated that [11C]
vinpocetine is indeed binding to PBBS and can be displaced
by PK11195 [3]. In this experiment it was shown that
vinpocetine binds with relatively high affinity to PBBS and
thus, [11C]-vinpocetine may act as a selective radioligand
for PBBS. Consequently, it may be used as a biological
marker in PET studies to label in vivo the glial PBBS
system.
In the present pilot study we tried to step further to human
patients in order to demonstrate the biological (and
diagnostic) marker properties of [11C]vinpocetine in CNS
diseases, resulting in local neuronal damage and, conse-
quently, reactive glia accumulation close to the local CNS
lesion sites. We set out to inject [11C]vinpocetine in tracer
doses into MS patients intravenously and to measure its brain
uptake and disposition with PET. In order to compare its
efficacy with a reference ligand, [11C]PK11195 has also been
injected in a separate set to the same patients.
2. Methods
2.1. Patients and ethical committee approval
Four MS patients participated in the study. The patients
were recruited at the Department of Neurology, Huddinge
University Hospital, Karolinska Institute. The patients
were informed both verbally and in written form about the
objectives, procedures and eventual risks of the experi-
mental procedure, in line with the Helsinki Declaration,
and they have signed an informed consent. The investi-
gation was conducted in line with the Karolinska
Institute's regulations regarding clinical experiments, and
permissions were obtained from the Ethical and Radiation
Safety commissions of the Institute. An overview of the
patients' characteristics and the loci of the disease-related
magnetic resonance (MR) imaging lesions in standard
anatomical Talairach coordinate space [12] are to be found
in Table 1.
Fig. 1. The structure of [11C]PK11195 and [11C]vinpocetine (asterisk
indicates the site of radiolabelling).
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2.2. The MR scanning
In each case MR images (T1-weighted, T2-weighted,
proton density) were made on the patients with a GE Signa
1.5 T scanner. The plaques in the images were described by
two independent expert observers (B.G. and A.T.). Initial
agreement between the two observers was over 90%; final
decision was made in a common session by consensus.
2.3. Radiochemistry
2.3.1. Materials
All the chemicals used for radiosynthesis were purchased
from commercial suppliers and used without further
purification. Vinpocetine and the starting material apovinca-
minic acid were provided by Gedeon Richter Ltd., Budapest,
Hungary. [11C]methane and [11C]CO2were produced in a
GEMS PETtrace cyclotron. [11C]methyl iodide was prepared
from [11C]methane by gas-phase iodination [13].
2.3.2. Synthesis of [11C]vinpocetine
The synthesis was performed according to the method
previously published [9]. The specific radioactivity obtained
at the time of injection of [11C]vinpocetine was higher than
2.8 GBq/μmol, corresponding to a total mass injected of less
than 20 μg. The radiochemical purity was better than 99%.
2.3.3. Synthesis of [11C]PK11195
The synthesis was performed according to the procedure
previously published [14]. The specific radioactivity
obtained at time of injection of [11C]PK11195 was higher
than 50 GBq/μmol, corresponding to a total mass injected of
less than 2 μg. The radiochemical purity was better than
99%.
2.4. The PET system and procedures
The PET measurements were made in 3D acquisition
mode on a Siemens ECAT EXACT HR scanner, with 47
image planes placed at 3.125 mm from each other [15]. The
scanner's in-plane resolution (FWHM) is 3.8 mm. The
acquisition time was 66 min, consisting of 15 frames
(3×1 min, 3×3 min, 9×6 min). Attenuation correction was
calculated, using 10 min transmission scans in each subject
with a68Ge source.
The subjects were equipped with individually moulded
head fixation helmets during the PET scans [16,17]. Each
patient participated in two consecutive PET examinations:
one with [11C]PK11195 and one with [11C]vinpocetine as
the tracer. 10 mCi (=370 MBq) radioligand was given to the
patients through an i.v. cannula, placed in the cubital vein.
The two ligands were injected in tracer doses (the injected
mass was between 3 and 15 μg), i.e. the injected dose in the
case of the labelled vinpocetine was over 104times less than
the pharmacological dose. The two PET investigations were
made in the same session, the labelled PK11195-PET
investigation being followed by the labelled vinpocetine-
PET investigation. The time interval between the injections
was 2 h.
2.5. Image analysis and calculations
Following image reconstruction, the MR and PET images
were further processed and analysed in the Karolinska
Institute's Human Brain Atlas (HBA) system [18].
For analysis of global regional radioactivity in the human
brain, standard regions of interest (ROI's) were drawn on the
reconstructed PET-images for all major anatomical regions
of the brain, using at least two or more image sections for
each ROI. The anatomical delineation of ROI's was guided
by the Karolinska Institute's computerised Human Brain
Atlas (HBA).
