close

Вход

Забыли?

вход по аккаунту

?

Cerebral metabolism and atrophy in huntington's disease determined by 18FDG and computed tomographic scan.

код для вставкиСкачать
Cerebral Metabolism and Atrophy in
Huntington's Disease Determined by I'FDG
and Computed Tomographc
n
David E. Kuhl, MD,"t Michael E. Phelps, PhD,"t$ Charles H. Markham, MD,$ E. Jeffrey Metter, MD,"S:
Walter H. Riege, PhD,$ and James Winter, MD, P hDI
~
Patterns of local cerebral glucose utilization were measured with positron emission computed tomography using
the 'sF-fluorodeoxyglucose method in 13 patients with Huntington's disease (HD), 15 subjects at risk for HD, and 40
normal control subjects. These data were compared with computed tomographic measures of cerebral atrophy,
with age, and with duration and severity of symptoms. The results indicate that in HD there is a characteristic
decrease in glucose utilization in the caudate and putamen and that this local hypometabolism appears early and
precedes bulk tissue loss. In contrast to patients with senile dementia, in these HD patients glucose utilization
typically was normal throughout the rest of the brain, regardless of the severity of symptoms and despite apparent
shrinkage of brain tissue. Our results suggest the possibility that the caudate may be hypometabolic in some
asymptomatic subjects who are potential carriers of the autosomal dominant gene for HD.
Kuhl DE, Phelps ME, Markham CH, Metter EJ, Riege WH, Winter J: Cerebral metabolism and atrophy in
Huntington's disease determined by '*FDG and computed tomographic scan. Ann Neurol 12:425-434, 1982
Huntington's disease (HD) is an inherited degenerative disorder of unknown cause characterized by the
development and progressive increase of chorea
and dementia. There is evidence that at least the
motor symptoms may result from an imbalance in
the effects of dopamine, acetylcholine, and gammaaminobutyric acid released from nerve terminals in
the striatum (the putamen and caudate nucleus) and
substantia nigra [44]. At autopsy, the brain typically
shows widespread neuronal cell loss and glial proliferation, particularly in the caudate, putamen, and
cerebral cortex [ 151. Characteristic striatal atrophy
accompanied by ventricular dilatation and cortical
sulcal widening have been demonstrated by pneumoencephalography [7] and computed tomography
(CT) [2, 34, 451. Although extensive studies have
been performed in presenile and senile dementia
using measurements of cerebral blood flow (CBF)
[21, 31, 331, oxygen utilization [16, 17, 291, and glucose utilization (CMRgI,) [5, 13, 191, these methods
have rarely been applied to H D .
The necessity of measuring brain function, blood
flow, metabolism, and structure locally rather than
globally is now recognized. Previously, we found that
in both stroke [27] and epilepsy [25], altered lo-
cal glucose utilization (LCMR,,,), determined by
positron emission computed tomography of 18Ffluorodeoxyglucose (FDG) [36, 381, is a more sensitive indicator of altered local cerebral function than is
the accompanying structural abnormality determined
by CT. In the study reported here, we applied these
same study methods to learn the relationship of local
cerebral metabolism and atrophy in HD patients and
in subjects at risk for HD. The results indicate that in
HD, a characteristic decrease in glucose utilization
affects the caudate and putamen, and that this local
hypometabolism appears early and precedes bulk tissue loss. In contrast to patients with senile dementia,
in these HD patients glucose utilization typically was
normal throughout the rest of the brain, regardless of
the severity of symptoms and in spite of apparent
shrinkage of brain tissue. Finally, our results suggest
the possibility that the caudate may be hypometabolic in some asymptomatic subjects who are
potential carriers of the autosomal dominant gene
for HD. (Preliminary results of this study were presented at the Tenth International Symposium on
Cerebral Blood Flow and Metabolism, St. Louis,
MO, June 23, 1981 [28], and as part of the Foster
Elting Bennett Memorial Award Lecture at the 106th
From the "Laboratory of Nuclear Medicine, the Divisions of +Nuclear Medicine and TBioDhvsics
and the lISection of Ultrasound
- ,
and Body Computed TomOgraPhY Of the Department Of Radiological Sciences, and the §Department of Neuroloby, UCLA
School of Medicine, Los Angeles, CA 90024.
Received Dec 8, 1981, and in revised form Mar 8, 1982. Accepted
for publication Mar 24, 1982.
Address reprint requests to Dr Kuhl, Laboratory of Nuclear Medicine, UCLA School of Medicine, Los Angeles, CA 90024.
0364-5134/82/110425-10$01.25 @ 1982 by the American Neurological Association
425
Annual Meeting of the American Neurological Association, San Francisco, CA, Sept 16, 1981.)
Methods
Subjects
Three categories of subjects were studied: HD patients,
offspring of HD patients who were at risk for the disease,
and normal subjects.
