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Clinical history brain metabolism and neuropsychological function in Alzheimer's disease.

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Clinical History, Brain Metabolism,
and Neuropsychological Function
in Alzheimer's Disease
Neal R. Cutler, MD," James V. Haxby, PhD,' Ranjan Duara, MD," Cheryl L. Grady, PhD,"
Arthur D. Kay, MD," Robert M. Kessler, MD,? Magesh Sundaram,' and Stanley I. Rapoport, MD*
Data concerning 7 patients with a diagnosis of presumptive Alzheimer's disease (mean age, 65.6 years) are presented in
detail in relation to the patients' regional cerebral metabolic rates for glucose. Rates were measured by positron
emission tomography with Auorine 18-labeled Auoro-2-deoxy-D-glucose under conditions of reduced visual and auditory stimulation. A relationship was found between severity of dementia and brain metabolism. In patients with mild
to moderate Alzheimer's disease, memory and intellectual deficits were evident without major reductions in absolute
metabolic rates, while ratios of regional to whole brain metabolism revealed reductions in regions of the parietal lobes.
In the late, severe form of the disease, brain metabolic rates were consistently and significantly reduced. The findings
suggest that memory and intellectual deficits are reflected in reductions of brain metabolism in some brain regions in
mild to moderate forms of Alzheimer's disease and that, in the late, severe form of the disease, reductions occur
consistently throughout the brain.
Cutler NR, Haxby JV, Duara R, Grady CL, Kay AD, Kessler RM, Sundaram M, Rapoport SI: Clinical history,
brain metabolism, and neuropsychological function in Alzheimer's disease. Ann Neurol 18:298-309, 1985
Dementia of the Alzheimer type is a progressive disorder associated with disruption of neuronal function
and a gradual deterioration in intellectual function and
personality El]. It is accompanied by reductions in the
numbers of large cortical neurons in the temporal and
frontal lobes and cholinergic neurons in the basal nucleus of Meynert [S], and in choline acetyltransferase,
as well as other neuropathological changes. Postmortem studies attempting to relate clinical findings to
brain disorder have found most cell loss occurring in
the temporal and frontal lobes and, in severe Alzheimer's disease (AD), in the parietal lobes as well
[ 5 , 61With the recent development of positron emission
tomography (PET) using fluorine 18-labeled fluoro-2deoxy-D-glucose ( "FDG), brain metabolism can be examined in specific brain regions. Previous studies C7,
14-1 71 have indicated that the frontal and parietal
lobes are most affected in A D and that dramatic reductions in overall cerebral metabolism occur in late, severe AD.
Because of the heterogeneous course and symptomatology of AD, descriptive criteria for each patient
and age-matched control subject must be satisfied before metabolic results from PET can be correlated with
From the "Section on Brain Aging and Dementia, Laboratory of
Neurosciences, National Institute on Aging, and the +Nuclear
Medicine Department, Clinical Center, National Institutes of
Health, Berhesda, M D 20205.
clinical condition. These criteria include clinical history, laboratory test results, physical and neurological
examination findings, neuropsychometric assessment,
and grading of severity for each patient and agematched control subject. These descriptive criteria
have been incomplete in previous PET studies of AD.
For example, Frackowiak and associates { 161 found the
greatest metabolic reductions in the parietal lobe in
mild AD and in the frontal and parietal lobes in severe
AD. However, their data are inconclusive because
careful clinical descriptions of patients were lacking.
Foster and colleagues [14] examined the focal metabolic asymmetries in AD and related them to language
and visuoconstructive dysfunctions, but did not adequately distinguish metabolically and descriptively patients with mild, moderate, and severe AD [ 151.
The present report describes 7 patients with AD
who underwent PET scanning. Detailed case histories,
as well as results from computed tomographic (CT)
scanning of the brain, electroencephalography (EEG),
and neuropsychometric tests, are given. S i x of the 7
patients remain alive and therefore no neuropathological confirmations of AD are available. In the seventh
patient, who died, neuropathological examination
confirmed AD.
Received June 15, 1984, and in revised form Feb 1, 1985. Accepted
for publication Feb 19, 1985.
Address reprint requests to Dr Curler, Depmment of Neurology,
Naval Medical Command. National CaDital Region. Bethesda, MD
20814.
I
298
TabIe 1. Description of Seven Patients with Alzheimer’s Disease
~
Patient
No.
Age (yr),
Sex
Duration
Severity Test Scores
of Illness
(yr)
MMSE BMICT BDS MS
1
2
65, M
81, F
4
3
24
19
26
23
3
49, M
67, F
57, F
2
3
2.5
20
15
13
21
22
20
63.8
67, M
73, F
2.8
6
6
18.2
5
22.4
70
65.6
6
3.7
4
5
Meana
6
7
Meanb
Group
mean
...
...
9
16.0
18.6
Neurological Signs
Snout reflex
Snout reflex, rooting reflex,
fine tremor of fingers
Mild tremor
Dy sdiadochokinesia
Snout, palmomental
reflexes
123
104
2
1
6.5
119
2
3
3
...
8.5
9
9
HS
2.5
2.5
...
108
~
5.8
9.5
10.5
113.5 2.2
2
33
... ...
10.0
6.7
97.4 2.1
Snout reflex, grasp
Snout, palmomental
reflexes
~
~~
~
Dominant EEG
Background
Frequency (Hz)
10-1 1
18-24
10-11
6-7
3-7
3-5
4-6
7.7- 10.1
“For Patients 1 to 5 with mild to moderate Alzheimer‘s disease.
bFor Patients 6 and 7 with late, severe Alzheimer’s disease.
M = male; F = female; MMSE = Mini-Mental State Examination; BMICT = Blessed Memory Information Concentration Test; BDS
Blessed Dementia Scale; MS = Mattis Dementia Scale; HS = Hachinski score; EEG = electroencephalogram.
=
Table 2. Clinical Diagnostic Features and Computed Tomographic Findings in Seven Alzheimer’s Disease Patients
Patient
No.
Memory
Deficits
1
2
3
+
+
++
+
+
++
+++
4
5
6
7
+
= mild;
++
Disorientation
Aphasia
Apraxia
Deterioration
of Personality
Reflexes
(Snout, Grasp)
Cortical
Atrophy
+
++
...
...
...
...
...
...
...
...
...
...
+
++
...
...
+
+++
...
...
++
+++
+++
+++
+++
= moderate;
++
=
severe; CT
...