Regional radioactivity was determined for each frame,
corrected for decay, and plotted versus time. The summation
images were based on the sampling period between 9 min
and 66 min after tracer administration. Total radioactivity
(nCi/ml) in the whole brain was obtained by calculating the
average radioactivity concentration in a ROI representing the
whole brain.
The total radioactivity in the cerebellum was used as a
reference regionfor comparisonwith the concentration of the
Table 1
Clinical parameters of the patients
PatientAge Sex Last relapseLoci
(right hemisphere)
Loci
(right hemisphere)
A.S.28F3 m20, −52, 30 (2)
17, 6, 23 (2.5)
19, −29, 21 (2.5)
14, −38, 21 (3)
33, −40, 7 (4)
10, 16, 15 (2)
19, −6, 26 (1)
32, −47, 20 (1)
−32, 11, 34 (3)
−24, −11, 34 (1)
−16, −32, 30 (7)
−24, 8, 27 (3)
−18, −6, 26 (4)
−16, −17, 25 (2)
−16, −40, 19 (7)
−24, −32, 18 (3)
−26, −49, 17 (6)
−37, −46, 16 (11)
−29, −38, 16 (6)
−36, −48, 1 (1)
−10, −42, 19 (2)
−38, −42, 6 (2)
−20, 8, 36 (1)
−18, −22, 36 (2)
−20, −20, 32 (2)
−29, −46, 31 (1)
−18, −22, 33 (2)
−18, −6, 20 (1)
−18, −23, 6 (4)
−32, −49, −9 (1)
D.B. 41M17 m 22, 18, 32 (7)
24, −40, 27 (1)
21, 10, 38 (1)
18, −12, 33 (2)
22, −7, 29 (2)
14, −7, 29 (2)
14, 27, 33 (1)
T.C.32F 3 m
T.W. 30F 7 m 21, −69, −12 (1)
23, 8, −12 (1)
16, 8, −12 (1)
23, 3, 8 (1)
19, −5, −9 (1)
Remarks: Age: in years; last relapse: in months; loci: expressed in Talairach
coordinates (x, y, z; left hemisphere is −, right hemisphere is +), values in
parentheses indicate the average diameter of the plaque in mm.
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tracers' uptake in other brain regions. On the basis of former
PET studies with [11C]PK11195 and [11C]vinpocetine, the
cerebellum was operationally defined as the reference
region. The time radioactivity curves were integrated for
the interval between 9 to 66 min. The values were compared
with the value for the cerebellum which was set to 100%.
The target ROI's around the plaques were drawn on the
basis of the anatomical signs shown in the patients' MR
images. Due to the individual differences in the neuropath-
ological changes, in each patient the disease-specific ROI's
were determined on an individual basis. As in the plaque
region itself no active glia processes can be expected, the
“plaque-ROI” was complemented with another ROI, the
“peri-plaque-ROI”: a 1 cm “thick” spherical ROI around the
plaque (Fig. 2).
Binding potential (BP) values were determined using the
linear graphical analysis according to Logan [19] using the
cerebellar cortex as reference region and corresponding to
the linear part of the plot covering the last 42–66 min of
measurement. The choice of the cerebellum is operational, as
until today no more optimal reference region has been
identified for quantitative modeling of PBBS ligands [20].
In order to compare the BP values in the plaque region,
the following reference regions were chosen: the frontal
lobes (average values), the thalamus (left and right: average
values), and the cerebral hemispheres (average values). Due
to the nature of the disease, we have avoided using the
mirror-symmetric ROI values as reference values, as it was
not sure that the region is healthy. For similar reasons, no
reference white matter region was chosen.
MR-PET image co-registrations as well as volume
measurements were made with a modified version (co-
author Z.C.) of SPM2 (Statistical Parametric Mapping for
Table 2
Volume measurements in the four patients
Gray matter White matter IV CSF Brain SA. CSF Total
A.S. 791.441
D.B. 722.496
T.C.839.795
T.W. 862.326
386.145
533.234
429.509
506.679
30.9468 1208.53 278.379
26.0401 1281.77 274.462
27.2486 1296.55 267.788
27.6051 1396.61 242.718
1486.91
1556.23
1564.34
1639.33
IV CSF: Intra-ventricular cerebrospinal fluid, SA CSF: sub-arachnoideal
cerebrospinal fluid. The brain's volume comprises only the grey matter,
white matter and IV CSF volumes.
Fig. 2. The identification of the plaques (A) and the peri-plaque region (D) on an MRI image and the corresponding [11C]PK1195 (B, E) and [11C]vinpocetine
(C, F) PET images.