We performed FDG and C T scans on 13 HD patients, 8
men and 5 women, between 17 and 62 years of age (mean
age, 4 1.6 years). All had a family history of HD and typical
symptoms. The duration of symptoms in each was between
one and fifteen years. Chorea was present in all but was
severe in only 1. Dementia was present in all but 2, but was
severe in only 1. An interview and neurological examination were conducted for each subject. The chorea grading
employed was as follows: severe-3,
moderate-2,
mild-1, and none-0. Assessment of dementia was based
on testing for orientation, recent and remote memory, recall, serial 7 subtractions, simple arithmetic, digit retention
forward and backward, and interpretation of proverbs. The
dementia grading was as follows: severe-3, moderate-2,
mild-1, and none-0. Nine of the 13 HD patients were
receiving medication with butyrophenone, benzodiazepine, or phenothiazine derivatives at the time of the
scans, but no patient was sedated for the purpose of performing these studies.
We also studied 15 subjects, 5 male and 10 female, between 12 and 53 years of age (mean age, 33.7 years), who
were at risk for HD. FDG scans were performed on all 1 5
subjects and CT scans on 12; suspicion of HD was made
known to the diagnostic radiologists interpreting the CT
scans. An interview and neurological examination was
performed for each subject. All had a family history of H D ,
but none had evidence of chorea, dementia, or personality
change suggesting a diagnosis of HD. None were receiving
medication with butyrophenone, benzodiazepine, or phenothiazine derivatives.
For cerebra! metabolism controls, we performed FDG
scans on 40 normal subjects, 17 men and 23 women aged
between 18 and 78 years, who were healthy and had no
evidence of dementia, hypertension, or cerebral vascular
disease. This group is reported in more detail in a previous
publication [26]. For cerebral atrophy controls, normal CT
measurements were obtained from retrospective examination of scan records from 48 subjects, aged 20 to 85 years,
who had no evidence of dementia and in whom no focal
cerebral abnormalities had been found by C T scan. Note
that different individuals comprised the FDG and C T control groups.
Positron Emission Computed Tomography
The FDG method for determining LCMR,,, in humans [36,
381 is analogous to the ‘‘C-deoxyglucose autoradiographic
method [42]; a cross-section scan image is substituted for
the autoradiograph. After intravenous injection, FDG enters the brain and is phosphorylated by brain hexokinase;
the metabolic product, FDG-6-phosphate, remains fixed,
with little further metabolism. The time course of “F ac-
tivity and glucose concentration is measured in arterialized venous blood, and brain activity is determined by
scan; with knowledge of predetermined rate constants, an
operational equation allows calculation of LCMRgl, [36].
Fluorine 18 was produced in the UCLA medical cyclotron, and FDG was synthesized by a semiautomated method
[3]. The usual intravenous dose was 10 mCi. Scans were
performed with the ECAT I1 tomograph [35] (E.G.8rG.I
Ortec Inc., Life Sciences, Oak Ridge, TN). Throughout
each study, all subjects were awake with eyes open and ears
unplugged, subject to ambient laboratory light and sound,
but without movement or loud noises. N o subjects were
sedated for the examination. The full width at half
maximum (FWHM) measure of spatial resolution was 16
mm within the image plane and 16 mm in the axial direction. Scans were started 40 minutes after injection. Each
scan lasted 5 to 7 minutes, collecting 1 to 1.5 million counts
per image. At leas,t six levels parallel to the canthomeatal
plane were scanned sequentially from upper cerebellum to
above the cerebral ventricles. A lumped constant value of
0.42 was used in calculating metabolic rate; the final values
were increased by 10% as an attenuation correction. In
each scan, values of LCMR,,, were calculated for anatomical zones of gray and white matter using appropriate gray
and white matter rate constants [36], and for hemispheres
and whole brain using averaged rate constants. Zonal,
hemispheric, and whole-brain averages were then made for
the entire scan series. The metabolic ratio of frontal to
parietal cortex, FIP, was calculated from measures at the
more superior levels of the brain as an index of metabolic
“hyperfrontality” [22].
While the location of the thalamus could easily be
identified, the image of the caudate merged with adjacent
cerebral cortex in normal subjects and usually was not seen
in HD patients. To better quantify alterations in caudate
metabolism, especially in the absence of severe atrophy, a
caudate MR index was defined so that a decline in caudate
glucose utilization would cause an increase in index value.
This was based on separation measured from the side-toside line of 18F activity data that had been determined
through the midportion of the heads of the caudate nuclei,
as shown in Figure .I.The index was the central separation of
caudate activity, El, expressed as a percentage of the bilateral separation of cortical activity, E,, where El was measured midway between lateral maximum and central
minimum activities and E, was measured at half-maximum
activity. In HD subjects in whom caudate activity could not
be seen, this activity profile was determined at a fixed distance (25 mm) forward of peak thalamic activity, according
to the average location of caudate found in normal subjects.
The value of the caudate MR index is influenced by the
severity of caudate shrinkage, but when atrophy is absent
or mild, it depends primarily on caudate glucose utilization.
Other details of the FDG method are contained in our previous publications [26, 27, 30, 361.
To assess the relative distribution of cerebral perfusion,
positron emission computed tomography was performed
on 2 of the HD patients starting several minutes after intravenous injection of 20 mCi of 13NH3.The method is
described in previous publications [25, 27, 371.