=
++
++
+
+++
computed tomography; L
Methods
S.a bjects
Seven patients with presumptive AD were selected from
160 patients being seen at our outpatient clinic. Each met the
AD diagnostic criteria of the Diagnostic and Statistical
Manual I11 (DSM 111) [2], and each diagnosis was confirmed
by at least two neurologists. Each patient had a Hachinski
ischemic score [18] of less than 4, had no medical diseases
(including hypertension) other than AD, had received no
medications for at least two weeks prior to study, and had no
history of alcohol or illicit drug abuse.
Ratings of severity were based on previous medical history, information given by family informants, and the results
of four severity rating scales: the Mini-Mental State Examination 1137, the Blessed Dementia Scale, the Blessed Memory
Information Concentration Test 141, and the Mattis Dementia Scale 1221 (Table 1). In order to exclude other causes of
dementia, all patients were evaluated for a vascular disorder
...
...
...
++
++
+++
=
+++
+
++
+
++
++
Lateral Ventricle
Enlargement on
CT Scanning
+
+
+ (L > R)
++
+
++
+
left; R = right.
using the Hachinski scale, and for a depressive illness using
the depression criteria of the DSM I11 [23. Each patient
underwent CT scanning, EEG testing, and a spinal tap for
diagnostic and research purposes (Table 2). All were given a
thorough neuropsychological evaluation. Tests administered
included the following: (1)Wechsler Adult Intelligence Scale
(WAIS) 1321, which includes tests of verbal intelligence, calculations, immediate verbal memory, and visuospatial construction, as well as the Wechsler Memory Scale {31] with
delayed verbal and visual memory tests. In order to be
classified as having AD of mild to moderate severity, patients
had to have a Mini-Mental State Examination score greater
than 10, while patients with severe AD were those who
scored less than 10.
Patients’ characteristics are described in Table 1. Control
subjects were healthy male volunteers between the ages of
45 and 83 years (mean age, 60.8 years) who underwent
rigorous medical, neurological, and laboratory screening 110,
Cutler et al: Brain Metabolism and Alzheimer’s Disease
299
111. Individuals who exhibited any evidence of cardiovascular,cerebrovascular, or neurosensory disorders, or who had a
history of drug or alcohol abuse or a major psychiatric disorder, were excluded from the study. All control subjects had
at least two years of college education.
All subjects who participated in our study, as well as their
nearest relatives, gave verbal and written consent, as approved in the National Institutes of Health (NIH) protocol
No. 81-AG-10, “Regional Cerebral Glucose Utilization in
Organic Dementia of the Alzheimer’s Type,” and N I H protocol No. 80-AG-26, “Regional Cerebral Metabolism in
Man During Normal Aging.”
PET Scanning
PET was performed with an ECAT I1 scanner (ORTEC, Life
Sciences, Oak Ridge, TN) in the medium resolution mode,
as described previously [lo, 11). Patients and control subjects were scanned under the same conditions. At least 30
minutes before the intravenous injection of 5 mCi of ‘*FDG,
subjects were placed in a darkened and quiet room and their
eyes were covered with a blindfold and their ears plugged
with cotton to reduce sensory input. Forty-five minutes after
injection, the blindfold and earplugs were removed and up
to seven serial scans were obtained, each parallel to a line
drawn between the inferior orbital rim and external auditory
meatus, i.e., the inferior orbitomeatal (IOM) line. Blood
samples from a vein of a heated hand (both hands were
heated) were taken at timed intervals to measure the concentrations of 18FDG and glucose in the plasma. Brain radioactivities (in microcuries per gram) were calculated with a calibration factor derived by prior scanning of a water-filled flask
that contained a known uniform concentration of 18FDG.
Regions of interest (ROIs) within a given PET slice at
specific heights above the IOM line were identified from an
atlas of slices of one brain at defined heights above the IOM
line for that brain { 10, 111 and were outlined by a computer
image-processing procedure. Sample PET scans and ROIs
have been previously defined in detail 1261. Mean regional
cerebral metabolic rates for glucose (rCMRglc’s) and mean
areas of each ROI in a given slice were determined as described by Duara and associates 110, l l ) . Twenty-nine pairs
of bilaterally symmetrical and three midline ROIs were
identified, along with right and left hemisphere ROIs in each
slice. The area of the ROIs was kept constant in order to
keep the recovery coefficients relatively constant over all
ROIs.
The regional and overall cerebral metabolic rates for glucose (CMRglc) were calculated in units of mg . 100 gm-’ .
min- by means of an operational equation [lo, 11, 20J The
lumped constant was taken as 0.418 and the four transfer
constants for gray matter as: kl* = 0.102 min-’, k2* =
0.130 min-’, k3* = 0.062 min-’, and k4 = 0.0068 min-’;
and those for white matter as: klx = 0.054 min-’, k2* =
0.109 min-’, k3* = 0.045 min-’, and k4* = 0.0058 min-’.
Normalized regional metabolic rates (Q values) were obtained as follows:
’
’
=
rCMRglc
CMRglc
where rCMRglc is either a regional or lobar rate and CMRglc
is the rate for the whole brain between 30 and 80 mm above
the IOM line, as previously reported [lo, 11).
Statistical Analysis
A group analysis (control versus patient groups) was performed by analysis of variance (ANOVA) and Bonferroni t
statistics for multiple comparisons. All single PET scan
values were analyzed by a 2-score analysis from the control
means. Significance is indicated by a 2 score of at least 1.95
or greater. All other analyses were performed by a two-tailed
t test. Significance was defined at or below 0.05 [29].
A number of variables were observed prior to PET scanning and remained within the normal range (Table 3). Global
anxiety ratings, previously described 11I), were assessed by
two independent raters. The control group showed a mean
anxiety score of 0.96 t 0.73 (SD), whereas patients scored
1.57
1.39, a nonsignificant difference (p > 0.05).
*
Results
Patient Reports
The following patient summaries include brief synopses of the notable results from patient evaluation.
Each case is presented with the NIH number, date of
Table 3. Patient Data Obtained Prior to Positron Emission Tomography
Patient
No.
1
2
3
4
5
6
7
Mean
Mean Arterial
Blood Pressure
(mm Hg)
Heart Rate
(beatdmin)
Height
(m)
Weight
(kg)
Hgb
(gm/dl)/
Hct (%)
96.6
66
110
88
78
92.6
95
56
62
68
56
72
56
96
1.73
1.56
1.82
1.56
1.45
1.54
...
91.0
48.1
86.8
51.9
46.9
54.7
52.0
15.3144.7
15.0/43.4
15.8145.7
13.8/40.0
14.3/41.4
14.9/41.9
12.9136.9
66.6
1.61
61.6
14.6/42.0
89.5
“Anxiety score: 0
=
minimal to 3
Hgb = hemoglobin; Hct
=
=
Pa02
(mm
Hg)
7.39
7.38
43
35
77
108
...
