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Cortical abnormalities in Alzheimer's disease.

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Cortical Abnormahties
in Alzheimer’s Disease
Norman L. Foster, MD, Thomas N. Chase, MD, Luigi Mansi, MD, Rodney Brooks, PhD, Paul Fedio, PhD,
Nicholas J. Patronas, MD, and Giovanni Di Chiro, MD
Regional cerebral glucose metabolism, an index of neuronal activity, was compared in 20 patients with Alzheimer’s
disease and 8 age-matched normal volunteers by positron emission tomography following [‘*F] 2-fluoro-2-deoxy-~glucose administration. Overall cortical glucose utilization in the Alzheimer’s group was 10 to 49% below that of
control individuals. The posterior parietal cortex and contiguous portions of posterior temporal and anterior occipital
lobes were most severely affected; frontal cortex was relatively spared. This pattern of cortical involvement is consistent with the major clinical features of Alzheimer’s disease. Comparison of patients with early and more advanced
dementia suggested that a substantial decline in glucose metabolism occurs before cognitive impairment becomes
evident; once the patient is symptomatic, however, small additional metabolic decrements are associated with a
marked deterioration in intellectual function.
Foster NL, Chase TN, Mansi L, Brooks R, Fedio P, Patronas NJ, Di Chiro G: Cortical abnormalities in
Alzheimer’s disease. Ann Neurol 16:649-654, 1984
Alzheimer’s disease has often been considered a rather
uniformly diffuse cortical degenerative disorder associated with a global decline in cognitive function. Recent
morphological and biochemical evidence suggests,
however, that dementia of the Alzheimer type reflects
a relatively selective, even transmitter-specific, cerebral
abnormality 113, 311. Unfortunately, much of our
knowledge of Alzheimer’s disease derives from postmortem study of individuals with advanced disease; at
this time initial, critical changes may be obscured by
later, secondary alterations. Positron emission tomography (PET) 123, 32, 361 avoids this limitation by allowing the examination of brain function at relatively
earlier stages. Reliable estimates of local neuronal activity can be obtained using [‘8F)2-fluoro-2-deoxyDglucose (FDG) to determine cerebral glucose utilization 1421. The application of this technique has suggested a relatively focal pattern of cortical involvement
18-10, 181. The purpose of the present study was to
characterize further the cortical and cognitive dysfunction occurring in patients with mild and relatively more
advanced Alzheimer’s disease.
Methods
Twenty patients with Alzheimer’s disease (14 men, 6
women; mean age +- SEM, 60 +- 1.3 years; age range, 48 to
72 years) were compared with 8 age-matched, healthy control subjects (4 men, 4 women; mean age, 59 ? 1.7 years;
age range, 52 to 66 years). Included in the Alzheimer’s
From the Intramural Research Program, National Institute of
Neurological and Communicative Disorders and Stroke, Bethesda,
MD 20205.
group were patients initially selected on the basis of disproportionately severe verbal impairment (3 patients) or visuospatial impairment (4 patients) {IS]; all subsequent patients,
some the subject of previous preliminary reports C9, 101,
were admitted without regard to the nature of their cognitive
deficits. Average age at symptom onset was 57
1.4 years.
The diagnosis of Alzheimer’s disease was based on a history
of gradually progressive intellectual deterioration without
focal motor or sensory signs or other known causes of dementia. None of the patients with Alzheimer’s disease had
clinical or laboratory evidence of cerebrovascular disease
(Hachinski ischemic scores {37] all 4 or less) or other
significant illness. Their electroencephalographic recordings
were generally free of localized abnormalities,and computed
tomographic (CT) scans revealed generalized cerebral atrophy. The educational background of the patient and control groups was similar (15 & 0.5 years for patients, compared with 17 5 0.5 years for control subjects).
All subjects were alert, cooperative, and unmedicated for
at least the prior month of the time of study. Each received a
complete neurological and general medical examination, as
well as an extensive psychometric battery including the
Wechsler Adult Intelligence Scale (WAIS), the Wechsler
Memory Scale, and the Mattis Dementia Scale. To evaluate
relative cognitive and metabolic changes with disease progression, findings in those considered clinically to be mildly
affected ( 5 men, 2 women; mean age, 60 -t 1.4 years; mean
symptom duration, 2.4 +- 0.5 years) were compared with
those judged most severely impaired (6 men, 2 women;
mean age, 60 2 1.9 years; mean symptom duration, 4. I &
0.9 years).