426 Annals of Neurology Vol 12 No 5 November 1982
F i g I . Caudate CT indices (left: CT scan) and caudate MR
indices (center right: FDG scan) were measured as the intercaudate separations ( D ,and E ,) expressed as percentages of the
bilateral diameter of the brain image (D,) or activtty profile
( E J . (Top) I n this 41-year-old normal subject, the caudate
CT index was 10.8% and the caudate M R index was 18.0%.
(Bottom) In this 29-year-old H D subject (Patient 3 , Table),
the caudate CT index was increased to 20.4% and the cazdate
M R index to 45.9%.
Computed Tomography
Three indices were calculated from the CT scans of each
subject. The caudate CT index (see Fig l), an estimate of
caudate atrophy, was defined as the intercaudate span, D,,
expressed as a percentage of the maximum biparietal
diameter, D,, of the brain in that image [23]. The lateral
ventricle CT index, an estimate of central atrophy, was
defined as the width of the center of the bodies of the lateral ventricles expressed as a percentage of the biparietal
brain diameter [ 111. The cortical szlcus CT index, an estimate of cortical atrophy, was defined 3s the width of the
largest cortical sulcus, on a level high in the brain, expressed as a percentage of the maximum biparietal brain
diameter measured on a lower level [40].With increased
atrophy, the values of these indices should rise.
Results
Patients with Huntington’s Disease
In HD patients, the three CT indices of atrophy
(Table) were elevated from the gradual increase with
age seen in normal controls (Fig 2 ) , and differed
multivariately from those of 13 age-matched controls
(approximate F = 10.8, df = 3,22; p < 0.0001).
When CT indices of both groups were adjusted in
stepdown analysis for the intercorrelation of the
caudate CT index with the ventricle C T index (Y =
0.85,p < 0.01) and with the cortical sulcus CT (r =
0.55,p < O.Ol), the caudate C T index was found to
be the only source of multivariate significance (F =
8.32, df = 1,24;p < 0.008). Within the group of HD
patients, the measures of disease duration (Y = 0.64)
and dementia (Y = 0.61) correlated @ < 0.05) with
ventricle C T index; chorea (Y = 0.57) correlated with
caudate C T index.
In contrast to the ventricle C T index, mean
CMR,,, did not correlate with the severity of symptoms (Fig 3). The average measure of whole-brain
mean CMR,,, of HD patients (mean +- standard deviation, 4.46 k 1.45 mg/100 gm/min, N = 1 3 ) was
comparable to that of the normal controls (4.72 t
1.12 mg/100 gm/min, N = 40) (Fig 4). Compared
multivariately within the set of cortical, thalamic, and
Kuhl et al: FDG Scan in Huntington’s Disease 427
Data from 13 Patients with Huntington’s Disease
FDG Scan
Patient
No.,
Sex, and
Age (yr)
1. M , 17
2. M , 2 5
3. M, 29
4. F, 33
5. M , 37
6. F, 37
7 . F, 46
8. M , 4 7
9. M, 4 9
10. F, 50
11. F, 53
12. M , 56
13. M , 6 2
Disease
Duration
(yr)
4
3
4
Mean
CMR,,,
Chorea
Grade
1
1
1
1
1
3
2
1
2
2
2
1
1
1
3
9
7
3
10
2
15
11
3
A
+
0
*
A
40
Dementia (mg/100
Grade
gm/min)
2
5.87
1
5.05
1
3.44
0
5.60
1
7.90
1
4.28
2
4.48
1
2.60
2
3.33
0
3.52
1
4.94
3
2.82
2
4.10
A
*
T
0
Mean
Cortex Thalamus
MR,k
MR,,,
(mg/100 (mg/100
gm/min) gm/min)
7.89
6.87
4.53
7.19
9.33
6.39
6.20
3.11
4.67
4.73
5.71
3.80
5.28
7.50
7.10
3.50
7.00
9.90
6.40
5.80
3.20
4.20
4.40
5.10
4.70
5.70
CT Scan
Lateral
Caudate
MR
Index
(%)
581.3
22.7
45.9
44.6
41.6
35.4
34.6
41.4
41.2
49.7
37.0
35.5
39.3
Ventricle
Sulcus
Caudate
CT
CT
Index
(%)
Index
CT
Index
(%I
(%I
22.8
22.2
22.8
17.5
20.8
35.4
29.7
29.0
31.0
24.2
28.6
34.8
32.1
4.6
2.2
3.1
3.0
1.7
5.2
8.1
7.4
4.9
3.0
2.2
2.7
7.5
15.3
11.1
20.4
13.4
12.8
35.4
23.2
18.0
17.9
15.1
17.6
26.8
22.0
caudate MR measures (see the Table) or directly,
with correction for age as the covariate, the mean
CMR,,, did not differ between HD patients and
controls, nor could groups be separated in stepdown
analysis on cortical or thalamic metabolic rate measures. These measures, however, and mean CMR,,,
were highly intercorrelated (Y < 0.9). On the other
hand, HD patients had significantly higher (F = 239,
df = 1,47;p < 0 0001) caudate MR scores than controls, even after adjustment for age and for thalamic
and cortical MR,,,.