...
...
...
. . .
. . .
. . .
. . .
. . .
7.39
.
.
.
.
.
. .
. .
. .
. .
. .
39
...
92.5
Glucose
(gddl)
*
79 0.11
73 4 0.11
100 t 1.1
80 0.09
90 t 0.17
...
84 t 0.16
84
Anxiety
Ratinga
0
1
1
3
3
0
3
1.6
intense.
hematocrit; PaCO,
300 Annals of Neurology
PH
PaCo2
(mm
Hg)
=
partial pressure of arterial carbon dioxide; PaOz = partial pressure of arterial oxygen
Vol 18 No 3 September 1985
Table 4. WechslerAdult Intelligence Scale Scores for Alzheimer‘s Disease Patients and Age-Matched Healthy Controls”
Intelligence Quotient
Patient No.
Age (yr)
Severity
Premorbidb
Full Scale
Verbal
Performance
1
2
3
4
5
Mean
65
81
49
67
Mild
Mild-moderate
Mild-moderate
Moderate
Moderate
...
Severe
Severe
119
110
12 1
114
111
77
97
65
75
85 5 9
57
. . .d
114
84
100
78
105
70
93
53
57
?
SD‘
63.8
6
67
7
Meane
Controls
(n = 9)
(mean 2 SD)
73
70
63.3
...
...
97
112 2 11
119
121
120
120 c 7
89
93
59
5
10
63
. . .d
...
...
134 c 6
135
76
55
%
9
. . .d
...
5
5
128 ? 10
‘The grouped patients’ scares of the full, verbal, and performance scales were significantly lower than those for age-matched controls ( I test, p
0.05.)
bPredicted from demographic factors [33].
‘For Patients 1 to 5 with mild to moderate Alzheimer’s disease.
dNot testable.
‘For Patients 6 and 7 with late, severe Alzheimer’s disease.
<
Table 5 . WechslerMemory Scale Scores for Alzheimds Disease Patients and Age-Matched Healthy Controls’
Story Recall Score
Visual Reproduction Score
Patient No.
Age (yr)
Severity
Immediate
Delayed
Immediate
Delayed
1
2
3
4
5
Mean -+ SDb
65
Mild
Mild-moderate
Mild-moderate
Moderate
Moderate
...
Severe
Severe
...
...
11
8
1
11
5
7.2 c 3
2
1
0
0
1
0
0.4 c 0.6
0
. . .C
12
0
2
0
2
0
0
0
0
0.4 c 0.6
0
. . .C
...
8.8 ? 2.9
6
7
Meand
Controls
(n = 9)
(mean 2 SD)
81
49
67
57
63.8
67
’
73
70
63.3
. . .c
...
...
21.4 2 4.2
16.8
?
3.3
1
3.0 2 2
0
, . .C
...
11.7 -+ 2.3
“The grouped patients’ scores on the immediate and delayed story recall and visual reproduction scales were significantly lower than age-matched
controls ( t test, p < 0.05).
bFor Patients 1 to 5 with mild to moderate Alzheimer’s disease.
‘Not testable.
dFor Patients 6 and 7 with late, severe Alzheimer’s disease
birth (DOB), and date of admission (DOA). The full
neuropsychological battery of tests was administered
to all subjects except Patient 7, who was unable to
follow instructions on most tests (Tables 4, 5). Patients’
premorbid IQs were estimated using the formula of
Wilson and colleagues 1331.
Patient 1 (No 15-68-93-0; DOB: 1121118;
DOA: 712Sl83)
This 65-year-old, right-handed man had been employed as
an aviator in the Navy and had taught high school mathema-
tics for approximately 10 years. H e had had 16 years of
education. He had retired about 4 years earlier because of an
inability to maintain discipline in his classes. At that time, he
had also begun to have minor memory lapses, such as inability to recall where he put his glasses, what he had eaten, or
whether he had eaten.
Six months before admission to NIH, which was
prompted by problems with driving, he sought treatment at a
Veterans Administration hospital, where he received a tentative diagnosis of AD. Family history revealed the patient‘s
mother is demented and living in a nursing home.
Clinical laboratory values and results of physical examina-
Cutler et al: Brain Metabolism and ALzheimer’s Disease
301
tion were within normal limits. Neurological examination
revealed a snout reflex with no palmomental or grasp reflexes.
O n neuropsychometric evaluation, the patient’s premorbid
IQ {33] was estimated to have been in the high average to
superior range. Test results demonstrated no deficits in immediate verbal and visuospatial memory. Clear deficits of
moderate severity were found on tests of visual and verbal
recent memory. Overall, his cognitive dysfunction was
minimal and his memory impairment was moderate.
Patient 2 (No 15-73-51 -2; DOB: 1 Ill 7/01;
DOA: 12110182)
The patient, an 81-year-old, right-handed woman living in a
residential care facility, had a 3-year history of progressive
memory dysfunction. H e r son had first noted uncharacteristic forgetfulness. There is no family history of dementia.
Physical examination revealed bilateral lenticular opacities.
Neurological examination revealed an active snout and rooting reflex. There also was decreased vibratory sensation in
both feet.
The patient’s premorbid I Q is estimated to have been in
the average to high average range [33}. Marked deficits were
found in immediate visuospatial memory, and recent verbal
and visual memory. Immediate verbal memory was normal.
Overall, the patient appeared to be moderately demented
with diffuse cortical dysfunction.
Patient 3 (No 15-61-67-4; DOB: 11/29/32;
DOA: 1011 8/82)
The patient, a right-handed, 49-year-old man, first noticed
problems with his memory 2 years prior to admission. Currently he can recall events that happened years ago and in
childhood, but may not recall incidents that happened a few
minutes earlier; he is unable to retain a phone number. Although never a talkative man, the patient has become even
more quiet and says he has difficiilty finding the correct
words to express himself. His personality has remained relatively stable, although he has recently begun to accuse his
wife of mishandling his money and of having a boyfriend.
There is no family history of dernenting illness. Physical
examination and laboratory findings were within normal limits. Neurological examination revealed a mild tremor of all
four extremities, more pronounced on intention.
The patient’s premorbid I Q is estimated to have been in
the superior range 1331. Moderate deficits were found on
tests of immediate verbal and visuospatial memory. Marked
deficits were found on tests of comprehension of syntactically constrained verbal relationships. Verbal recent memory
appeared to be more severely affected than visual memory.
Overall, the patient has a moderate to marked memory impairment with cognitive deficits suggesting cortical dysfunction, specifically as demonstrated by left inferior parietal dysfunction, language dysfunction, and acalculia.