*
Received Nov 30, 1983, and in revised form Mar 19, 1984. Accepted for publication Mar 24, 1984.
Address reprint requests to Dr Chase, Bldg 10, Rm 5C103,
NINCDS, NIH Bethesda, MD 20205.
649
Table 1 . Cerebral Glucose Metabolism in Alzheimer‘s Disease“
Grout,
Normal control
subjects
Patients
% reduction
Left Cerebral
Cortex
Right Cerebral
Cortex
Left Basal
Ganglia
Right Basal
Ganglia
7.4
0.50
7.1
* 0.20b
6.0
5.3
k
0.48
7.1
?
0.21b
5.1
28
?
29
?
0.33
7.1
?
0.21‘
5.9
15
?
0.34
* 0.20d
17
“Mean 2 SEM level of glucose metabolism (in milligrams per 100gm per minute) is reported for 20 patients with Alzheimer’s disease and 8 agematched normal control subjects.
Statistical significance: ’p < 0.0001; ‘p < 0.01; dp < 0.005 compared with control values.
After informed consent had been obtained, PET scanning
(ECAT I1 tomograph, ORTEC, Oak Ridge, TN) at 10 mm
increments parallel to the canthomeatal (eye-to-ear) plane
was begun 30 minutes after rapid injection of approximately
5 mCi of FDG through an intravenous catheter in one arm.
Following isotope administration, serial “arterialized” venous
blood samples were obtained from the opposite arm for
determination of FDG and glucose concentrations 1351.
Throughout the procedure all subjects were kept at rest in a
quiet environment, with eyes patched and ears plugged to
minimize the effects of external stimuli. Calculation of local
metabolic rates for glucose was based on rate constants determined from normal individuals using a modification of the
Sokoloff operational equation {b, 2 5}. Image reconstruction
was performed on the ECAT computer employing the standard ellipse method of attenuation correction and the
medium-resolution convolution filter. The resulting spatial
resolution in the imaging plane was 1.7 cm full width at half
maximum and 2.0 cm in the axial plane.
By means of the ECAT “region of interest” program,
metabolic rates were obtained for sixty-three contiguous
nonoverlapping regions in both the right and left cerebral
cortex. O n each horizontal scan a rectangular box, approximately 3 mm along the X (transverse) axis and 14 mm along
the Y (anteroposterior) axis, was centered on a line equidistant from the anterior and posterior poles of the brain. As
the rectangle was moved laterally along this line across the
cerebral cortex, the peak mean ECAT number for all pixels
enclosed by the rectangle was used to compute the metabolic
rate for that cortical area. After readings from both right- and
left-hemisphere cortex were obtained, the rectangle was advanced in 14 mm increments, anteriorly and posteriorly, to
yield metabolic values for nine adjoining cortical regions in
both the right and left hemispheres at each of seven scan
levels. Metabolic values were excluded from analysis when
the rectangle appeared to fall beyond the cortical limits; cortex at the extreme frontal and occipital poles was thus generally not analyzed. Concern for partial volume effects likewise
prevented the inferior temporal surface and medial (interhemispheric) cortex from being accurately evaluated.
Metabolic values were also obtained in 9 mm x 9 mm (in
X Y plane) regions centered in the left and right basal ganglia
(mainly corpus striatum). Hemispheric glucose metabolic
rates were the means of all cortical values analyzed (sixtythree regions on each side). The position in the axial plane of
each horizontal slice was determined by the use of characteristic landmarks 122,321. The location of these regions on the
lateral surface was confirmed by comparison with C T scans
and standard atlases. Values approximating specific Brodmann areas were the mean of values in eight to twelve of the
cortical regions. Unless otherwise specified, the data are presented as means 2 SEMs and are compared statistically by
two-tailed Student t test.