Although both the caudate CT and MR indices
clearly differentiated HD patients from normal controls, neither cortical CT nor cortical MR measures
did so. Cerebral glucose utilization appeared symmetrical; the ratio of CMR,,, in left to right hemisphere of the 40 normal subjects and the 13 HD patients was 1.01 ? 0.02 and 0.99 +- 0.02 (mean
SD), respectively. The F/P ratios, indices of
metabolic “hyperfrontality” [22], were subnormal in
almost half the HD patients, particularly in those
with disease duration greater than six years (t = 2.49,
p = 0.017). The HD patient with lowest F/P ratio had
the most severe dementia, but overall the F/P ratio
did not correlate with severity of dementia. A comparison of the decline of F/P ratios with age in HD
patients (b = -0.004) and in controls (b = -0.002)
indicated that the ratio declined in parallel with age in
both groups (F = 11.4, df = 1,47;p < 0.001). Values
of mean cortical and thalamic MR,,, did not differ in
HD patients (paired t = 0.63) and controls (paired t
= 0.83), and were correlated (Y = 0.89,p < 0.01).
Cortical and thalamic MR,,, declined in both groups
*
10
20
30
40
50
60
Age (years)
70
80
F i g 2. CT indices of central (lateral ventricle), cortical (sulcus), and caudate atrophy versus age. I n H D patients, indices
of caudate atrophy are clearly separated from those in normal
subjects and become more abnormal with increasing age and
duration of disease; indices of cortical atrophy are more variable. Each solid symbol represents a single H D subject. Each
open symbol is the mean of measurementsfrom the number of
normal control subjects shown above the abscissa; error bars are
one standard deviation.
428 Annals of Neurology Vol 12 No 5
November 1982
T
AtrWY
A
A
I-
Y
.-
8
201
4
A
A
kc
:
0
t
I
A
A
A HD (Dura.t*
1-4 yfs)
(Ouration 7-16 y r d
-1
I
0
0
3
2
1
++
aA
A
a
Normal
A HD(Duration 1-4 yrs)
I
0
3
Dementia
F i g 3 . Relationship of central brain atrophy and whole-brain
glucose metabolism t o symptoms i n H D subjects. The severity of
ventricular dilatation correlates with the severity of chorea and
dementia, but global CMR,,, does not. Each closed symbol represents 1 H D subject. Each open symbol is the mean of measurementsfrom 13 age-matched normal subjects; error bars are
one standard deviation.
0
2
1
Chorea
at comparable rates; their common slope (b =
-0.03 7) indicated a significant decrease with age.
Local glucose utilization was markedly depressed
in the caudate and putamen of HD subjects (Fig 5 ) ,
regardless of disease duration or the presence (Fig 6)
or absence (Fig 7) of caudate atrophy. The caudate
MR index was abnormal in all HD patients (approximate F = 245, df = 1,48;p < 0 . 0 1 ) (Fig 5), and the
percentage dgferences from normal were greater h
caudate MR than for caudate CT i d i c e s (see Fig 2).
The caudage stnd paamen were hypometabkc r d a tive to the rest of the brain in 3 paiknts with ewiy
HD who had lit& or no evidence of strisbtal atrophy
(Fig 7) (2 of these patients were receiving IK)medication). The presence of caudate atrophy correlated (r
= 0.57, p C 0.05) with the severity d chorea.
Local relative perfusion was assessed by 13NH3
scans [25, 27, 371 in 2 HD parients who showed
marked striittal hypometabolism. One patient had a
one-year duration of disease (Fig 7C) and the other a
fifteen-year duration. In each, the relative striatai
concentration cd 13N was subnormal, indicating that
striatal hypometabolism is accompanied by striatal
hypoperfusion.
4
10
20
40
50
Age ( y e a r s )
30
60
70
80
Fi g 4. Mean glucose utilization in whole brain decreases
significantly with age ( F = 9.61, p < 0.01). The slope of regression for H D patients (b = -0.052) did not differ from
that for normal control persons (b = -0.024). Each solid
symbol represents a single H D subject. Each open symbol is the
mean measurement from 5 normal control subjects; error bars
are one standard deviation.
Subjects at Risk for Hgntington’s Disease
CT scans were reported as normal in the formal reports by diagnostic radiologists in dl 12 subjects at
risk for HD who were scanned. Measured values of
lateral ventricle, cortical sulcus, and caudate CT indices were within one standard deviation of the normal
means for age-matched controls (see Fig 2) in all but
2 subjects. In those 2 subjects, aged 16 and 33 years,
Kuhl et al: F I X Scan in Huntington’s Disease 429
the lateral ventricle CT indices were increased more
than one but less than two standard deviations.
In the 15 subjects at risk who had FDG scans, measured values of mean CMRgl,, mean cortical MR,,,,
thalamic MRglc, and the metabolic ratio E/P were
within one standard deviation of the normal means
for age-matched controls, but not all values of caudate MR index were. While paired t test analysis
showed no significant difference Cp = 0.14) between the mean caudate MR index of the at-risk
group (N = 15) and an age-matched normal group
(N = 15), 6 of the 15 at-risk subjects (ages 12 to 53
years) had values increased more than two standard
deviations from the normal mean (Fig 8). All 6 subjects had normal caudate C T indices, and 1 had a
small increase in lateral ventricle C T index as noted.