Patient 4 (No 13-75-46-6; DOB: 6/20/15;
DOA: 1 1I1182)
The patient is a right-handed, 67-year-old woman whose
memory difficulties developed 3 years prior to examination.
At that time she also began feeling disoriented in both famil-
302 Annals of Neurology
Vol 18 No 3
iar and new surroundings and became reluctant to make decisions. She consulted a psychiatrist and neurologist and was
given a diagnosis of AD. In the last 2 years her condition has
rapidly deteriorated and she is now unable to care for herself.
A pertinent finding is a family history of cardiovascular
disease; her 86-year-old mother is alive and demented, and a
sister died at age 70 of an unknown dementing illness. Results of physical and neurological examinations and clinical
chemistry tests were within normal limits. The neurological
examination revealed impairment of rapid alternating movements of both hands.
The patient’s premorbid IQ is estimated to have been in
the average to high average range [33]. Test results demonstrated normal immediate verbal memory. Tests of immediate visuospatial memory showed marked deficits. Tests
of recent verbal and visual memory revealed moderate to
marked deficits, but recent visual memory was more impaired than was recent verbal memory. The patient was unable to perform simple calculations. Apraxia when dressing
was observed on the ward. Visual neglect of the left hemispace was observed on tests of visuospatial construction and
immediate visuospatial memory. Neglect of the left half of
her body was observed on a test of whole-body movements.
Her performance on a test of ideational praxis was grossly
deficient; ideomotor praxis was adequate except for wholebody movements. Marked deficits in a number of cognitive
abilities suggest substantial cortical dysfunction. Visuospatial
deficits and neglect for the left hemispace and left side of the
body suggest that cortical dysfunction is more severe on the
right side than on the left. Preserved verbal repetition and
sentence comprehension support this hypothesis.
Patient 5 (No 15-99-64-1; DOB: 6:20/15;
DOA: 1I3 1/83)
The patient is a 57-year-old, right-handed woman with a 3year history of progressive memory difficulty. The patient
was first brought to medical attention 2% years ago, after a
daughter noticed increasing confusion, disorientation, and
paranoid fixed delusions. The patient was diagnosed as having A D based on a C T scan that revealed mild atrophy, an
EEG that revealed bilateral nonspecific slow-wave activity,
and findings from an extensive psychometric evaluation suggested an early dementing illness. The patient continued to
live on her own until approximately 4 months before N I H
admission, when it became increasingly apparent to the
daughter that the patient’s difficulties were increasing. Because of her anxious, agitated, and paranoid state, the patient
was placed on a regimen of haloperidol (Haldol) which appeared to reduce her irritability and hostile behavior.
All results of clinical chemistry testing were within normal
limits. A heart murmur of grade IN1 (systolic ejection type)
and snout and bilateral palmomental reflexes are present.
The patient’s deceased mother had psychiatric difficulties,
but there was no documented evidence of a dementing process.
The patient’s premorbid intelligence is estimated to have
been in the average range [33]. H e r neuropsychological tests
revealed a marked deficit of recent memory and a moderate
deficit of remote memory. H e r performance on tests of cortically mediated cognitive functions (e.g., visuospatial construction, language, abstract reasoning, immediate memory)
September 1985
suggested diffuse cortical dysfunction. Marked deficits were
found on all tests of recent memory.
Patient 6 (No 16-25-32-9; DOB: 12/22/16;
DOA: 7/25/83)
The patient, a 67-year-old man, had experienced a gradual
progressive memory problem for 6 years. When first seen he
was unable to manage his own affairs, to dress himself without assistance, or to find his way about familiar places. He is
still able to jog and dance and to comprehend and speak
fluently French, Spanish, German, and English. The patient
was treated with ergoloid mesylates (Hydergine), which his
doctor believes improved his general behavior.
His physical examination revealed a blood pressure of
130180 mm Hg and a heart rate of 64 beats per minute. His
neurological examination revealed anomic aphasias, dressing
apraxia, and right-left disorientation.
The patient’s premorbid IQ is estimated to have been in
the high average to superior range 1331. The patient’s speech
was fluent but circumlocutory, with occasional paraphasias.
His performance o n standardized neuropsychological tests
revealed profound deficits in all areas examined. He has lost
his ability to write and read. He could repeat only three
digits forward and four-word sentences. He demonstrated
buccofacial and limb apraxia and severe ideational apraxia.
He is unable to copy any geometric figures, including a single
line and a circle, and demonstrates some visuomotor ataxia
(increasing in visually guided reaching). Overall the patient is
severely demented.
Patient 7 (No 1448-77-3; DOB: 11/7/08;
DOA: 10112/82; died 9130l84)
The patient was a 73-year-old, right-handed woman with a 6year history of increasing memory dysfunction. Her earliest
symptoms included forgetfulness and episodes of becoming
lost. Two years ago, following a CT scan, EEG, and clinical
evaluation, she was diagnosed as having AD. Approximately
1 year ago she was found by police wandering aimlessly in
the streets. Personality alterations were minimal, but she was
able to understand only simple commands.
Her family history is positive for cardiovascular disease
and cancer but negative for dementing illness. Physical examination revealed a grade I/VI systolic ejection murmur, but
otherwise findings were normal. The results of neurological
examination revealed snout and palomental reflexes. The
laboratory chemistry tests were within normal limits.
Neuropsychologicalevaluation of this patient was difficult.
She was unable to respond to test questions in a coherent
connected discourse or even in simple sentences. She could
sign her name and repeat three digits. Her immediate visuospatial memory was grossly deficient. She could draw a circle
but not a square, and was unable to copy a square. Overall
this patient was severely demented.
Neuropathological findings following the patient’s death
confirmed AD.
Neuropsychological Findings
Tables 4 and 5 depict the scores of patients and controls on the WAIS I Q and Wechsler Memory Scale
[31, 321. Patients were divided into two groups: mild
to moderate dementia (Patients 1 to 5 ) , and severe
dementia (Patients 6 and 7), as in Table 1. The WAIS
1321 (Table 4 ) revealed a full scale IQ of 134 k 6
(mean ? SD) for controls and 80 t 20 for the 6
testable patients with AD. The verbal and performance WAIS lQs were significantly lower in the patient group than in the control group.
Table 5 shows the Wechsler Memory Scale scores
1311 for immediate and delayed story recall and visual
reproduction. Patients with both mild to moderate and
severe A D showed marked memory impairment. The
patients with mild to moderate A D had significantly
lower scores on all measures when compared with
aged-matched controls (by t test). However, the greatest deficits were seen in delayed verbal and visual
memory.