Results
Cerebral glucose utilization was markedly reduced in
the Alzheimer’s disease group (Table 1). For the individual patient, overall cortical metabolism was 10 to
49% below control levels. Cortical changes substantially exceeded those found in the basal ganglia (see
Table 1). For the entire group of patients with Alzheimer’s disease, no significant interhemispheric metabolic differences were discerned, although substantial
right-left asymmetries were present in some individuals.
Psychometric test results demonstrated considerable
impairment in the Alzheimer’s group. WAIS FullScale IQ scores averaged 87 ? 3.4 in patients and 133
-+ 3.4 in control subjects, Wechsler Memory Scale
scores averaged 75 t 3.1 in patients and 136 t 4.4 in
controls, and Mattis Dementia Scale scores averaged
104 ? 4.6 in patients and 142 ? 0.73 in control
individuals. All differences between patients and controls were highly significant ( p < 0.001). Overall dementia severity was closely associated with the degree
of cortical metabolic dysfunction: Analysis of data
from all subjects admitted to this study revealed a
significant correlation between cortical glucose metabolism and performance on the WAIS Full-Scale test,
the Wechsler Memory Scale, and the Mattis Dementia
Scale (all p < 0.001 by two-tailed Pearson productmoment correlation analysis).
The pattern of cortical hypometabolism was not uniform (Table 2; Figs 1 and 2). The posterior parietal
cortex (especially Brodmann area 39) manifested the
most profound metabolic reduction, twice that found
in a representative area of frontal cortex (Brodmann
area 10;p < 0.0001). Portions of the anterior occipital
and posterior temporal cortex adjoining the parietal
lobe were also severely affected. The frontal cortex
650 Annals of Neurology Vol 16 No 6 December 1984
Table 2. Regional Cortical Glucose Metabolism in Alzheimer's Disease"
Group
Frontal Region
(Brodmann 10)
Parietal Region
(Brodrnann 39)
Temporal Region
(Brodmann 22)
Occipital Region
(Brodmann 18)
~~
Normal control
7.4
2
0.43
7.6
2
0.22b3'
4.4
k
0.55
6.7 r 0.56
7.0 k 0.56
&
0.2jb
4.4 k 0.20b
34
4.6 r 0.23b
34
subjects
Patients
% reduction
5.6
24
42
"Mean & SEM level of glucose metabolism (in milligrams per 100 gm per minute) is reported for cerebral cortex approximating specified
Brodmann areas for 20 patients with Alzheimer's disease and 8 control subjects.
Statistical significance: bp < 0.0005 compared with normal control values; 'p < 0.0001 compared with all other areas of cortex in patients.
was relatively spared; glucose metabolism in the frontal
lobes exceeded that in any other cerebral lobe in 19 of
the 20 patients. This pattern of cortical involvement
was not significantly different in the patients selected
initially on the basis of predominant language or
visuospatial deficits and the patients selected later
without regard to their dementia profile: Compared
with normal control values, glucose metabolism in the
latter patients was reduced by only 19% in the frontal
cortex (Brodmann area lo), in contrast to reductions
of 32% in the parietal (Brodmann 39) and 34% in the
temporal (Brodmann 22) lobes ( p < 0.05 for difference between frontal and either parietal or temporal
lobe metabolism).
Comparison of patients judged clinically to be
mildly demented with those considered to be severely
affected revealed substantial differences in cognitive
test performance. For example, relative to values obtained from normal controls, WAIS IQ scores were
reduced by 26% (98 2 4.7) in the mild and by 44%
(74 ? 2.5) in the severe cases, Wechsler Memory
Scale scores by 38% (85 & 4.9) and 54% (63 -+ 2.4),
and Mattis Dementia Scale scores by 13% (123 ? 3.5)
and 39% (86 r 5.6), respectively. All these differences between the mild and severe patient groups
were highly significant ( p < 0.001). Mean overall cortical glucose metabolism was significantly below normal
control rates in both patient groups ( p < 0.01). The
0.3 mg per 100
reductions averaged 25% (to 5.5
gm per minute) in the mildly affected and 30% (to 5.1
2 0.3) in the severely affected patients. Comparison
of glucose metabolic rates in the mildly and the severely demented patients, whether for the entire cerebral cortex or only for selected Brodmann areas (Table
3), failed to yield statistically significant differences. In
both mild and severe disease, the posterior parietotemporal cortex was most profoundly hypometabolic,
although the metabolic difference between the two
patient groups appeared to involve the frontal lobe at
least as much as posterior cortical areas (see Table 3).