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neuroimaging data), using segmentation outlines for white
matter, grey matter and cerebrospinal fluid. The latter
compartment was divided into the intraventricular and sub-
arachnoideal space.
3. Results
3.1. Volume measurements
Volume measurements were made in order to estimate the
subjects' brain volumes' changes as a possible consequence
of disease. The results are shown in Table 2. The data
indicate no significant alterations from normal brain
volumes.
3.2. Global brain uptake of radioactivity
The global uptake values of radioactivity are shown in
Table 3. Total uptake of [11C]PK11195 was 1.25±0.42%,
whereas that of [11C]vinpocetine was 1.85±0.73%. On the
average, 40.4±24.3% more administered radioligand en-
tered the brain after [11C]vinpocetine injection that after
[11C]PK11195 injection. Regarding the peak uptake values
(at 2 min after injection), [11C]vinpocetine peaked at 2.72±
1.05% of total inject radioactivity, whereas [11C]PK11195
peaked at 1.87±0.50%. On the average 40.7±22.3% more
administered radioligand were in the brain 2 min after [11C]
vinpocetine injection than 2 min after [11C]PK11195
injection.
3.3. Regionalradioactivitydistributionandbindingpotentials
of [11C]PK11195 and [11C]vinpocetine in the brain of MS
patients
For [11C]PK11195 the range of the reference BP values
(whole hemispheres, frontal cortex, thalamus) was between
0.000 and 0.174. The maximal average BP values adjacent to
the plaques were between 0.000 and 0.271.
For [11C]vinpocetine the range of the reference BP values
was between 0.000 and 0.300. The maximal average BP
values in regions adjacent to the plaques were between 0.338
and 0.452. The data are shown in Table 4.
Examples with two patients' MR, [11C]PK11195-PETand
[11C]vinpocetine-PET images are shown in Figs. 3 and 4.
3.4. Peri-plaque patterns with [11C]PK11195 and
[11C]vinpocetine
A typical example of co-registered MR and PET images,
using both ligands, are shown in Fig. 5A and B. In Fig. 5C, a
peri-plaque region is shown demonstrating that the two
ligands' behaviour is somewhat different in the peri-plaque
region. [11C]PK11195 is accumulating in and around the
plaque, whereas [11C]vinpocetine appears to be shown
higher uptake in elongated regions, most probably fibre
tracts, that are interrupted by the plaque.
4. Discussion
4.1. PBBS and its biological tracers
It is well accepted, that glial cells and especially microglia
are in a seemingly down-regulated state in the human brain
but they get activated by a wide array of brain injuries
including MS in and around the lesion [21]. The PBBSs are
expressed in the glial cells at a low level but become
abundant in the activated glia, although their exact function
is still not known [22]. [11C]PK11195 binds to the glial
PBBS and is one of the most studied tracers for PET studies
[4–6]. Its brain penetration and binding potential is, however
rather poor [6] and there is a search for better tracers like eg.
DAA1106 [23] or DPA713 [24].
We demonstrated earlier in a PET study in cynomolgous
monkeys that [11C]vinpocetine binds to the PBBS and can be
Table 3
Injected radioactivity and brain uptake values of [11C]PK-11195 (PK) and
[11C]vinpocetine (Vin) in the patients
Patient PK
(MBq)
PK
(mCi)
Max
uptake
Sum
uptake
Vin
(MBq)
Vin
(mCi)
Max
uptake
Sum
uptake
1.
2.
3.
4.
Mean
SD
375
281
344
368
342
43
10.13 2.19
7.59 1.76
9.27 2.33
9.95 1.21
9.24 1.87
1.16 0.50
1.55
1.25
1.55
0.65
1.25
0.42
234
206
122
237
200
54
6.32
5.57
3.30
6.40
5.40
1.45
3.43
2.53
3.59
1.31
2.72
1.05
2.70
1.75
2.00
0.93
1.85
0.73
Max uptake: maximal uptake, expressed as % of total injected radioactivity,
at 2 min after injection, Sum uptake: averaged uptake of radioactivity for the
period between 9 and 66 min, expressed as % of total injected radioactivity.
Table 4
Binding potential values of [11C]PK-11195 (PK) and [11C]vinpocetine (Vin) in different brain regions of the patients (Logan's simplified reference tissue model;
reference region: cerebellum)
BP valuesPK Vin
MS Patients: P-P-ROIRef: frontal lobe Ref: thalamus Ref: hemispheresP-P-ROI Ref: frontal lobe Ref: thalamus Ref: hemispheres
1.
2.
3.
4.