PET Findings
The rCMRglc’s in individual lobes of the A D patients
were compared with control means from 2 5 healthy
male volunteers (Table 6; Figs 1, 2 ) . Three of the 61
bilateral pairs of regions scanned (midfrontal gyri,
superior parietal gyri, and inferior temporal gyri)
showed significant metabolic reductions in the mild to
moderate A D group as compared with controls. O n
the whole, the differences revealed no consistent pattern. The coefficients of variation of the means of the
KMRglc’s were 20 to 25%. None of the 61 regions
examined revealed a greater mean metabolic rate than
that found in controls.
The two patients with severe A D showed consistently significant metabolic reductions throughout all
61 regions evaluated, as compared with controls. In
fact, the mean KMRglc for this group was approximately one-third the metabolic rate found in the patient group with mild to moderate AD.
Table 7 and Figure 3 present the analysis of regional
rates normalized to the mean cerebral metabolic rate
or Q values (see Eq 1) at different brain regions
(CMRglc is the mean CMRglc for both hemispheres)
for both the mild to moderate and severe A D patient
groups as compared with the 25 healthy controls.
These Q values generally revealed findings similar to
those obtained with the absolute rCMRglc values (Fig
3). The coefficients of variation were approximately
lo%, b o u t one-half those found with the absolute
KMRglc values. The regions that showed significant
bilateral reductions in mild to moderate AD, as compared with controls, were the midfrontal gyri, superior
and inferior parietal gyri, parietal lobes, and superior
and inferior temporal gyri. In the right and left lenticular nuclei, however, significant elevations were found.
The group with severe A D exhibited significant bilateral reductions in Q scores throughout a majority of
regions. The reductions were found in the frontal,
parietal, temporal, and occipid lobes (Fig 3), but on
Cutler et al: Brain Metabolism and Alzheimer’s Disease 303
Table 6. Cerebral Metabolic Rates for Glucose in Alzbeimerk Disease Patients and Age-Matched Controlsa
Regional Cerebral Metabolic Rate for Glucose (mg . 100 gm-'
Bran Regon
Hemisphere
Frontal lobe
Superior frontal gyrus
Midfrontal ~ Y N S
Inferior frontal gym
Cingulate gyms
Orbitofrontal gyrus
Precentral ~ Y N S
Paracentral lobule
Parietal lobe
Postcentral gyrus
Superior parietal
gyms
Inferior parietal
mm Above
IOMkne
Controlsb
AD (severeid
A D (mild-mod)'
Right
Left
Lght
Left
Lght
70-100
55-70
70-100
4.53 f
5.32 2
5.65 2
5.53 f
5.34 f
5.95 f
5.40 2
5.61 2
5.56 2
5.55 ?
4.73 f
5.92 f
5.50 2
5.92 f
5.42 f
5.65 f
5.28 2
5.61 2
1.15
1.32
1.46
1.59
1.50
1.67
1.51
1.77
1.43
1.40
1.14
1.56
1.56
1.35
1.34
1.36
1.61
1.43
4.60 2 1.17
5.36 f 1.31
5.59 2 1.42
5.41 2 1.46
5.33 2 1.49
6.01 f 1.51
5.54 f 1.58
5.69 f 1.79
5.58 f 1.54
5.55 f 1.40
4.82 f 1.21
6.05 2 1.52
5.80 2 1.63
5.92 f 1.35
5 51 f 1.42
5.76 f 1.42
5.53 f 1.63
5.65 f 1.55
4.20 2 0.48
4.57 f 0.80
4.44 t 0.79
4.45 f 0.80
4.86 2 0.75
4.17 2 0.97'
4.34 f 1.26
4.46 f 1.20
4.63 f 1.22
5.33 2 0.62
4.29 f 0.84
5.35 f 0.69
5.48 f 0.58
5.26 f 0.75
4.43 f 0.98
5.12 2 0.89
5.81 f 0.47
3.97 f 1.04'
4.35 t 0.61
4.83 t 0.65
4.70 t 1.02
4.77 2 0.88
4.96 -t 0.79
4.65 2 1.03'
4.67 t 1.27
4.94 t 1.28
4.94 t 0.95
5.33 2 0.62
4.56 t 0.36
5.27 t 0.88
5.70 t 0.43
5.26 t 0.75
4.62 t 1.25
5.35 t 1.20
5.88 t 0.64
4.31 t 1.42'
2.90 f 0.37'
3.20 t 0.70'
2.82 2 1.02'
3.40 2 1.38
3.69 f 0.91'
2.66 f 0.66'
3.32 f 1.01
3.03 f 0.52
3.41 f 0.82
3.71 f 0.97'
3.00 f 0.81'
3.23 f 0.49e
3.61
3.57 f 0.18'
2.36 f 0.08'
3.30 f 0.31'
3.12
1.99 f 0.32'
2.74 f 0.15'
3.07 2 0.61'
2.78 t 1.02'
3.31 f 0.89
3.38 f 0.77
2.52 f 0.67'
2.93 f 0.62'
2.97 t 0.78'
3.17 2 0.65
3.71 f 0.97'
2.98 f 0.70'
3.10 f 0.54'
3.56
3.57 f 0.18'
2.31 f 0.30'
3.25 f 0.53'
3.00
1.86 f 0.45'
45-70
5.09 2 1.34
5.29 f 1.44
4.26
1.25
4.45 t 1.39
2.21
65-80
6.44
5.36
5.98
5.43
4.60
5.52
5.36 2 1.62
5.15 f 0.82
5.59 2 1.44
4.99 2 0.79
4.55 f 0.46
5.48 f 1.51
5.34 2 1.74
5.26 t 0.92
5.71 t 1.57
4.96 t 0.85
4.59 t 0.77
5.48 i 1.15
3.18 f 0.33'
3.67 f 0.05"
4.06 t 0.00
3.81 f 0.15
3.27 f 0.14
3.87 f 0.07'
30-80
...
80-100
60-80
35-60
65-90
45-65
50-70
35-50
35-70
20-35
70-100
55-70
80- 100
...
Left
. min-')
f
f
0.27
2.26
f
0.13
gYns
Precuneus
Occipital lobe
Cuneus
Calcarine
Lingual
Retrosplenial
gray matter
Temporal lobe
Superior temporal
Inferior middle
temporal gyrus
Inferior temporal
...