Thus, with increasing severity of dementia, small additional decrements in glucose utilization were associated with substantially greater declines in cognitive
ability.
*
Fig 1, Positron emission tomographic scan image of a normal control subject (A)and a patient with Alzheimer's disease (B) fil/ w i n g {'8F)2-fEuoro-2-deoxy-D-glucose
administration. Both
horizontal sections were taken in a plane parallel t o and 80 mrn
rostral t o the canthomeatal line. The patient scan shows interruption of the relatively rapid glucose utilization occurring in the
cortical area frontally (red and yellow areas) by a hypometabolic
zone (green and blue areas) primarily involving the posterior
parietal lobes.
Foster et al: PET in Alzheimer's Disease
651
Left
Right
Fig 2. Pattern of cortical hypometabolism in Alzheimer’s disease.
Regional decrements in average glucose metabolismfor 20 patients
compared with 8 age-matched control subjects are indicated by
stippling: dense, 35% or more; medium, 25 to 34%; none, less
than 25%. The cortical metabolic rate for glucose in normal individuals averaged 7.3 ? 0.49 mgll OOgmlmin.
Discussion
The present results confirm and extend our earlier
findings {S, 10, lS} of relatively focal cortical dysfunction, primarily involving the posterior parietotemporal areas, in Alzheimer’s disease. Although previous
neuropathological [ 11, 12, 431, cerebral blood flow
[28, 34, 40}, and glucose metabolism [l, 4 , 15-171
investigations generally have emphasized the diffuse
nature of this disorder, there have been notable exceptions [7, 271. Moreover, our results now appear to
have been partially corroborated by FDG studies from
other laboratories 13, 2 11. The current observations
also support earlier reports { 2 , 241 of relative sparing
of the primary sensorimotor cortex in patients with
Alzheimer’s disease. Prior failure to appreciate fully
the focal nature of the cortical alterations in Alzheimer’s disease could be due to the study of relatively
more advanced illness, because the present findings
suggest that in the later stages frontal cortex may no
longer be less subject to deterioration than more posteriorly situated cortex. This possibility is consistent
with the results of a cerebral oxygen utilization study
comparing patients with mild and severe Alzheimer’s
disease [ 191. It appears unlikely that the observed pattern of cortical involvement is merely a reflection of
the special cognitive features of the individuals initially
selected for PET evaluation: patients with predominantly visuospatial or language disability had conspicuous right-left hemispheric asymmetries, but their
ratios of frontal to parietal or temporal glucose metabolism did not differ significantly from those found in
patients chosen without regard to the clinical characteristics of their dementia.
Artifacts introduced by the procedures used for data
coilection and analysis are unlikely to account for the
abnormalities in cortical metabolism found in this
study. For example, partial volume effects can alter
estimates of glucose metabolism [333. However, by
using peak values in narrow regions of interest and
excluding from analysis frontal and occipital poles and
inferior temporal surfaces, such problems are minimized. Although sulcal widening can make the interpretation of results difficult, such changes, at least as
determined by CT scanning, do not seem to differ
consistently in patients with Alzheimer’s disease and
age-matched controls [26]. In the calculation of glucose utilization rates, constants were used that so far
have been measured only in young normal volunteers
[25]. The lumped constant, which accounts for the
difference in cellular transport and phosphorylation of
FDG as compared with glucose, should vary little un-
Table 3. Regional Cortical Glucose Metabolism in Patients with Mild and Relatively Severe Alzheimet’s Disease‘
Group
Mildly affected
patients
Severely affected
patients
% change
Frontal Region
(Brodmann 10)
Parietal Region
(Brodmann 39)
Temporal Region
(Brodmann 22)
Occipital Region
(Brodmann 18)
6.0 4 0.4b,‘
4.6
I
0.2b
4.9 t 0.4b
4.8 t 0.3b
5.5 t 0.4b.‘
9
4.4 ’. 0.4b
4.5 t 0.3b
8
4.5 t 0.4b
6
4
”Mean t SEM level of glucose metabolism (in milligrams per 100 grn per minute) is reported for cerebral cortex approximating specified
Brodmann area for 7 mildly affected and 8 severely affected patients with Alzheimer’s disease.