0.271
0.000
0.000
0.179
0.041
0.000
0.000
0.018
0.099
0.103
0.037
0.174
0.000
0.000
0.000
0.024
0.357
0.356
0.452
0.338
0.185
0.000
0.146
0.073
0.300
0.116
0.284
0.114
0.221
0.006
0.143
0.074
Remark: P-P-ROI=Peri-plaque-ROI. In each patient's case, 3–5 peri-plaque-ROI measurements were averaged.
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Fig. 4. MR and PET images of a 30 year old female patient. Arrows show the plaques.
Fig. 3. MR and PET images of a 28 year old female patient. Arrows show the plaques.
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Fig. 5. A and B: Co-registered PETand MR images, with [11C]PK11195 (A) and [11C]vinpocetine (B) as the ligand. C: Peri-plaque uptake using [11C]PK11195
(left panel) and [11C]vinpocetine (right panel).
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displaced by PK11195. The BP values showed a relatively
high affinity to PBBS compared to [11C]PK11195 and thus
[11C]vinpocetine might have acted as a selective radioligand
for PBBS. Consequently we suggested that it might be used
as a biological marker in PETstudies to label in vivo the glial
PBBS system [3].
4.2. [11C]vinpocetine and [11C]PK11195 as PET markers in
MS
In the present preliminary PET study of four MS patients
we found that the global brain uptake (measured between
42–66 min after injection) of [11C]vinpocetine surpassed
that of the [11C]PK11195 (means: 1.85% vs. 1.25%).
[11C]PK11195 has shown a clearly increased BP only in
one case. Surprisingly, the patient proved to be the youngest
one of the group (28 years of age). In all the three other
patients there seemed to be no or very little BP increase for
[11C]PK11195 in or around the lesions.
In contrast to this, [11C]vinpocetine exhibited basically in
all the four patients relatively good BP values in and around
the plaque regions. This was especially clear when the
regional BP values in the disease regions were compared
with the BP values in the reference regions.
4.3. Methodological considerations
In all neurodegenerative and neuroinflammatory diseases
one should consider the possibility of volume changes in the
diseased brain. In MS the changes may primarily affect the
volume of the white matter, as most lesions' appear in white
matter fibre tracts. To exclude the effect of volume changes
on regional binding potential values, we have made image
segmentation and found no apparent changes in white matter,
grey matter of CSF volumes in the patients.
The choice of region of interest has also unique
importance in neurodegenerative and neuroinflammatory
diseases. One can hardly expect increased metabolic
activation or receptor expression inside, for instance, a
plaque region in MS or a necrotic stroke region, where no
neurons or glia cells exist any more. The ROI in such cases
should therefore be “operational” and include adjacent
anatomical regions where increased cellular activity can be
expected. We have therefore placed ROI's around the
plaques where activated microglia might be found. This
strategy proved to be useful when “intra-plaque” and “peri-
plaque” binding potentials were compared.
The time factor may also be important with regard to glia
activation in active MS processes. There is no consensus
between authors regarding the “optimal” time window for
targeting PBBS with their biological markers, including
PK11195 and vinpocetine. In our case the patients' last
known active period was between 3 and 17 months before
the PET investigation. This may explain the findings that
only one of the four patients had increased BP with [11C]
PK11195, whereas all four patients had, though to various
extent, increased BP with [11C]vinpocetine.
4.4. Possibility for two different binding sites?
At least two observations call our attention to the
possibility that the two ligands used in the present study
Fig. 5 (continued).
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may target the PBBS in different manners. (i) The
aforementioned fact that only in one of four patients did
BP with [11C]PK11195 increased whereas in all four patients
[11C]vinpocetine showed increased BP, may indicate that the
two ligands act differentially and display increased or
“optimal” binding to the PBBS at various stages of its active
“time window”. (ii) The co-registered images (Fig. 5A, B)
show no overlap or minimal overlap regarding the peak
uptake regions around the plaque for the two ligands. This
fact may support the hypothesis that the two ligands bind
differentially to the activated glia cells, depending on their
activation phase. The PBBS is not a classical receptor site but
rather a huge molecular complex consisting of various sub-
units. The two herewith used ligands may show binding to
different parts of the PBBS complex and their binding
affinity can change as a function of the various phases of glia
activation process. This hypothesis should, of course, be
explored in dedicated experiments in the future.
4.5. Conclusion
The present preliminary results in four MS patients seem
to corroborate our previous findings in cynomolgous
monkeys, that [11C]vinpocetine might serve as a promising
potent PET marker in case of regional brain damage resulting
in glia accumulation and increased PBBS expression, like
MS.
Acknowledgment
The authors express their gratitude to Prof. Banati RB,
MRC, Chair of Medical Radiation Sciences, University of
Sydney, School of Medical Radiation Sciences, East Street
PO Box 170, Lidcombe NSW 1825, Australia.
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