45-65
30-45
15-30
45-70
...
f
f
f
f
f
1.56
1.33
1.36
1.36
1.44
1.50
30-45
4.33 t 1.05
4.94 2 1.13
15-30
4.25
6.36 f
5.39 2
5.94 f
5.45 2
4.84 f
5.52 f
1.51
1.33
1.39
1.33
1.57
1.50
3.16 f 0.1G'
3.54 f 0.05'
3.86 f 0.13'
3.75 f 0.06
3.07 f 0.15
3.87 f 0.07'
4.41 t 1.09
5.04 f 1.28
3.69
3.72
0.73
0.96
3.98 t 0.64
4.02 f 0.95
2.10
2.54
1.10
4.30
f
1.19
3.61 2 0.06
3.79 t 0.83
2.43 2 0.49'
2.05
3.63 f 0.93
3.48
f
0.71
2.23 f 1.OG'
3.05 f 0.63'
2.39'
1.11'
20-35
20-35
4.37
3.66
f 0.84
4.35 f 1.26
3.74 f 0.83
4.60
3.62
f 0.32
4.93 f 0.62
3.77 f 0.62
3.74 2 0.37'
2.36 2 0.92
3.53 f 0.41'
2.09 2 0.46
35-55
40-50
35-55
40-60
0-15
70-90
5.30 f 1.53
5.29 f 1.62
5.75 t 1.65
5.80 f 1.42
4.37 2 1.05
2.69 f 0.67
5.29 f 1.62
5.38 f 1.62
5.77 f 1.66
5.98 f 1.55
4.52 f 1.11
2.54 2 0.57
5.34 t 0.72
5.28 f 0.46
5.81 0.61
5.09 2 0.85
4.43 t 0.59
2.44 f 0.49
5.25 2 1.10
5.38 f 0.58
6.08 f 0.89
5.54 t 0.94
4.35 2 0.38
3.00 f 0.84
3.81 f 0.33
3.95 f 0.82
4.18 f 0.52
3.74 f 0.79'
3.18 f 0.40
1.13
4.00 f 0.50
3.66 f 0.48
4.24 t 0.35
3.68 f 0.47'
3.28 f 0.17
1.14
5-15
f
f
2
f
f
0.35'
0.42'
2.63 t 0.22'
2.04 2 0.27'
f
0.16'
gyms
Hippocampal region
Anterior medial
temporal gyrus
Caudate nucleus
Thalamus
Lenticular nucleus
h u l a cortex
Cerebullum
Centnun semiovale
f
1.25
+
*
0.44
"Values given as means rt SD. SD not given in certain cases because of missing values.
bMean age, 61 yr (n = 25).
'Mean age, 64 yr (n = 5).
dMean age, 70 yr (n = 2).
'Significantly different from control values (p < 0.05) by ANOVA (single values by 2 scores).
AD = Alzheimer's disease; IOM
=
304
Vol 18 No 3 September 1985
Annals of Neurology
inferior orbitomeatal; mod
=
moderate.
0Controls IP a g e = 6 l y r i
AD
(X age=64yr mild moderate form)
0
AD IX age=70yr severe form1
(Rt)
FRONTAL
PARIETAL
TEMPORAL
Fig 1 . Absolute mean lobar metabolic rates (i.e., regional cerebral
metabolic rates for glucose ErCMRglc]) are shown for patients
with both the mild to moderate and severe forms of Alzheimev’s
disease (AD) compared with controls. There is a lack of
significant reduction in m a n (* SE) absolute lobar metabolic
rates in the group with mild to moderate A D and consistent
significant reductions in lobar metabolism in the group with seuere A D , compared with control subjects. (* = signifcantly d$ferent from controls; t age = mean age.)
the whole, significant bilateral decreases in Q values
were found only in the parietal lobar regions.
Discussion
We found the following: (1) marked cognitive deficits,
as represented by low WAIS and Wechsler Memory
Scale scores, are found in the mild to moderate forms
of AD; (2) mean rCMRglc values, as derived by PET,
are minimally altered at a p < 0.05 level in mild to
moderate A D as compared with controls, but regional
to whole-brain metabolic ratios (Q scores) are bilaterally reduced in the middle arcuate frontal gyri,
superior and inferior parietal gyri, parietal lobes, and
superior and inferior temporal gyri; and (3) cerebral
metabolic rates are consistently reduced and Q scores
are signlficantly reduced in the late, severe form of
AD. Our conclusions regarding cerebral metabolism in
AD in relation to severity agree with cerebral blood
flow measurements in neuropathologically proved
cases.
Clinically (see Table 2), the patients with mild to
moderate A D were characterized primarily by an impairment surrounding recent events. This was noted in
Patients 1 to 3 by their inability to synthesize or incorporate new information or to carry out routine com-
OCCIPITAL
plex tasks. In the moderate AD category, Patients 3
and 4 exhibited difficulty with language (Broca’s
aphasia). Difficulty in word finding and impaired comprehension (Wernicke’s aphasia) have been characterized in the moderate form of AD. Of the patients with
mild to moderate AD, apraxia was noted only in Patient 4 (231. Our patients with late, severe AD (Nos 6
and 7) had a number of difficulties functioning in daily
living activities and exhibited disorientation to time
and place, in addition to having substantial memory
loss. Both were unable to comprehend language
(Broca’s aphasia), and both had extreme difficulty
finding words (Wernicke’s aphasia). Their symptoms of
becoming lost in a familiar environment, increased
motor movement (agitation), and pacing and nocturnal
confusion are previously reported symptoms of severe
AD 1.231.
The few significant bilateral reductions in rCMRglc
occurred in the midfrontal, superior parietal, and inferior temporal gyri, all regions that have been
identified as having reduced cerebral metabolism in
moderate AD 114-161. These changes probably are
biologically meaningful because they occur as rightleft pairs and correspond in part to the significant
changes in Q scores.
One reason for the few significant differences in absolute PET values may be the fact that our patients
were rigidly selected and did not have as severe debilitations as patients in other reports [12, 14-17), as
well as the fact that we used a small number of patients. Our group with mild to moderate AD had a
Blessed Dementia Scale score of 5.8, as compared with
a score of 10.0 for our group of patients with severe
AD. In other investigations [ S , 14-17], the Mattis
Dementia Scale severity score was 90, whereas our
Cutler et al: Brain Metabolism and Alzheimer’s Disease
305
group had a Mattis Dementia Scale score of 113.5,
indicating that our AD patients were less demented.
In contrast to our findings, Frackowiak and colleagues [l6}, in a study of AD using PET, found
rCMRglc reductions in the temporal and parietal lobes
in the mild A D group. Our findings may show similar
absolute values of rCMRglc as our number of subjects
with A D increases. Our finding of reduced Q values in
the parietal lobes supports this supposition.
The study of early dementia cases permits examination of the pathophysiological progression of this disease, whereas using PET to assess moderate to severe
forms of A D in which areas of brain have very low
metabolic rates may prove of little use.