Discussion
Qualzjcations of the FDG Method
A potential source of error in calculating glucose
utilization by the FDG method is inappropriate use
F i g 6. Late Huntington's disease (7 t o I I years'duration).
These 3 patients (A, Patient 6 ; B , Patient 12; C , Patient 71
had the most severe symptoms and the most seuere central and
caudate atrophy seen on C T scans (top).The FDG scans
(bottom) show marked hypometabolism of the caudate and
6ol
50
A.
A
A
A
*
A
*
4
++
+A-
A HD(Duration 1-4 y r s )
I
50
60
70
80
Age ( y e a r s )
F i g 3. H D patients had marked hypometabolism of caudate
and putamen. regardless of disease duration or the presence of
caudate atrophy. Note that the percentage dzfferencesfrom
normal are greater jbr caudate M R indices than for the caudate
C T indices shown in Figure 2. Solid symbols represent single
H D subjects. Each open symbol is a mean measurementfor 5
normal control subjt>cts;error bars are one standard dezfiution.
putamen. Note thalamic separation, seen i n FDG scan, which
is due to dilatation qf the third ventricle, seen i n C T scan.
Compare with the normal FDG scun in Figure 1 and data in
the Table.
430 Annals of Neurology Vol 12 No 5 November 1982
F i g 7 . Early Huntington’s disease ( I t o 3 years’ duration).
These 3 patients (A,Patient 2; B , Patient 5; C , Patient 4)
had the mildest symptoms, with little or no atrophy seen on C T
scans (top). FDG scans (bottom) show definite hypometab-
60
Normal
= 15)
(N
At Risk
(N = 15)
50
-aQ
40
x
V
al
-
5
b
30
al
e
V
m
m
0
20
t
‘lt
?
b
10
E
P
t
P=014
0
I
i
!b
b
olism of the caudate and putamen, which is profound in B
and C. Compare with normal FDG scan in Figure I and
data in the Table.
in the operational equation [36] of transport rate
constants obtained from young human subjects that
may not be valid in HD subjects [18]. The
significance is unknown, but such a cautionary consideration applies whenever the FDG method is used
in any but the normal state. Another source of possible error is based on geometry and is better understood. With the FDG method, LCMR,,, is determined less accurately in small structures in which
only a fraction of the activity is measured. This fraction, or recovery coefficient, depends on scanner
resolution and on the size, shape, and orientation
of the brain structure. Accurate comparisons of
LCMR,I, in dissimilar structures, e.g., cortex and
F i g 8. Values of caudate M R index in subjects at risk for H D
contrasted with those of an age-matched normal group andpatients with H D . Although there is no significant dgference by
paired t test between the means of the at-risk and normal
groups, 6 subjects at risk had indices increased more than two
standard deviations above the normal mean value.
Kuhl et al: FDG Scan in Huntington’s Disease
431
thalamus, require knowledge of their relative recovery coefficients. In the work reported here, the relacionship of resolution within and perpendicular to
the image plane caused the recovery coefficients of
the geometrically different cortex and thalamus to
approach each other, making valid the comparison
shown in Figure 7 [26, 301. The partial volume effect
causes overestimation of LCMR,,, in white matter
and underestimation in gray matter; whether selective gray matter atrophy further exaggerates underestimation of LCMRgI, is unknown. The partial volume effect has less influence on mean CMRgI,.
It was difficult to measure LCMRgl, in the hypometabolic caudate nuclei of HD patients; a
caudate MR index was used instead. This index will
be elevated from normal by caudate hypometabolism
but also by any abnormal increase in intercaudate distance, whether caused by caudate atrophy or by ventricular dilatation alone. Because of this, caudate
hypometabolism can be inferred only when the caudate MR index is elevated and the caudate C T index is
not, or when the metabolic index is increased out of
proportion to any increase found in the C T index.
For example, in our patients who had had HD for less
than four years, selective caudate hypometabolism
caused higher caudate MR indices (42.1 t 8.8%,
mean ? SD; N = 8) than we found in patients
with Parkinson’s disease (21.1 2 3.4%,mean ? SD,
N = 7), while equivalent degrees of ventricular dilatation in the two groups resulted in similar caudate
CT indices: mean 2 SD, 16.0 % 3.8% (N = 8) and
14.4 ? 2.5% (N = 7), respectively (unpublished results). In age-matched normal control subjects (separate group for MR and for CT) the caudate MR and
CT indices were 16.7 2 2.6% and 9.1 t 1.7@, respectively (mean SD; N = 13).