Statistical significance: ’p < 0.03 compared with normal control values; ‘p < 0.02 compared with all other areas of cortex in the same group of
patients.
652 Annals of Neurology Vol 16 No 6 December 1984
less substrate concentration becomes rate limiting.
Such an event is unlikely in the absence of hypoglycemia or cerebrovascular disease 1361. Although it remains possible that some change in the glycolytic pathway occurs in Alzheimer’s disease 129, 4 11, there is no
evidence of altered hexokinase or membrane transport
kinetics that would modify rate constants in the
Sokoloff equation. The regional changes seen in our
subjects would be affected only if similar regional
changes in rate constants occurred.
This study, like several published previously [4, 8, 9,
15, 167, found significant correlations between various
measures of global dementia and overall cortical glucose metabolism. Nevertheless, the precise relation
between glucose metabolism and intellectual performance remains uncertain. This complexity is illustrated
by the recent report of increased cortical glucose utilization in adults with Down’s syndrome 1391. Moreover, studies in experimental animals suggest that relatively low glucose metabolism can occur in normal
individuals depending on state of alertness 1301 or
presence of medication 120). Care was directed toward
the control of such variables in our study, however,
and it appears reasonable to assume that the observed
cortical metabolic reductions in Alzheimer’s disease
reflect a net diminution in synaptic activity 142).
Whether the metabolic deterioration found in our
patients can be attributed to a loss of intrinsic cortical
neurons or to their hypofunction caused by partial degeneration o r deafferentation remains to be determined. Preponderant involvement of the parietal association cortex, a site of integration of somatosensory,
visual, and auditory inputs to the cortex, is consistent
with the major clinical features of Alzheimer’s disease.
In fact, damage to the dominant posterior cortex in the
setting of cerebrovascular or cardiovascular disease
reportedly simulates many of the clinical features of
Alzheimer’s disease 121. Additional features in our
patients may reflect the cortical dysfunction found in
the nondominant posterior cortex as well as in the remainder of cortex generally. Unfortunately, portions
of the medial temporal lobe, such as the amygdala and
hippocampus, which have been implicated in memory
function, cannot be assessed reliably by our present
methods and have not been included in this analysis.
The parietal association area is richly endowed with
stellate interneurons f441.Consistent with the results
of this study, recent neuropathological observations indicate that the neurodegenerative process in Alzheimer’s disease may primarily affect portions of the parietal
and temporal lobes C71.
The marked metabolic dysfunction found in even
mildly demented patients with Alzheimer’s disease, as
well as the small differences in cortical glucose metabolism found between patients with mild and those with
severe cognitive impairment, suggests that a relatively
high threshold of cortical metabolic dysfunction must
be exceeded before cognitive dysfunction becomes
clinically evident; once clinical decompensation has occurred, however, small additional increments in cortical dysfunction may be associated with relatively substantial increases in dementia severity. It is reasonable
to assume that the cortex has a considerable margin of
safety in regard to neuronal injury. The present data
would be consistent with a model in which Alzheimer’s disease has reduced this margin of safety so that
relatively minor changes in glucose metabolism lead to
major changes in mentation. The sensitivity of cognition in Alzheimer’s disease to environmental changes
and drugs provides further support for this concept { 5 ,
451.
The present observations cast some doubt on the
possibility that Alzheimer’s dementia results from the
selective degeneration of acetylcholine-releasing neurons that project throughout the cerebral hemispheres
from certain forebrain nuclei 1131; except in the very
elderly, current biochemical evidence suggests fairly
uniform cortical abnormalities of the cholinergic system 113, 14, 381. Additional, more anatomically focused biochemical studies will be necessary to establish which, if any, single neurotransmitter serves as the
critical determinant for the functional abnormalities in
Alzheimer’s disease. Information deriving from such
research could have important implications for the rational development of effective symptomatic therapies.
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