Another reason for the discrepancy between our
metabolic values and those of other groups 17,157 may
have to do with differences found among the control
Fig 2. Positron emission tomographic scans at 45 m m above the
inferior orbitomeatal line for (A)a normal 63-year-old subject,
(B) a 64-year-old patient with mild Alzheimer's disease (AD),
and (C) a 66-year-oldpatient with severe A D . (rCMRglc =
regional cerebral metabolic rate for glucose.)
metabolic values. The small number of control subjects used by these other investigators 17,151, only 5
and 8 subjects, respectively, may contribute to the incompatibility with our findings, which were based on
data from 25 normal subjects. Results of our normal
metabolic rates as previously reported [lo, 111 agree
with findings of studies by Frackowiak et al [161 and
Kuhl et al{2 13 with PET scanning using "FDG. Chase
et al [71 and Foster et a1 Cl51, however, give findings
for normal controls that represent some of the highest
metabolic rates yet reported in the literature.
306 Annals of Neurology Vol 18 No 3 September 1985
Table 7. Q Values in Alzheimer's Disease Patients and Age-Matched Controls'
Regional Cerebral Metabolic Rate for Glucose (mg . 100 gm-'
Brain Region
Frontal lobe
Superior frontal gyms
Midfrontal g y ~ s
Inferior frontal gyrus
Cingulate gyrus
Orbitofrontal gyrus
Precentral gyrus
Paracentral lobule
Parietal lobe
Postcentral g y ~ s
Superior parietal
gyms
Inferior parietal
gyms
Precuneus
Occipital lobe
Cuneus
Calcarine
Lingual
Retrosplenial
gray matter
Temporal lobe
Superior temporal
gyms
Inferior middle
temporal gyms
Inferior temporal
mm Above
IOMLine
Controlsb
. min-')
AD (severe)d
AD (mild-mod)'
Left
Rght
Left
Right
Left
Right
70-100
55-70
70-100
1.17 f 0.11
1.20 f 0.15
1.21 f 0.13
1.16 2 0.12
1.26 f 0.15
1.17 f 0.10
1.24 f 0.12
1.22 f 0.12
1.22 f 0.09
1.05 f 0.19
1.25 f 0.14
1.20 f 0.14
1.27 f 0.11
1.20 f 0.11
1.20 f 0.12
1.15 f 0.13
1.19 f 0.14
1.18 f 0.10
1.19 f 0.15
1.18f 0.11
1.16 f 0.12
1.27 2 0.12
1.20 f 0.10
1.25 f 0.12
1.22 f 0.12
1.22 f 0.09
1.07 t 0.17
1.29 f 0.14
1.27 f 0.13
1.27 f 0.11
1.21 f 0.12
1.23 f 0.12
1.20 f 0.16
1.20 f 0.15
1.08 f 0.20
1.05 2 0.27
1.05 f 0.22
1.14 f 0.13
0.98 f 0.25'
1.01 f 0.25'
1.06 f 0.26
1.08 f 0.27
1.25 f 0.10
1.02 f 0.25
1.26 f 0.13
1.24 f 0.09
1.23 f 0.21
1.03 f 0.16'
1.20 f 0.15
1.31 f 0.01
0.93 f 0.21'
1.13 f 0.12
1.10 f 0.27
1.12 f 0.21
1.16 t 0.08
1.09 f 0.21'
1.08 f 0.19'
1.16 t 0.17
1.15 f 0.13
1.25 f 0.10
1.08 f 0.13
1.24 f 0.16
1.29 f 0.15
1.23 f 0.21
1.07 f 0.23'
1.25 f 0.22
1.33 f 0.01
1.00 f 0.28'
1.13 f 0.14
0.99 f 0.27
1.19 f 0.38
1.30 f 0.20
0.93 t 0.15'
1.17 f 0.25'
1.07 f 0.08'
1.20 f 0.18
1.30 t 0.22
1.05 t 0.19
1.16 f 0.28
1.37
1.27 f 0.05
0.84 f O . l l e
1.18 f 0.22
1.18
0.71 f 0.18'
1.08 f 0.12
0.97 f 0.27
1.16 f 0.21
1.19 f 0.16
0.89 t 0.16'
1.03 f 0.12
1.04 f 0.18'
1.12 f 0.13
1.30 f 0.22
1.05 f 0.15
1.11 -+ 0.30
1.35
1.27 f 0.05
0.83 f 0.18'
1.17 f 0.30
1.14
0.67 f 0.22'
45-70
1.12 f 0.11
1.16 f 0.13
0.98 +. 0.19'
1.02 f 0.25'
0.78
0.80 t 0.03'
65-80
1.40 f 0.18
1.19 f 0.17
1.33 f 0.18
1.21 t 0.18
1.04 f 0.25
1.22 f 0.16
1.38 f 0.16
1.20 f 0.17
1.32 f 0.19
1.21 f 0.17
1.09 f 0.27
1.22 f 0.16
1.24 +- 0.31
1.20 & 0.10
1.29 f 0.25
~1.16-C 0.06
1 . 0 8 2 0.14
1.27 & 0.28
1.24 f 0.35
1.23 t 0.13
1.32 f 0.29
1.16 f 0.07
1.08 f 0.13
1.27 f 0.28
1.13 f O.Ole
1.30 f 0.14
1.44 t 0.13
1.35 f 0.07
1.16 f 0.16
1.38 t 0.15
1.13 f 0.1G'
1.26 f 0.13
1.38 f 0.18
1.33 t 0.14
1.09 f 0.05
1.38 f 0.15
30-45
0.96 t 0.13
1.10 f 0.15
0.98 t 0.14
1.12 f 0.18
0.87
0.87
0.18
0.18'
0.93 f 0.07
0.93 f 0.12'
0.75 f 0.19'
0.90 & 0.06'
0.93 f 0.01
0.73 f 0.1G'
15-30
0.94
0.16
0.95 f 0.18
0.86
* 0.14
0.89 f 0.08
0.86
0.73
0.82 f 0.14
0.80 f 0.13
0.50 f 0.23'
0.68 f O.lle
0.79
0.37
20-35
20-35
0.97
0.82
0.97
0.84
0.21
0.14
1.09 2 0.16
0.87 2 0.18
1.16 t 0.13
0.89 f 0.11
1.34 f 0.26'
0.82 f 0.25
1.26 f 0.26
0.74 f 0.09
35-55
40-50
35-55
40-60
0-15
70-90
1.13 f 0.11
1.15 f 0.15
1.26 f 0.14
1.28 f 0.14
0.98 t 0.19
0.58 f 0.14
1.15 f 0.13
1.17 f 0.15
1.26 f 0.13
1.31 f 0.13
1.01 f 0.21
0.56 0.17
1.25 f 0.07
1.24 f 0.10
1.36 f 0.09'
1.19 f 0.16
0.99 f 0.17
0.58 0.13
1.22 f 0.16
1.26 f 0.07
1.42 f 0.12'
1.28 f 0.12
0.97 f 0.03
0.71 f 0.21
1.35 f 0.01'
1.39 f 0.16'
1.48 f 0.05'
1.32 f 0.16
1.14 f 0.25
0.38
1.42 f 0.05'
1.29 f 0.05'
1.50 f 0.01
1.30 f 0.04
1.17 t 0.17
0.38
...