*
Cortex and Dementia in H D
In this HD group, severity of dementia was closely
associated with C T measures of central atrophy. In
contrast, other researchers have found no relationship between indices of C T atrophy and clinical severity in HD [32, 341. Also, in patients with presenile
and senile dementia, severity of dementia has consistently failed to correlate with CT measurements of
cortical sulcal widening [5, 39, 401; the severity has
correlated positively with C T measurements of ventricular dilatation in some studies [9, 37, 461 and not
in others [13,20, 3 I]. While the FDG scan is a sensitive indicator of local cortical dysfunction [ 2 5 , 271,
CT measurement of sulcal widening is considered an
imprecise method for quantifying cortical atrophy
[39,40]and should be interpreted with caution. The
close association among the three C T indices and
their correlations with duration and symptoms
suggest only that general cerebral atrophy accom-
panies the more specific striatal shrinkage in HD and
that atrophy and symptoms worsen together as the
disease progresses.
A more important finding was that overall CMRgl,, and particularly mean cortical CMR,l,,
were normal in most HD patients (see Fig 4 ) and correlated with neither duration of disease nor severity
of dementia. In contrast, patients with presenile and
senile dementia have consistently been found to have
approximately 35% reductions in global cerebral
blood flow [21, 31, 331, oxygen utilization [16, 17,
291, and glucose utilization [13, 191 when dementia
was severe, and lesser reductions when it was mild. In
FDG scans of patients with Alzheimer’s disease, Benson and associates [5] found markedly reduced glucose utilization in association cortex. Instead, in HD
patients we found only a minor decrease in frontal
relative to parietal cortex metabolism in those with
disease duration greater than six years; the decrease
did not correlate with the severity of dementia.
Finding nearly normal cortical CMRglc in demented HD subjects is in agreement with both clinical and biochemical data suggesting that the primary
dementing process in HD may not be cortical in location. The behavioral syndrome in HD includes
preservation of vocabulary and facility with language
and comprises a so-called subcortical dementia, in
which the symptoms include apathy, mental slowing,
memory disorder, and personality change [ 11.
Pathological change is most prominent in subcortical
structures, in contrast to the “cortical dementias”
such as Alzheimer’s disease, in which change is most
prominent in the association cortex [ l , 4,51. In HD
there is a normal cortical level of choline acetyltransferase, the marker enzyme for cholinergic
neurons [43];the level is decreased in Alzheimer’s
disease [8].
Caudate, Putamen, and Thalamus i n H D
An important finding of this study is that early in
H D , hypometabolism is out of proportion to atrophy
in the caudate and appears to be a process that occurs
prior to bulk loss of striatal tissue. Since the synapse
is the primary site of glucose utilization in the brain
[41], this disproportionate metabolic decline might
result from an early reduction of striatal terminals,
which may occur in HD before neuron death. Alternatively, early striatal hypometabolism may reflect
only early neuron dropout, the volume of which has
been balanced by glial cell replacement. In support of
this possibility, Jacobs and associates [23] found glial
cell replacement of neurons in the unshrunken caudate of a patient with an 18-month history of HD
symptoms. Pathological examination of such tissue is
rare, but it is known that a 70 to 80% loss of striatal
neurons can be tolerated without obvious functional
432 Annals of Neurology Vol 1 2 No 5 November 1982
alteration [6].Later, with increasing duration of H D ,
striata1 neuron loss progresses further and symptoms
appear, then worsen, explaining the subsequent
relation of caudate atrophy with disease duration and
severity of symptoms.
Subcortical metabolic patterns were otherwise unaltered. Although Divac [ 121 has hypothesized that
neuron death in HD striatum may develop as a consequence of excessive stimulation by glutamate or its
analogues, none of our subjects showed hypermetabolism in the striatum, which, if present, might
have supported a concept of overexcitation resulting
in degeneration of synapses, dendrites, and neurons.
In advanced H D , the dilated third ventricle spread
apart the left and right thalami (see Fig 6 ) ;but in all
subjects, metabolism of the thalamus was neither increased, as might have resulted from any thalamic
disinhibition [lo], nor decreased, as should have resulted if it were the site of selective neuron degeneration.
At-Risk Group
In asymptomatic subjects at risk for HD, we found
normal CT scans, as have others [32, 341, and normal
CMR,,, patterns except for possible caudate
hypometabolism in some (see Fig 8). Early after the
first appearance of symptoms in HD patients, striatal
glucose utilization was usually markedly decreased
(see Fig 5), as noted. Klawans and co-workers [24]
and Finch [ 141 have proposed a hypothetical
preexisting deficit in number or function of striatal
neurons in asymptomatic carriers; when this deficit
exceeds a critical threshold, choreiform movements
should appear. Since no information is available
about the time course of striatal neuron loss in carriers or in HD patients, it is not known if such a
striatal deficit would be present at birth or would appear later [14].Our finding of elevations in caudate
M R indices greater than two standard deviations
above the normal mean in 6 of the 15 at-risk subjects
suggests the possibility that striatal glucose utilization
may be reduced in asymptomatic carriers of the autosomal dominant HD gene. It is important that the
FDG scan be applied now in careful long-term longitudinal studies of asymptomatic offspring of parents who have H D , in order to learn whether striatal
hypometabolism is common in carriers and, if so, to
determine if its presence increases the probability of
developing the disease.
Supported in part by Contract DE-AM03-76-SF00012 from the
Department of Energy and by Research Grants CA32855 and
NS-15654 from the US Public Health Service.
We thank R. Frank Benson, MD, for his stimulating discussions;
Norman MacDonald, PhD, and his cyclotron staff; and Jorge Barrio, PhD, and his chemistry staff for preparing FDG; Shirley
Diamond, MS, for organizing the patient group; Joanne Miller,
Ronald Sumida, Francine Aguilar, and Larry Pang for technical assistance; Mary Lee Griswold for illustrations; and Claire Lira for
preparing the manuscript.
References
1. Albert ML: Subcortical dementia. In Katzman R, Terry RD,
Bick KL (eds): Alzheimer’s Disease: Senile Dementia and
Related Disorders (Aging, Vol 7). New York, Raven, 1978,
pp 173-180
2. Barr AN, Heinze WJ, Dobben GE, et al: Bicaudate index in
computerized tomography of Huntington disease and cerebral
atrophy. Neurology (Minneap) 28:1196-1200, 1978
3. Barrio JR, MacDonald NS, Robinson GD, et al: Remote,
semiautomated production of ’sF-labeled 2-deoxy-2-fluoro-Dglucose. J Nucl Med 22:372-375, 1981
4. Benson DF: Dementia: a clinical approach. Roche Seminars
on Aging, no. 1. Nutley, NJ, Hoffman-LaRoche, 1980
5. Benson DF, Kuhl DE, Phelps ME, et al: Positron emission
computed tomography in the diagnosis of dementia (abstract).
Ann Neurol 10:76, 1981
6. Bernkeimer H, Birkmayer W, Hornykiewicz 0, et al: Brain
dopamine and the syndromes of Parkinson and Huntington.
Clinical, morphological, and neurochemical correlations. J
Neurol Sci 20:415-455, 1973
7. Blinderman EE, Weidner W, Markham CH: The
pneumoencephalogram in Huntington’s chorea. Neurology
(Minneap) 14:601-607, 1964
8. Bowen DM, Smith CB, White P, Davison AN: Neurorransmitter related enzymes and indices of hypoxia in senile
dementia and other abiotrophies. Brain 99:459-496, 1976
9. Bridkman SD, Sarwar M, Levin HS, Morris H H : Quantitative
indexes of computed tomography in dementia and normal
aging. Radiology 138:89-92, 1981
10. Curtis DR, Tebecis AK: Bicuculline and thalamic inhibition.
Exp BrainRes 16:211-218, 1972
11. DeLeon MJ, Ferris SH, George AE, et al: Computed tomography evaluations of brain-behavior relationships in senile
dementia of the Alzheimer’s type. Neurobiol Aging 1 :69-79,
1980
12. Divac I: Possible pathogenesis of Huntington’s chorea and a
new approach to treatment. Acta Neurol Scand 56:357-360,
1977
13. Ferris SH, DeLeon MJ, Wolf SP, et al: Positron emission tomography in the study of aging and senile dementia.
Neurobiol Aging 1:127-131, 1980
14. Finch CE: The relationships of aging changes in the basal
ganglia to manifestations of Huntington’s chorea. Ann Neurol
7:406-411, 1980
15. Forno LS, Jose C: Huntington’s chorea: a pathological study.
In Barbeau A, Chase T N , Paulson GW (eds): Huntington’s
Chorea, 1872-1972. Adv Neurol 1:453-470, 1973
16. Frackowiak RSJ, Pozzilli C , Legg NJ, et al: Regional cerebral
oxygen supply and utilization in dementia. A clinical and
physiological study with oxygen-15 and positron tomography.
Brain 104:753-778, 1981
17. Grubb RL, Raichle ME, Gad0 MH, et al: Cerebral blood flow,
oxygen utilization, and blood volume in dementia. Neurology
(Minneap) 27:905-910, 1977
18. Hawkins RA, Phelps ME, Huang SC, Kuhl DE: Effect of
ischemia on quantification of local cerebral glucose metabolic
rate in man. J Cer Blood Flow Metab 1:37-51, 1981
19. Hoyer S: Blood flow and oxidative metabolism of the brain in
different phases of dementia. In Katzman R, Terry RD, Bick
Kuhl et al: F D G Scan in Huntington’s Disease
433
KL (eds): Alzheimer’s Disease: Senile Dementia and Related
Disorders (Aging, Vol 7). New York, Raven, 1978, pp 219226
20. Hughes CP, Gad0 M: Computed tomography and aging of the
brain. Radiology 139:391-396, 1981
21. Ingvar D H : Cerebral blood flow and metabolism in complete
apallic syndromes, in states of severe dementia, and in akinetic
mutism. Acta Neurol Scand 49:233-244, 1973
22. Ingvar DH: “Hyperfrontal” distribution of the cerebral grey
matter flow in resting wakefulness; on the functional anatomy
of the conscious state. Acta Neurol Scand 60:12-25, 1979
23. Jacobs L, Hinkel WR, Painter F, et al: Computerized tomography in dementia with special reference to changes in size of
normal ventricles during aging and normal pressure hydrocephalus. In Katzman R, Terry RD, Bick KL (eds): Alzhekner’s Disease: Senile Dementia and Related Disorders
(Aging, Vol 7). New York, Raven, 1978, pp 241-260