80- 100
60-80
35-60
65-90
45-65
50-70
35-50
35-70
20-35
70-100
55-70
80-100
...
...
45-65
30-45
15-30
45-70
...
5-15
f
2
-C
f
f
0.02'
0.10
f
0.01'
gYNS
Hippocampal region
Anterior medial
temporal gyrus
Caudate nucleus
Thalamus
Lenticular nucleus
h u l a cortex
Cerebellum
Centnun semiovale
f 0.21
f
0.13
2
f
*
See Table 6 for footnotes and key.
Another methodological concern, the method used
for determining the ROIs, may explain why our metabolic rates are lower than previously reported observations [7, 151. ROIs determined by these other groups
were assessed for any given anatomic region by the
peak metabolic rate found within a defined rectangular
box. Our ROIs represent a weighted mean rCMRglc
for a region, based on the number of slices in which
the region was identified and the regional surface area
per slice [lo, 111. It is possible that the weighted
rCMRglc may differ from other reported peak
rCMRglc values {7, 151.
The group with mild to moderate AD demonstrated
significant cognitive deficits that were apparent when
comparing IQs of patients with IQs of controls, and
IQs of patients with their estimated premorbid IQs
1331. Despite these deficits, most absolute rCMRgic
values in this sample of patients did not differ
Cutler et al: Brain Metabolism and Alzheimer's Disease 307
-
20
(controls
(1age=llyrl
AD C i age=64yr mild moderate form1
0AD IF age=70yr
Rt)
significantly from those of age-matched controls. The
relative lack of significance may be the result of the
large coefficients of variation (approximately 20 to
25%) in the cerebral metabolic rates and small population. Q scores reduce the coefficient of variation by
approximately one-half and thus increase the sensitivity of PET to smaller differences in rCMRglc. Using Q
scores, the mild to moderate group was found to have
statistically significant deficits in regions of the frontal,
parietal, and temporal lobes. The intellectual deficit,
even in the mild to moderate form of AD, is accompanied by selected changes in cortical cerebral metabolism.
The most notable and consistent neuropsychological
deficit in all AD patients was impaired recent memory.
The cerebral region that is most likely to be related to
memory impairment is the medial temporal lobe C5,6,
351, but the rCMRglc or Q score was not altered in the
two regions that encompass the hippocampus and
amygdala. Several explanations for the lack of
significant findings are possible. The first relates to a
limitation in the procedure. The medial temporal regions lie close to large bony structures, where measurement of rCMRglc is limited by partial voluming
from bone. Furthermore, the relevant structures in
AD, the hippocampus and amygdala C3, 301, are very
small and occupy only a small fraction of medial temporal ROIs [lo, 11). It is also possible that the hippocampus and amygdala are not particularly active in
the resting state, and consequently may not reflect a
decline of functional activity.
PET scanning with 18FDG did not reveal many
significant reductions in cerebral metabolism except in
the late severe form of AD. Previous studies with cerebral blood flow and PET that have carefully distinguished the severity of disease indicate that in mild
AD there is either no change C34) or a metabolic reduction in the temporal lobe C19) or parietal lobe Cl6l.
The late, severe form of the disease has been correlated with reduced metabolism in the frontal lobes
116). In severe AD, we and others have found metabolic reductions throughout the brain [12, 15, 16).
308 Annals of Neurology
PARIETAL
FRONTAL
TEMPORAL
seve:e tormi
OCCIPITAL
Fig 3. Mean lobar Q values are shown for patients with both
ihe mild to moderate and severe forms of Alzheime~sdisease
(AD} compared with controls. Significant reductions as compared
with controls in mean (t SE) Q values (see E q in text) are
found in the parietal Lobes of both the group with mild to moderate AD and the group with severe AD. (* = sign$canth dqferent from controls, p 4 0.0s; 2 age = mean age.)
These findings of reduced metabolic rates are further
supported by significant elevations in Q scores.
Some regions in the severe form of AD, including
the occipital lobes, demonstrated modest elevations in
Q scores, suggesting that these regions are spared in
face of a reduction in whole-brain metabolism. This
possibility is supported by postmortem studies that reveal the relative integrity of the occipital lobe f5, 6).
Another consideration based on the observation of
elevated Q scores in the group with late, severe AD
may be an increased ventricular size accompanying increased volume of cerebrospinal fluid (CSF) caused by
increased atrophy, which may result in an artifactually
decreased CMRglc. Simultaneous CT scans of these
patients, quantitated for gray matter volume and total
CSF volume C28) when correlated with CMRglc for
both the right and left hemispheres in 19 controls and
the 7 AD patients, revealed no significant relationships
(p > 0.05). In addition, a previous study was not able
to show a correlation between rCMRglc and CMRglc
in 40 healthy subjects with cerebral atrophy between
the ages of 21 to 84 years C27).
The reduced Q scores observed in both whole
parietal lobes in patients with mild and moderate AD
may correlate with the reduced verbally mediated
functions. However, because all of our mildly to moderately affected patients did not exhibit deficits in verbally mediated behavior, it is possible that a threshold
of metabolic reduction or brain damage must be met
before parietal lobe neuropsychological deficits are observed. Another speculation is that a critical parietal
lobe deficit in the concentration of cholinergic or other
Vol 18 No 3 September 1985
neurotransmitter substances [S, 91, including neuropeptides [24], is required before a patient exhibits
the associated cognitive changes found in AD. Reduced metabolism in the parietal lobe is consistent
with findings in a postmortem study conducted by
Brun and England IS]. They found that neuronal loss is
greatest in the parietal region in severe AD.
Our findings of significantly reduced metabolism in
the late severe form of AD, but minimal changes in
mild to moderate forms of AD, may be explained by
the “threshold principle” enunciated by Roth and associates [25], which states that there must be a certain
quantity of plaques and tangles (more than 12 plaques
per visual field) or infarcts (more than 50 per cm3)
before dementia is clinically evident.
Further studies of larger populations are needed to
relate clinical manifestations of AD to brain metabolism, neuropsychological function and other physiological aspects, and diagnostic history.
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