24. Klawans HL, Paulson GW, Ringel SP, Barbeau A: Use of Ldopa in the detection of presymptomatic Huntington’s
chorea. N Engl J Med 286:1331-1334, 1972
25. Kuhl DE, Engel J Jr, Phelps ME, Selin C : Epileptic patterns of
local cerebral metabolism and perfusion in humans determined by emission computed tomography of ‘*FDG and
I3NH,. Ann Neurol8:348-360, 1980
26. Kuhl DE, Metter EJ, Riege WH, Phelps ME: Effects of human
aging on patterns of local cerebral glucose utilization determined by the [‘*F]fluorodeoxyglucose method. J Cer Blood
Flow Metab 2:163-171, 1982
27. Kuhl DE, Phelps ME, Kowell AP, et al: Effects of stroke on
local cerebral metabolism and perfusion: mapping by emission
computed tomography of ‘*FDG and I3NH,. Ann Neurol
8:47-60, 1980
28. Kuhl DE, Phelps ME, Markham C, et al: Local cerebral glucose utilization in Huntington’s disease determined by emission computed tomography of 18F-fluorodeoxyglucose. J Cer
Blood Flow Metab 1:suppl 1:S459-S460, 1981
29. Lassen NA, Feinberg I, Lane MH: Bilateral studies of cerebral
oxygen uptake in young and aged normal subjects and in
patients with organic dementia. J Clin Invest 39:491-500,
1960
30. Mazziotta JC, Phelps ME, Plummer D, Kuhl DE: Quantitation
in positron emission computed tomography: 5. Physicalanatomical factors. J Comput Assist Tomogr 5:734-743, 1981
31. Melamed E, Lavy S, Siew F, et al: Correlation between regional cerebral blood flow and brain atrophy in dementia.
Combined study with %enon inhalation and computerized
tomography. J Neurol Neurosurg Psychiatry 4 1:894-899,
1978
32. Neophytides AN, DiChiro G , Barron SA, Chase T N : Com-
puted axial tomography in Huntington’s disease and persons
at-risk for Huntington’s disease. In Chase T N , Wexler NS,
Barbeau A (eds): Huntington’s Disease. Adv Neurol
23:185-191, 19;’9
33. Obrist WD, Chivian E, Cronqvist S, Ingvar D: Regional cerebral blood flow in senile and presenile dementia. Neurology
(Minneap) 20:315-322, 1970
34. Oepen G , Ostertag C: Diagnostic value of CT in patients with
Huntington’s chorea and their offspring. J Neurol 225:189196, 1981
35. Phelps ME, Hoffman EJ, Huang SC, Kuhl DE: E C A T a new
computerized tomographic imaging system for positron emitting radiopharmaceuticals. J Nucl Med 19:635-647, 1978
36. Phelps ME, Huang SC, Hoffman EJ, et al: Tomographic measurement of local cerebral glucose metabolic rate in humans
with (F-18)2-fluoro-2-deoxy-Dglucose: validation of method.
Ann Neurol 6:371-388, 1979
37. Phelps ME, Huang SC, Hoffman EJ, et al: Cerebral extraction
of N-13 ammonia: its dependence on cerebral blood flow and
capillary permeability-surface area product. Stroke 12:607619, 1981
38. Reivich M, Kuhl D, Wolf A, et al: The ‘*F-fluorodeoxyglucose
method for the measurement of local cerebral glucose utilization in man. Circ Res 44:127-137, 1979
39. Roberts MA, Caird FI: Computerized tomography and intellectual impairment in the elderly. J Neurol Neurosurg
Psychiatry 39986-989, 1976
40. Roberts MA, Caird FI, Grossart KW, Steven JL: Computerized tomography in the diagnosis of cerebral atrophy. J
Neurol Neurosurg Psychiatry 39:909-915, 1976
41. Sokoloff L The relationship between function and energy
metabolism: its use in the localization of functional activity in
the nervous system. Neurosci Res Program Bull 19:159-2 10,
1981
42. Sokoloff L, Reivich M, Kennedy C, et al: The (“C) deoxyglucose method for the measurement of local cerebral glucose
utilization: theory, procedure and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897-916,
1977
43. Spokes EGS: Neurochemical alterations in Huntington’s
chorea. A study of post-mortem brain tissue. Brain 103:
179-210, 1980
44. Spokes EGS: The neurochemistry of Huntington’s chorea.
Trends Neuroscii 4:115-118, 1981
45. Terrence CF, Delaney JF, Alberts MC: Computed tomography for Huntington’s disease. Neuroradiology 13:173- 175,
1977
46. Tomlinson BEA., Blessed G, Roth M: Observations of brains
of demented old people. J Neurol Sci 11:205-242, 1970
434 Annals of Neurology Vol 12 No 5 November 1982
Документ
Категория
Без категории
Просмотров
2
Размер файла
1 019 Кб
Теги
atrophy, metabolico, determiners, 18fdg, tomography, scan, disease, huntington, computer, cerebral
1/--страниц
Пожаловаться на содержимое документа